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1
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Hong HY, Zheng YJ, Li YJ, Dong YQ, Zhang JY, Lv X, Zhao CY, Zhen YS, Gong JH, Cai L, Zheng YB. An albumin-binding lidamycin prodrug for efficient targeted cancer therapy. J Drug Deliv Sci Technol 2024; 91:105213. [DOI: 10.1016/j.jddst.2023.105213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/12/2024]
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2
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Pal P, Alley JR, Cohen DR, Townsend CA. Dynemicin A Derivatives as Potential Cancer Chemotherapeutics by Mutasynthesis. Helv Chim Acta 2023; 106:e202300123. [PMID: 39308597 PMCID: PMC11415272 DOI: 10.1002/hlca.202300123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 10/19/2023] [Indexed: 09/25/2024]
Abstract
The enediyne antitumor antibiotics have remarkable structures and exhibit potent DNA cleavage properties that have inspired continued interest as cancer therapeutics. Their complex structures and high reactivity, however, pose formidable challenges to their production and development in the clinic. We report here proof-of-concept studies using a mutasynthesis strategy to combine chemical synthesis of select modifications to a key iodoanthracene-γ-thiolactone intermediate in the biosynthesis of dynemicin A and all other known anthraquinone-fused enediynes (AFEs). By chemical complementation of a mutant bacterial producer that is incapable of synthesizing this essential building block, we show that derivatives of dynemicin can be prepared substituted in the A-ring of the anthraquinone motif. In the absence of competition from native production of this intermediate, the most efficient utilization of these externally-supplied structural analogues for precursor-directed biosynthesis becomes possible. To achieve this goal, we describe the required Δorf15 blocked mutant and a general synthetic route to a library of iodoanthracene structural variants. Their successful incorporation opens the door to enhancing DNA binding and tuning the bioreductive activation of the modified enediynes for DNA cleavage.
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Affiliation(s)
- Paramita Pal
- Department of Chemistry, Remsen Hall, The Johns Hopkins University, 3400 North Charles St., Baltimore, MD 21218, USA
| | - Jamie R Alley
- Department of Chemistry, Remsen Hall, The Johns Hopkins University, 3400 North Charles St., Baltimore, MD 21218, USA
| | - Douglas R Cohen
- Department of Chemistry, Remsen Hall, The Johns Hopkins University, 3400 North Charles St., Baltimore, MD 21218, USA
| | - Craig A Townsend
- Department of Chemistry, Remsen Hall, The Johns Hopkins University, 3400 North Charles St., Baltimore, MD 21218, USA
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3
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Adhikari A, Shen B, Rader C. Challenges and Opportunities to Develop Enediyne Natural Products as Payloads for Antibody-Drug Conjugates. Antib Ther 2021; 4:1-15. [PMID: 33554043 PMCID: PMC7850032 DOI: 10.1093/abt/tbab001] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Calicheamicin, the payload of the antibody-drug-conjugates (ADCs) gemtuzumab ozogamicin (Mylotarg®) and inotuzumab ozogamicin (Besponsa®), belongs to the class of enediyne natural products. Since the isolation and structural determination of the neocarzinostatin chromophore in 1985, the enediynes have attracted considerable attention for their value as DNA damaging agents in cancer chemotherapy. Due to their non-discriminatory cytotoxicity towards both cancer and healthy cells, the clinical utilization of enediyne natural products relies on conjugation to an appropriate delivery system, such as an antibody. Here we review the current landscape of enediynes as payloads of first-generation and next-generation ADCs.
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Affiliation(s)
- Ajeeth Adhikari
- Department of Chemistry, The Scripps Research Institute, Jupiter, FL, USA.,Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA
| | - Ben Shen
- Department of Chemistry, The Scripps Research Institute, Jupiter, FL, USA.,Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA.,Natural Products Discovery Center at Scripps Research, The Scripps Research Institute, Jupiter, FL, USA
| | - Christoph Rader
- Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA
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4
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Yoshida M, Mori S, Matsumoto K, Hirokane T. Synthesis of Dihydrobenzo[1,4]oxazines by Palladium-Catalyzed Cyclization of N-Substituted 2-Aminophenols with Propargylic Carbonates. HETEROCYCLES 2020. [DOI: 10.3987/com-19-s(f)40] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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5
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Abstract
Acetylenic metabolites belong to a class of molecules containing triple bond(s). They are found in plants, fungi, microorganisms, and marine invertebrates. This review presents 139 active acetylenic molecules of plant, fungal, and soil bacterial origin that reveal cytotoxic and/or anticancer activities. Although many compounds of this group possess encouraging characteristics, they have never been evaluated as potential anticancer agents. They are of great interest, especially for the medicine and/or pharmaceutical industries. Here we describe structures and biological activities of acetylenic metabolites.
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Affiliation(s)
- Valery M Dembitsky
- Department of Medicinal Chemistry and Natural Products, School of Pharmacy, P.O. Box 12065, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
| | - Dmitri O Levitsky
- CNRS UMR 6204, Biotechnologie, Biocatalyse et Biorégulation, Faculté des Sciences et des Techniques, Université de Nantes, P.O. Box 92208, 44322 Nantes Cedex 3, France
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6
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Yan X, Hindra, Ge H, Yang D, Huang T, Crnovcic I, Chang CY, Fang SM, Annaval T, Zhu X, Huang Y, Zhao LX, Jiang Y, Duan Y, Shen B. Discovery of Alternative Producers of the Enediyne Antitumor Antibiotic C-1027 with High Titers. JOURNAL OF NATURAL PRODUCTS 2018; 81:594-599. [PMID: 29345939 PMCID: PMC6261254 DOI: 10.1021/acs.jnatprod.7b01013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/05/2023]
Abstract
The potent cytotoxicity and unique mode of action make the enediyne antitumor antibiotic C-1027 an exquisite drug candidate for anticancer chemotherapy. However, clinical development of C-1027 has been hampered by its low titer from the original producer Streptomyces globisporus C-1027. Here we report three new C-1027 alternative producers, Streptomyces sp. CB00657, CB02329, and CB03608, from The Scripps Research Institute actinomycetes strain collection. Together with the previously disclosed Streptomyces sp. CB02366 strain, four C-1027 alternative producers with C-1027 titers of up to 11-fold higher than the original producer have been discovered. The five C-1027 producers, isolated from distant geographic locations, are distinct Streptomyces strains based on morphology and taxonomy. Pulsed-field gel electrophoresis and Southern analysis of the five C-1027 producers reveal that their C-1027 biosynthetic gene clusters (BGCs) are all located on giant plasmids of varying sizes. The high nucleotide sequence similarity among the five C-1027 BGCs implies that they most likely have evolved from a common ancestor.
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Affiliation(s)
- Xiaohui Yan
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States
| | - Hindra
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States
| | - Huiming Ge
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States
| | - Dong Yang
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States
- Natural Products Library Initiative at The Scripps Research Institute, The Scripps Research Institute, Jupiter, Florida 33458, United States
| | - Tingting Huang
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States
| | - Ivana Crnovcic
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States
| | - Chin-Yuan Chang
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States
| | - Shi-Ming Fang
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States
| | - Thibault Annaval
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States
| | - Xiangcheng Zhu
- Xiangya International Academy of Translational Medicine, Central South University, Changsha, Hunan 410013, People’s Republic of China
- Hunan Engineering Research Center of Combinatorial Biosynthesis and Natural Product Drug Discovery, Changsha, Hunan 410013, People’s Republic of China
| | - Yong Huang
- Xiangya International Academy of Translational Medicine, Central South University, Changsha, Hunan 410013, People’s Republic of China
| | - Li-Xing Zhao
- Yunnan Institute of Microbiology, Yunnan University, Kunming, Yunnan 650091, People’s Republic of China
| | - Yi Jiang
- Yunnan Institute of Microbiology, Yunnan University, Kunming, Yunnan 650091, People’s Republic of China
| | - Yanwen Duan
- Xiangya International Academy of Translational Medicine, Central South University, Changsha, Hunan 410013, People’s Republic of China
- Hunan Engineering Research Center of Combinatorial Biosynthesis and Natural Product Drug Discovery, Changsha, Hunan 410013, People’s Republic of China
| | - Ben Shen
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States
- Natural Products Library Initiative at The Scripps Research Institute, The Scripps Research Institute, Jupiter, Florida 33458, United States
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, Florida 33458, United States
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7
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Zhang H, Shen J, Cheng G, Feng Y, Cui X. One-Pot Synthesis of Benzo[b][1,4]oxazins via Intramolecular Trapping Iminoenol. Org Lett 2018; 20:664-667. [PMID: 29338245 DOI: 10.1021/acs.orglett.7b03804] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
A highly atom-efficient "one-pot" protocol has been developed to construct multisubstituted 2-hydroxy-benzo[b][1,4]oxazins starting from N-(2-hydroxylaryl)enaminones. This procedure comprises a PIDA-mediated intramolecular iminoenol tautomer trapping reaction, followed by Et3N-promoted aerobic oxidative ring construction. In particular, an O2 molecule from air served as the oxygen source of the hydroxyl group in the titled products. This reaction proceeded smoothly at room temperature under air atmosphere and metal-free conditions.
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Affiliation(s)
- Hong Zhang
- Engineering Research Center of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Xiamen Marine and Gene Drugs, School of Biomedical Sciences, Huaqiao University , Xiamen 361021, P. R. China
| | - Jinhai Shen
- Engineering Research Center of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Xiamen Marine and Gene Drugs, School of Biomedical Sciences, Huaqiao University , Xiamen 361021, P. R. China
| | - Guolin Cheng
- Engineering Research Center of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Xiamen Marine and Gene Drugs, School of Biomedical Sciences, Huaqiao University , Xiamen 361021, P. R. China
| | - Yadong Feng
- Engineering Research Center of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Xiamen Marine and Gene Drugs, School of Biomedical Sciences, Huaqiao University , Xiamen 361021, P. R. China
| | - Xiuling Cui
- Engineering Research Center of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Xiamen Marine and Gene Drugs, School of Biomedical Sciences, Huaqiao University , Xiamen 361021, P. R. China
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8
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Singh K, Malviya BK, Roy TK, Mithu VS, Bhardwaj VK, Verma VP, Chimni SS, Sharma S. Catalyst-Controlled Structural Divergence: Selective Intramolecular 7-endo-dig and 6-exo-dig Post-Ugi Cyclization for the Synthesis of Benzoxazepinones and Benzoxazinones. J Org Chem 2017; 83:57-68. [DOI: 10.1021/acs.joc.7b02123] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Karandeep Singh
- Department
of Chemistry, Mohanlal Sukhadia University, Udaipur 313001, India
- Department
of Chemistry, U.G.C. Centre of Advance Studies in Chemistry, Guru Nanak Dev University, Amritsar 143005, India
| | | | - Tapta Kanchan Roy
- Department
of Chemistry and Chemical Sciences, Central University of Jammu, Jammu 180011, India
| | - Venus Singh Mithu
- Department
of Chemistry, U.G.C. Centre of Advance Studies in Chemistry, Guru Nanak Dev University, Amritsar 143005, India
| | - Vimal K. Bhardwaj
- Department
of Chemistry, Indian Institute of Technology Ropar (IIT Ropar), Rupnagar 140001, India
| | - Ved Prakash Verma
- Department
of Chemistry, Banasthali University, Newai-Jodhpuriya Road, Vanasthali 304022, India
| | - Swapandeep Singh Chimni
- Department
of Chemistry, U.G.C. Centre of Advance Studies in Chemistry, Guru Nanak Dev University, Amritsar 143005, India
| | - Siddharth Sharma
- Department
of Chemistry, Mohanlal Sukhadia University, Udaipur 313001, India
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9
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Zheng YB, Gong JH, Liu XJ, Li Y, Zhen YS. A CD13-targeting peptide integrated protein inhibits human liver cancer growth by killing cancer stem cells and suppressing angiogenesis. Mol Carcinog 2017; 56:1395-1404. [PMID: 27991698 DOI: 10.1002/mc.22600] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Revised: 12/02/2016] [Accepted: 12/15/2016] [Indexed: 12/20/2022]
Abstract
CD13 is a marker of angiogenic endothelial cells, and recently it is proved to be a biomarker of human liver cancer stem cells (CSCs). Herein, the therapeutic effects of NGR-LDP-AE, a fusion protein composed of CD13-targeting peptide NGR and antitumor antibiotic lidamycin, on human liver cancer and its mechanism were studied. Western blot and immunofluorescence assay demonstrated that CD13 (WM15 epitope) was expressed in both human liver cancer cell lines and vascular endothelial cells, while absent in normal liver cells. MTT assay showed that NGR-LDP-AE displayed potent cytotoxicity to cultured tumor cell lines with IC50 values at low nanomolar level. NGR-LDP-AE inhibited tumorsphere formation of liver cancer cells, and the IC50 values were much lower than that in MTT assay, indicating selectively killing of CSCs. In endothelial tube formation assay, NGR-LDP-AE at low cytotoxic dose significantly inhibited the formation of intact tube networks. Animal experiment demonstrated that NGR-LDP-AE inhibited the growth of human liver cancer xenograft. Immunohistochemical analysis showed that NGR-LDP-AE induced the down-regulation of CD13. In vitro experiment using cultured tumor cells also confirmed this result. NGR-LDP-AE activated both apoptotic and autophagic pathways in cultured tumor cells, while the induced autophagy protected cells from death. Conclusively, NGR-LDP-AE exerts its antitumor activity via killing liver CSCs and inhibiting angiogenesis. With one targeting motif, NGR-LDP-AE acts on both liver CSCs and angiogenic endothelial cells. It is a promising dual targeting fusion protein for liver cancer therapy, especially for advanced or relapsed cancers.
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Affiliation(s)
- Yan-Bo Zheng
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Tiantan Xili, Beijing, China
| | - Jian-Hua Gong
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Tiantan Xili, Beijing, China
| | - Xiu-Jun Liu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Tiantan Xili, Beijing, China
| | - Yi Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Tiantan Xili, Beijing, China
| | - Yong-Su Zhen
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Tiantan Xili, Beijing, China
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10
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Abstract
The enediyne family of natural products has had a profound impact on modern chemistry, biology, and medicine, and yet only 11 enediynes have been structurally characterized to date. Here we report a genome survey of 3,400 actinomycetes, identifying 81 strains that harbor genes encoding the enediyne polyketide synthase cassettes that could be grouped into 28 distinct clades based on phylogenetic analysis. Genome sequencing of 31 representative strains confirmed that each clade harbors a distinct enediyne biosynthetic gene cluster. A genome neighborhood network allows prediction of new structural features and biosynthetic insights that could be exploited for enediyne discovery. We confirmed one clade as new C-1027 producers, with a significantly higher C-1027 titer than the original producer, and discovered a new family of enediyne natural products, the tiancimycins (TNMs), that exhibit potent cytotoxicity against a broad spectrum of cancer cell lines. Our results demonstrate the feasibility of rapid discovery of new enediynes from a large strain collection. Recent advances in microbial genomics clearly revealed that the biosynthetic potential of soil actinomycetes to produce enediynes is underappreciated. A great challenge is to develop innovative methods to discover new enediynes and produce them in sufficient quantities for chemical, biological, and clinical investigations. This work demonstrated the feasibility of rapid discovery of new enediynes from a large strain collection. The new C-1027 producers, with a significantly higher C-1027 titer than the original producer, will impact the practical supply of this important drug lead. The TNMs, with their extremely potent cytotoxicity against various cancer cells and their rapid and complete cancer cell killing characteristics, in comparison with the payloads used in FDA-approved antibody-drug conjugates (ADCs), are poised to be exploited as payload candidates for the next generation of anticancer ADCs. Follow-up studies on the other identified hits promise the discovery of new enediynes, radically expanding the chemical space for the enediyne family.
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11
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Abstract
The Planctomycetes genus Gemmata is represented by both uncultured organisms and cultured Gemmata obscuriglobus and 'Gemmata massiliana' organisms. Their plasmidless 9.2 Mb genomes encode a complex cell plan, cell signaling capacities, antibiotic and trace metal resistance and multidrug resistance efflux pumps. As they lack iron metabolism pathways, they are fastidious. Gemmata spp. are mainly found in aquatic and soil environments but have also been found in hospital water networks in close proximity to patients, in animals, on human skin, the gut microbiota and in the blood of aplastic leukemic patients. Due to their panoply of attack and defense mechanisms and their recently demonstrated association with humans, the potential of Gemmata organisms to behave as opportunistic pathogens should be more widely recognized.
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Affiliation(s)
- Rita Aghnatios
- Aix Marseille Université, URMITE, UMR CNRS 7278, IRD 198, INSERM 1095. Faculté de Médecine, Marseille 13005, France
| | - Michel Drancourt
- Aix Marseille Université, URMITE, UMR CNRS 7278, IRD 198, INSERM 1095. Faculté de Médecine, Marseille 13005, France
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12
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Li W, Li X, Huang T, Teng Q, Crnovcic I, Rader C, Shen B. Engineered production of cancer targeting peptide (CTP)-containing C-1027 in Streptomyces globisporus and biological evaluation. Bioorg Med Chem 2016; 24:3887-3892. [PMID: 27094150 DOI: 10.1016/j.bmc.2016.04.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Revised: 04/06/2016] [Accepted: 04/07/2016] [Indexed: 11/25/2022]
Abstract
Conjugation of cancer targeting peptides (CTPs) with small molecular therapeutics has emerged as a promising strategy to deliver potent (but typically nonspecific) cytotoxic agents selectively to cancer cells. Here we report the engineered production of a CTP (NGR)-containing C-1027 and evaluation of its activity against selected cancer cell lines. C-1027 is an enediyne chromoprotein produced by Streptomyces globisporus, consisting of an apo-protein (CagA) and an enediyne chromophore (C-1027). NGR is a CTP that targets CD13 in tumor vasculature. S. globisporus SB1026, a recombinant strain engineered to encode CagA with the NGR sequence fused at its C-terminus, directly produces the NGR-containing C-1027 that is equally active as the native C-1027. Our results demonstrate the feasibility to produce CTP-containing enediyne chromoproteins by metabolic pathway engineering and microbial fermentation and will inspire efforts to engineer other CTP-containing drug binding proteins for targeted delivery.
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Affiliation(s)
- Wenli Li
- Division of Pharmaceutical Sciences, University of Wisconsin, Madison, WI 53705, USA
| | - Xiuling Li
- Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Tingting Huang
- Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Qihui Teng
- Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Ivana Crnovcic
- Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Christoph Rader
- Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA; Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Ben Shen
- Division of Pharmaceutical Sciences, University of Wisconsin, Madison, WI 53705, USA; Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA; Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA; Natural Products Library Initiative at The Scripps Research Institute, The Scripps Research Institute, Jupiter, FL 33458, USA.
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13
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Rudolf JD, Yan X, Shen B. Genome neighborhood network reveals insights into enediyne biosynthesis and facilitates prediction and prioritization for discovery. J Ind Microbiol Biotechnol 2016; 43:261-76. [PMID: 26318027 PMCID: PMC4753101 DOI: 10.1007/s10295-015-1671-0] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 08/09/2015] [Indexed: 01/24/2023]
Abstract
The enediynes are one of the most fascinating families of bacterial natural products given their unprecedented molecular architecture and extraordinary cytotoxicity. Enediynes are rare with only 11 structurally characterized members and four additional members isolated in their cycloaromatized form. Recent advances in DNA sequencing have resulted in an explosion of microbial genomes. A virtual survey of the GenBank and JGI genome databases revealed 87 enediyne biosynthetic gene clusters from 78 bacteria strains, implying that enediynes are more common than previously thought. Here we report the construction and analysis of an enediyne genome neighborhood network (GNN) as a high-throughput approach to analyze secondary metabolite gene clusters. Analysis of the enediyne GNN facilitated rapid gene cluster annotation, revealed genetic trends in enediyne biosynthetic gene clusters resulting in a simple prediction scheme to determine 9- versus 10-membered enediyne gene clusters, and supported a genomic-based strain prioritization method for enediyne discovery.
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Affiliation(s)
- Jeffrey D Rudolf
- Department of Chemistry, The Scripps Research Institute, Jupiter, FL, 33458, USA
| | - Xiaohui Yan
- Department of Chemistry, The Scripps Research Institute, Jupiter, FL, 33458, USA
| | - Ben Shen
- Department of Chemistry, The Scripps Research Institute, Jupiter, FL, 33458, USA.
- Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL, 33458, USA.
- Natural Products Library Initiative, The Scripps Research Institute, Jupiter, FL, 33458, USA.
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14
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Major Contributions towards Finding a Cure for Cancer through Chemotherapy: A Historical Review. TUMORI JOURNAL 2015; 102:6-17. [DOI: 10.5301/tj.5000387] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/29/2015] [Indexed: 02/06/2023]
Abstract
The history of cancer chemotherapy is as old as cancer itself. With the increase in the complexities of cancer and the development of resistance towards existing anticancer agents, increased attention is now being paid to the advancement of chemotherapy. Some chemotherapeutic agents were discovered by accident or trial-and-error methods while others were found to be useful for neoplasia when they were being evaluated for some other purpose. Broadly, these agents have been classified as alkylating agents, antimetabolites, platinum compounds, antitumor antibiotics and natural products. Hormones and compounds interfering with hormone metabolism are widely used in cancer treatment, besides monoclonal antibodies and small molecules targeting angiogenesis. In this review an attempt is made to discuss the major breakthroughs that have shaped the course of cancer chemotherapy, helping to decrease the mortality as well as lessen the suffering of patients.
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15
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Zhang Y, Liu R, Fan D, Shi R, Yang M, Miao Q, Deng ZQ, Qian J, Zhen Y, Xiong D, Wang J. The novel structure make LDM effectively remove CD123+ AML stem cells in combination with interleukin 3. Cancer Biol Ther 2015; 16:1514-25. [PMID: 26186454 DOI: 10.1080/15384047.2015.1071733] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
CD123 became a therapeutic target for acute myelocytic leukemia(AML) because of its overexpression only on AML stem cells. It is α subunit of interleukin-3 (multi-CSF, IL3) receptor. Lidamycin(LDM) is a novel antibiotic composed of an apoprotein (LDP) and a chromophore (AE). We cloned, expressed and isolated IL3LDP fusion protein first then assembled with AE in vitro. We found that131/132 amino acids of IL3 were the key factors for IL3 fusion protein stability and I131L/F132L mutation effectively improved the IL3 fusion protein stability. The toxicity of IL3LDM to CD123+ tumor cells was 2-10 times compared to LDM alone and 10000 times compared to ADR. Meanwhile, IL3LDM impaired the colony-forming ability of CD123+ stem-like cells but not to CD123 negative normal cord blood cells. Three drug delivery methods in vivo were adopted: prophylactic treatment and single/multiple-dosing administration. The tumor-free survival extended to 120 d and cancer cell invasion significantly decreased after IL3LDM continuous multiple treated. Moreover, IL3LDM had been shown to modulate apoptosis by arrested cell cycle in G2/M phase. Therefore, IL3LDM is expected to be a new drug for leukemia target therapy.
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Affiliation(s)
- Yanjun Zhang
- a State Key Laboratory of Experimental Hematology ; Institute of Hematology & Hospital of Blood Diseases ; Chinese Academy of Medical Sciences & Peking Union Medical College ; Tianjin , China
| | - Rong Liu
- b Department of biochemistry ; Microbiology and Immunology ; Faculty of Medicine ; University of Ottawa ; Ottawa , ON Canada
| | - Dongmei Fan
- a State Key Laboratory of Experimental Hematology ; Institute of Hematology & Hospital of Blood Diseases ; Chinese Academy of Medical Sciences & Peking Union Medical College ; Tianjin , China
| | - Rizan Shi
- c Institute of Medicinal Biotechnology Academy of Medical Sciences & Peking Union Medical College ; Beijing , China
| | - Ming Yang
- a State Key Laboratory of Experimental Hematology ; Institute of Hematology & Hospital of Blood Diseases ; Chinese Academy of Medical Sciences & Peking Union Medical College ; Tianjin , China
| | - Qingfang Miao
- d Department of Pharmacology ; Shanxi Medical University ; Taiyuan, Shanxi , PR China
| | - Zhao-Qun Deng
- e Affiliated People's Hospital of Jiangsu University ; Zhenjiang, Jiangsu , PR China
| | - Jun Qian
- e Affiliated People's Hospital of Jiangsu University ; Zhenjiang, Jiangsu , PR China
| | - Yongsu Zhen
- d Department of Pharmacology ; Shanxi Medical University ; Taiyuan, Shanxi , PR China
| | - Dongsheng Xiong
- a State Key Laboratory of Experimental Hematology ; Institute of Hematology & Hospital of Blood Diseases ; Chinese Academy of Medical Sciences & Peking Union Medical College ; Tianjin , China
| | - Jianxiang Wang
- a State Key Laboratory of Experimental Hematology ; Institute of Hematology & Hospital of Blood Diseases ; Chinese Academy of Medical Sciences & Peking Union Medical College ; Tianjin , China
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16
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Synthesis of triazole-fused tetracyclic glycosides in aqueous medium: application of nanodomain cubic cuprous oxide as reusable catalyst in one-pot domino Sonogashira-cyclization. Tetrahedron Lett 2015. [DOI: 10.1016/j.tetlet.2015.04.106] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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17
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Gao R, Li L, Shang B, Zhao C, Sheng W, Li D. A Gelatinases-targeting scFv-based Fusion Protein Shows Enhanced Antitumour Activity with Endostar against Hepatoma. Basic Clin Pharmacol Toxicol 2015; 117:105-16. [PMID: 25615234 DOI: 10.1111/bcpt.12379] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 01/09/2015] [Indexed: 12/26/2022]
Abstract
Gelatinases play important roles in tumour invasion and metastasis and are thus considered promising targets for cancer therapy. In this study, a new single-chain variable fragment (scFv)-based fusion protein Fv-LDP, composed of the anti-gelatinases scFv and lidamycin apoprotein (LDP), was prepared, and its combination with angiogenesis inhibitor Endostar was then investigated. The fusion protein Fv-LDP specifically bound to various tumour cells, and its binding capability to human pulmonary giant cell carcinoma (PG) cells was higher than that of LDP. Fv-LDP inhibited the expression and secretion of gelatinases and could be internalized into tumour cells via endocytosis. Fv-LDP also suppressed the growth of human hepatoma cells and murine hepatoma 22 transplanted in Kunming mice in various degrees. In addition, Endostar could enhance the synergistic or additive inhibition of Fv-LDP on the growth, migration or invasion of human hepatoma cells shown by a colony formation assay and a transwell-based migration or invasion assay, respectively. In vivo, Fv-LDP/Endostar combination showed a significantly synergistic effect on the growth of a human hepatoma xenograft, with an inhibition rate of 80.8% compared with the Fv-LDP (44.1%) or Endostar (8.9%)-treated group. The above-mentioned results indicate that the fusion protein Fv-LDP is effective against transplantable hepatoma in mice and human hepatoma xenografts in athymic mice. Moreover, Endostar can potentiate the inhibition effect of Fv-LDP on the growth of human hepatoma cells and xenografts. These data will provide a new combined strategy for improving the therapeutic efficacy of treatments for hepatoma or other gelatinase-overexpressing tumours.
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Affiliation(s)
- Ruijuan Gao
- Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Liang Li
- Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Boyang Shang
- Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Chunyan Zhao
- Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Weijin Sheng
- Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Diandong Li
- Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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18
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Malhotra R, Dey TK, Basu S, Hajra S. Enantiopure synthesis of dihydrobenzo[1,4]-oxazine-3-carboxylic acids and a route to benzoxazinyl oxazolidinones. Org Biomol Chem 2015; 13:3211-9. [DOI: 10.1039/c4ob02475c] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A two step protocol is developed for the enantiopure synthesis of dihydrobenzoxazine-3-carboxylic acids via RuPhos Palladacycle-catalyzed aminoarylation of β-(2-bromoaryloxy)amino acids.
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Affiliation(s)
- Rajesh Malhotra
- Department of Chemistry
- Guru Jambheshwar University of Science and Technology
- Hisar
- India
| | - Tushar K. Dey
- Department of Chemistry
- Guru Jambheshwar University of Science and Technology
- Hisar
- India
- TCG Life Sciences Ltd
| | | | - Saumen Hajra
- Centre of Biomedical Research
- Lucknow 226014
- India
- Department of Chemistry
- Indian Institute of Technology Kharagpur
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19
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Brahma K, Das B, Chowdhury C. A palladium-catalyzed facile and general method for the stereoselective synthesis of (E)-3-arylidene-3,4-dihydro-2H-1,4-benzoxazines and their naphthoxazine analogues. Tetrahedron 2014. [DOI: 10.1016/j.tet.2014.06.036] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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20
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Li XQ, Ouyang ZG, Zhang SH, Liu H, Shang Y, Li Y, Zhen YS. Synergy of enediyne antibiotic lidamycin and temozolomide in suppressing glioma growth with potentiated apoptosis induction. J Neurooncol 2014; 119:91-100. [PMID: 24842385 DOI: 10.1007/s11060-014-1477-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2013] [Accepted: 04/30/2014] [Indexed: 12/15/2022]
Abstract
The present work evaluated the synergistic efficacy of an enediyne antibiotic lidamycin (LDM) plus temozolomide (TMZ) against glioma in vitro and in vivo. LDM plus TMZ inhibited the proliferations of rat glioma C6 cells and human glioma U87 cells more efficiently than the single usage of LDM or TMZ. In addition, LDM also potentiated the apoptosis inductions by TMZ in rat C6 cells and human U87 cells. Meanwhile, the results of TdT-mediated dUTP Nick End Labeling assay for subcutaneous U87 tumor sections indicated an enhanced apoptosis induction in vivo by LDM plus TMZ, which confirmed the high potency of the combination for glioma therapy. As determined by Western blot, apoptosis signal pathways in C6 cells and U87 cells were markedly affected by the synergistic alteration of P53, bax, procaspase 3, and bcd-2 expression. In both subcutaneous U87 xenograft and C6 intracerebral orthotopic implant model, TMZ-induced glioma growth suppression was dramatically potentiated by LDM. As shown, the combination therapy efficiently reduced the tumor volumes and tumor weights of the human glioma U87 xenograft. Kaplan-Meier assay revealed that LDM plus TMZ dramatically prolonged the life span of C6 intracerebral tumor-bearing rats with decreased tumor size. This study indicates that the combination of LDM with TMZ might be a promising strategy for glioma therapy.
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Affiliation(s)
- Xing-Qi Li
- College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China
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21
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Chatterjee N, Sarkar S, Pal R, Sen AK. An approach toward the syntheses of triazolo benzoxazines, triazolo quinoxalines, triazolo benzodiazepines, triazolo benzoxazepines, and triazolo benzothiazines via a simple and convenient protocol using basic alumina as solid support. Tetrahedron Lett 2014. [DOI: 10.1016/j.tetlet.2014.02.080] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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22
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Li XQ, Ouyang ZG, Zhang SH, Liu H, Shang Y, Li Y, Zhen YS. Synergistic inhibition of angiogenesis and glioma cell-induced angiogenesis by the combination of temozolomide and enediyne antibiotic lidamycin. Cancer Biol Ther 2014; 15:398-408. [PMID: 24424202 DOI: 10.4161/cbt.27626] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Present work mainly evaluated the inhibitory effects of lidamycin (LDM), an enediyne antibiotic, on angiogenesis or glioma-induced angiogenesis in vitro and in vivo, especially its synergistic anti-angiogenesis with temozolomide (TMZ). LDM alone efficiently inhibited proliferations and induced apoptosis of rat brain microvessel endothelial cells (rBMEC). LDM also interrupted the tube formation of rat brain microvessel endothelial cells (rBMEC) and rat aortic ring spreading. The blockade of rBMEC invasion and C6 cell-induced rBMEC migration by LDM was associated with decrease of VEGF secretion in a co-culture system. TMZ dramatically potentiated the effects of LDM on anti-proliferation, apoptosis induction, and synergistically inhibited angiogenesis events. As determined by western blot and ELISA, the interaction of tumor cells and the rBMEC was markedly interrupted by LDM plus TMZ with synergistic regulations of VEGF induced angiogenesis signal pathway, tumor cell invasion/migration, and apoptosis signal pathway. Immunofluorohistochemistry of CD31 and VEGF showed that LDM plus TMZ resulted in synergistic decrease of microvessel density (MVD) and VEGF expression in human glioma U87 cell subcutaneous xenograft. This study indicates that the high efficacy of LDM and the synergistic effects of LDM plus TMZ against glioma are mediated, at least in part, by the potentiated anti-angiogenesis.
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Affiliation(s)
- Xing-Qi Li
- College of Life Science & Technology; Heilongjiang Bayi Agricultural University; Daqing, PR China; Institute of Medicinal Biotechnology; Chinese Academy of Medical Sciences & Peking Union Medical College; Beijing, PR China
| | - Zhi-Gang Ouyang
- Institute of Medicinal Biotechnology; Chinese Academy of Medical Sciences & Peking Union Medical College; Beijing, PR China
| | - Sheng-Hua Zhang
- Institute of Medicinal Biotechnology; Chinese Academy of Medical Sciences & Peking Union Medical College; Beijing, PR China
| | - Hong Liu
- Institute of Medicinal Biotechnology; Chinese Academy of Medical Sciences & Peking Union Medical College; Beijing, PR China
| | - Yue Shang
- Institute of Medicinal Biotechnology; Chinese Academy of Medical Sciences & Peking Union Medical College; Beijing, PR China
| | - Yi Li
- Institute of Medicinal Biotechnology; Chinese Academy of Medical Sciences & Peking Union Medical College; Beijing, PR China
| | - Yong-Su Zhen
- Institute of Medicinal Biotechnology; Chinese Academy of Medical Sciences & Peking Union Medical College; Beijing, PR China
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23
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Construction of functionalized spiro 1,4-benzoxazine oxindole derivatives via domino Mannich-alkylation of α-halocarbonyl compounds with imines. Tetrahedron Lett 2013. [DOI: 10.1016/j.tetlet.2013.08.076] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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24
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Jangili P, Kashanna J, Das B. Synthesis of dihydrobenzo[1,4]oxazines using copper catalyzed intramolecular ring closure reaction. Tetrahedron Lett 2013. [DOI: 10.1016/j.tetlet.2013.04.090] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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25
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Zheng YB, Shang BY, Li Y, Zhen YS. An NGR-integrated and enediyne-energized apoprotein shows CD13-targeting antitumor activity. Biomed Pharmacother 2013. [DOI: 10.1016/j.biopha.2012.10.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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26
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Ru Q, Shang BY, Miao QF, Li L, Wu SY, Gao RJ, Zhen YS. A cell penetrating peptide-integrated and enediyne-energized fusion protein shows potent antitumor activity. Eur J Pharm Sci 2012; 47:781-9. [PMID: 22982402 DOI: 10.1016/j.ejps.2012.09.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Revised: 08/20/2012] [Accepted: 09/03/2012] [Indexed: 01/19/2023]
Abstract
Arginine-rich peptides belong to a subclass of cell penetrating peptides that are taken up by living cells and can be detected freely diffusing inside the cytoplasm and nucleoplasm. This phenomenon has been attributed to either an endocytotic mode of uptake and a subsequent release from vesicles or a direct membrane penetration. Lidamycin is an antitumor antibiotic, which consists of an active enediyne chromophore (AE) and a noncovalently bound apoprotein (LDP). In the present study, a fusion protein (Arg)(9)-LDP composed of cell penetrating peptide (Arg)(9) and LDP was prepared by DNA recombination, and the enediyne-energized fusion protein (Arg)(9)-LDP-AE was prepared by molecular reconstitution. The data in fixed cells demonstrated that (Arg)(9)-LDP could rapidly enter cells, and the results based on fluorescence activated cell sorting indicated that the major route for (Arg)(9)-mediated cellular uptake of protein molecules was endocytosis. (Arg)(9)-LDP-AE demonstrated more potent cytotoxicity against different carcinoma cell lines than lidamycin in vitro. In the mouse hepatoma 22 model, (Arg)(9)-LDP-AE (0.3mg/kg) suppressed the tumor growth by 89.2%, whereas lidamycin (0.05 mg/kg) by 74.6%. Furthermore, in the glioma U87 xenograft model in nude mice, (Arg)(9)-LDP-AE at 0.2mg/kg suppressed tumor growth by 88.8%, compared with that of lidamycin by 62.9% at 0.05 mg/kg. No obvious toxic effects were observed in all groups during treatments. The results showed that energized fusion protein (Arg)(9)-LDP-AE was more effective than lidamycin and would be a promising candidate for glioma therapy. In addition, this approach to manufacturing fusion proteins might serve as a technology platform for the development of new cell penetrating peptides-based drugs.
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Affiliation(s)
- Qin Ru
- Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Medical College, Beijing, PR China
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27
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DNA damage by C1027 involves hydrogen atom abstraction and addition to nucleobases. Bioorg Med Chem 2012; 20:4744-50. [PMID: 22748380 DOI: 10.1016/j.bmc.2012.06.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2012] [Revised: 05/30/2012] [Accepted: 06/01/2012] [Indexed: 12/13/2022]
Abstract
C1027 is a potent antitumor agent that damages DNA. It has the unusual ability to produce double strand breaks and interstrand cross-links (ICLs) intracellularly, which enable it to initiate concurrent ataxia-telangiestasia mutated (ATM) and Rad-3 related (ATR) independent damage responses. The latter form of damage is not well characterized. We have examined the effect of DNA sequence on C1027 reactivity and found it to be more diverse than previously thought. In addition, analysis of the chemical stability of ICLs suggests that they result from reaction with the deoxyribose ring on one strand but direct addition to a nucleobase on the opposite strand.
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28
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Zhang Q, Liu X, Xu S, Li C, Zhang Y, Yang J, Zheng J. Factor VII light chain-targeted lidamycin shows intensified therapeutic efficacy for liver cancer. Cancer Biother Radiopharm 2012; 27:384-91. [PMID: 22651685 DOI: 10.1089/cbr.2012.1209] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The overexpression of tissue factor (TF) observed in numerous cancer cells and clinical samples of human cancers makes TF an ideal target for cancer therapy. The purpose of this study is to develop a TF-targeting energized fusion protein hlFVII-LDP-AE, which is composed of a human Factor VII light chain (hlFVII) as the targeting domain conjugated to the cytotoxic antibiotic lidamycin (LDM, LDP-AE) as the effector domain. The potential efficacy of hlFVII-LDP-AE for cancer therapy was tested in vitro by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays and in vivo with a BALB/c nude mouse xenograft model of human liver cancer line HepG2. The inhibitory concentration (IC(50)) value of hlFVII-LDP-AE varied from 0.15 to 0.64 nM for the various human tumor lines. hlFVII-LDP-AE showed a tumor growth inhibition rate of 90.6% at the dose of 0.6 mg/kg in in vivo animal experiments. The mechanism through which hlFVII-LDP-AE inhibits tumor growth also was determined by Hoechst 33342 staining and Tdt-mediated dUTP nick-end labeling (TUNEL) assay. hlFVII-LDP-AE causes tumor cell death through inducing chromatin condensation and cleavage of genomic DNA. These findings suggest that the hlFVII-LDP-AE protocol is efficacious and tolerated in the mouse model of human liver cancer HepG2 and has clinical applicability for treating cancer patients.
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Affiliation(s)
- Qing Zhang
- Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, PR China.
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29
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Zhang YR, Xie JW, Huang XJ, Zhu WD. Construction of functionalized 2,3-dihydro-1,4-benzoxazines via [5 + 1] annulations of 2-halo-1,3-dicarbonyl compounds with imines. Org Biomol Chem 2012; 10:6554-61. [DOI: 10.1039/c2ob25927c] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Affiliation(s)
- Ya-Ru Zhang
- Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry and Life Science, Zhejiang Normal University, Jinhua 321004, P.R. of China
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30
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Abstract
Once considered to be isolation artifacts or chemical "mistakes" of nature, the number of naturally occurring organohalogen compounds has grown from a dozen in 1954 to >5000 today. Of these, at least 25% are halogenated alkaloids. This is not surprising since nitrogen-containing pyrroles, indoles, carbolines, tryptamines, tyrosines, and tyramines are excellent platforms for biohalogenation, particularly in the marine environment where both chloride and bromide are plentiful for biooxidation and subsequent incorporation into these electron-rich substrates. This review presents the occurrence of all halogenated alkaloids, with the exception of marine bromotyrosines where coverage begins where it left off in volume 61 of The Alkaloids. Whereas the biological activity of these extraordinary compounds is briefly cited for some examples, a future volume of The Alkaloids will present full coverage of this topic and will also include selected syntheses of halogenated alkaloids. Natural organohalogens of all types, especially marine and terrestrial halogenated alkaloids, comprise a rapidly expanding class of natural products, in many cases expressing powerful biological activity. This enormous proliferation has several origins: (1) a revitalization of natural product research in a search for new drugs, (2) improved compound characterization methods (multidimensional NMR, high-resolution mass spectrometry), (3) specific enzyme-based and other biological assays, (4) sophisticated collection methods (SCUBA and remote submersibles for deep ocean marine collections), (5) new separation and purification techniques (HPLC and countercurrent separation), (6) a greater appreciation of traditional folk medicine and ethobotany, and (7) marine bacteria and fungi as novel sources of natural products. Halogenated alkaloids are truly omnipresent in the environment. Indeed, one compound, Q1 (234), is ubiquitous in the marine food web and is found in the Inuit from their diet of whale blubber. Given the fact that of the 500,000 estimated marine organisms--which are the source of most halogenated alkaloids--only a small percentage have been investigated for their chemical content, it is certain that myriad new halogenated alkaloids are awaiting discovery. For example, it is estimated that nearly 4000 species of bryozoans have not been examined for their chemical content. The few species that have been studied contain some extraordinary halogenated alkaloids, such as hinckdentine A (610) and the chartellines (611-613). Of the estimated 1.5 million species of fungi, secondary metabolites have been characterized from only 5000 species. The future seems bright for the collector of halogenated alkaloids!
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Affiliation(s)
- Gordon W Gribble
- Department of Chemistry, Dartmouth College, Hanover, New Hampshire, USA.
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31
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Antitumor effects of an engineered and energized fusion protein consisting of an anti-CD20 scFv fragment and lidamycin. SCIENCE CHINA-LIFE SCIENCES 2011; 54:255-62. [DOI: 10.1007/s11427-011-4143-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2010] [Accepted: 10/26/2010] [Indexed: 11/26/2022]
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32
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Releasing of the chromophore from the drug delivery protein C-1027: A molecular dynamics simulations study. J Struct Biol 2010; 172:284-93. [DOI: 10.1016/j.jsb.2010.08.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2010] [Revised: 08/12/2010] [Accepted: 08/18/2010] [Indexed: 11/19/2022]
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33
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La Ferla B, Airoldi C, Zona C, Orsato A, Cardona F, Merlo S, Sironi E, D'Orazio G, Nicotra F. Natural glycoconjugates with antitumor activity. Nat Prod Rep 2010; 28:630-48. [PMID: 21120227 DOI: 10.1039/c0np00055h] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cancer is one of the major causes of death worldwide. As a consequence, many different therapeutic approaches, including the use of glycosides as anticancer agents, have been developed. Various glycosylated natural products exhibit high activity against a variety of microbes and human tumors. In this review we classify glycosides according to the nature of their aglycone (non-saccharidic) part. Among them, we describe anthracyclines, aureolic acids, enediyne antibiotics, macrolide and glycopeptides presenting different strengths and mechanisms of action against human cancers. In some cases, the glycosidic residue is crucial for their activity, such as in anthracycline, aureolic acid and enediyne antibiotics; in other cases, Nature has exploited glycosylation to improve solubility or pharmacokinetic properties, as in the glycopeptides. In this review we focus our attention on natural glycoconjugates with anticancer properties. The structure of several of the carbohydrate moieties found in these conjugates and their role are described. The structure–activity relationship of some of these compounds, together with the structural features of their interaction with the biological targets, are also reported. Taken together, all this information is useful for the design of new potential anti-tumor drugs.
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Affiliation(s)
- Barbara La Ferla
- Department of Biotechnology and Bioscience, University of Milano Bicocca, Piazza della Scienza 2, I-20126, Milano, Italy.
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34
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Xin C, Ye S, Ming Y, Shenghua Z, Qingfang M, Hongxing G, Xu S, Yuanfu X, Yuan Z, Dongmei F, Juanni L, Yingdai G, Lianfang J, Rongguang S, Zhenping Z, Jianxiang W, Tao C, Chunzheng Y, Dongsheng X, Yongsu Z. Efficient inhibition of B-cell lymphoma xenografts with a novel recombinant fusion protein: anti-CD20Fab-LDM. Gene Ther 2010; 17:1234-43. [PMID: 20463754 DOI: 10.1038/gt.2010.76] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Lidamycin (LDM) is a new member of enediyne antitumor antibiotics family that can be separated and reconstituted. It consists of a labile active enediyne chromophore (AE) and a noncovalently bound apoprotein (LDP). LDM is now in phase II clinical trials. In this study, we described the antitumor features of a fusion protein of LDM, anti-CD20Fab-LDM, targeted to CD20 expressed by B-lymphoid malignancies. Especially, LDM was prepared by a novel two-step method including DNA recombination and molecular reconstitution. Anti-CD20Fab-LDM exerted potent cytotoxicity against CD20+ B-cell lymphoma cell lines in vitro (IC50: 10-30 pM) and in the Raji xenograft model. Two Raji xenografts were allowed to grow to an initial mass of 80 and 500 mm³, respectively, and then anti-CD20Fab-LDM was administered intravenously with the highest dose of 4 nmol kg⁻¹ . The inhibition rates of tumor growth were 90.1 and 85%, which were saliently superior to those of nontargeted LDM. It is noteworthy that anti-CD20Fab-LDM can inhibit the growth of patient-derived cells, including rituximab-resistant patient-derived cells. Thus, CD20-targeted delivery of LDM is a specific and potent therapeutic strategy for B-lymphoid malignancies. In addition, the two-step approach could serve as a new technology platform for making a series of highly potent engineered antibody-based drugs.
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Affiliation(s)
- C Xin
- State Key Laboratory of Experimental Hematology, Department of Pharmacy, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, PRC
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35
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Al-Harrasi A, Pfrengle F, Prisyazhnyuk V, Yekta S, Koós P, Reissig HU. Enantiopure aminopyrans by a Lewis acid promoted rearrangement of 1,2-oxazines: versatile building blocks for oligosaccharide and sugar amino acid mimetics. Chemistry 2010; 15:11632-41. [PMID: 19780107 DOI: 10.1002/chem.200900996] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
1,3-Dioxolanyl-substituted 1,2-oxazines, such as syn-1 and anti-1, rearrange under Lewis acidic conditions to provide bicyclic products 2-5. Subsequent reductive transformations afforded enantiopure 3-aminopyran derivatives such as 7 and 9 or their protected diastereomers 16 and 18, which can be regarded as carbohydrate mimetics. An alternative sequence of transformations including selective oxidation of the primary hydroxyl groups in 21 and 24 led to two protected beta-amino acid derivatives with carbohydrate-like backbone (sugar amino acids). Treatment of bicyclic ester 23 with samarium diiodide cleaved the N--O bond and furnished the unusual beta-lactam 27 in excellent yield. Alternatively, gamma-amino acid derivative 29 was efficiently prepared in a few steps. Fairly simple transformations gave azides 32 and 35 or alkyne 30 which are suitable substrates for the construction of oligosaccharide mimetics such as 34 by copper iodide catalyzed cycloadditions. With this report we demonstrate that enantiopure rearrangement products 2-5 are protected precursors of a variety of polyfunctionalized pyran derivatives with great potential for chemical biology.
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Affiliation(s)
- Ahmed Al-Harrasi
- Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195 Berlin
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36
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Cai L, Chen H, Miao Q, Wu S, Shang Y, Zhen Y. Binding capability of the enediyne-associated apoprotein to human tumors and constitution of a ligand oligopeptide-integrated protein. J Biotechnol 2009; 144:142-50. [PMID: 19737585 DOI: 10.1016/j.jbiotec.2009.09.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2009] [Revised: 08/16/2009] [Accepted: 09/01/2009] [Indexed: 10/20/2022]
Abstract
The molecule of lidamycin that belongs to the chromoprotein family of antitumor antibiotics is composed of an apoprotein (LDP) and an enediyne chromophore. The enediyne moiety of the molecule is responsible for the potent cytotoxicity; however, the biological function of the apoprotein moiety, particularly its interaction with cancer cells, remains unclear. In present study, the binding capability of LDP to human tumors was detected for the first time by tissue microarray. LDP bound to various human tumors with significant difference from the corresponding normal tissues. Positive correlation between binding activity and the overexpression of VEGF and EGFR was confirmed by lung carcinoma tissue microarray. A fusion protein LG-LDP that consists of LDP and a ligand oligopeptide to EGFR was constructed by DNA recombination. LG-LDP showed augmented binding to EGFR-overexpressing cancer cells. Furthermore, an energized fusion protein LG-LDP-AE was prepared by integrating the active enediyne (AE) into LG-LDP molecule. By MTT assay, LG-LDP-AE displayed extremely potent cytotoxicity to cancer cells with IC50 approximate to 0.01nM. The results indicate that LDP binds to various human tumors and it might serve as a delivery carrier by integration of ligand oligopeptide to manufacture motif-based, targeted fusion proteins for cancer.
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Affiliation(s)
- Lin Cai
- Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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37
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Chowdhury C, Sasmal AK, Dutta PK. Efficient synthesis of [1,2,3]triazolo[5,1-c][1,4]benzoxazines through palladium–copper catalysis. Tetrahedron Lett 2009. [DOI: 10.1016/j.tetlet.2009.03.120] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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38
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Nicolaides DN, Gautam DR, Litinas KE, Hadjipavlou-Litina DJ, Kontogiorgis CA. Synthesis and biological evaluation of benzo[7,8]chromeno[5,6-b][1,4]oxazin-3-ones. J Heterocycl Chem 2009. [DOI: 10.1002/jhet.5570410421] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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39
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Feng E, Huang H, Zhou Y, Ye D, Jiang H, Liu H. Copper(I)-Catalyzed One-Pot Synthesis of 2H-1,4-Benzoxazin-3-(4H)-ones from o-Halophenols and 2-Chloroacetamides. J Org Chem 2009; 74:2846-9. [DOI: 10.1021/jo802818s] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Enguang Feng
- The Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 201203, China, and School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - He Huang
- The Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 201203, China, and School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Yu Zhou
- The Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 201203, China, and School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Deju Ye
- The Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 201203, China, and School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Hualiang Jiang
- The Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 201203, China, and School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Hong Liu
- The Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 201203, China, and School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
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Wang L, Hu Y, Zhang Y, Wang S, Cui Z, Bao Y, Jiang W, Hong B. Role of sgcR3 in positive regulation of enediyne antibiotic C-1027 production of Streptomyces globisporus C-1027. BMC Microbiol 2009; 9:14. [PMID: 19159491 PMCID: PMC2657911 DOI: 10.1186/1471-2180-9-14] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2008] [Accepted: 01/22/2009] [Indexed: 12/03/2022] Open
Abstract
Background C-1027, produced by Streptomyces globisporus C-1027, is one of the most potent antitumoral agents. The biosynthetic gene cluster of C-1027, previously cloned and sequenced, contains at least three putative regulatory genes, i.e. sgcR1, sgcR2 and sgcR3. The predicted gene products of these genes share sequence similarities to StrR, regulators of AraC/XylS family and TylR. The purpose of this study was to investigate the role of sgcR3 in C-1027 biosynthesis. Results Overexpression of sgcR3 in S. globisporus C-1027 resulted in a 30–40% increase in C-1027 production. Consistent with this, disruption of sgcR3 abolished C-1027 production. Complementation of the sgcR3-disrupted strain R3KO with intact sgcR3 gene could restore C-1027 production. The results from real time RT-PCR analysis in R3KO mutant and wild type strain indicated that not only transcripts of biosynthetic structural genes such as sgcA1 and sgcC4, but also putative regulatory genes, sgcR1 and sgcR2, were significantly decreased in R3KO mutant. The cross-complementation studies showed that sgcR1R2 could functionally complement sgcR3 disruption in trans. Purified N-terminal His10-tagged SgcR3 showed specific DNA-binding activity to the promoter region of sgcR1R2. Conclusion The role of SgcR3 has been proved to be a positive regulator of C-1027 biosynthesis in S. globisporus C-1027. SgcR3 occupies a higher level than SgcR1 and SgcR2 in the regulatory hierarchy that controls C-1027 production and activates the transcription of sgcR1 and sgcR2 by binding directly to the promoter region of sgcR1R2.
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Affiliation(s)
- Lifei Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
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Beerman TA, Gawron LS, Shin S, Shen B, McHugh MM. C-1027, a radiomimetic enediyne anticancer drug, preferentially targets hypoxic cells. Cancer Res 2009; 69:593-8. [PMID: 19147573 PMCID: PMC2758494 DOI: 10.1158/0008-5472.can-08-2753] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The hypoxic nature of cells within solid tumors limits the efficacy of anticancer therapies such as ionizing radiation and conventional radiomimetics because their mechanisms require oxygen to induce lethal DNA breaks. For example, the conventional radiomimetic enediyne neocarzinostatin is 4-fold less cytotoxic to cells maintained in low oxygen (hypoxic) compared with normoxic conditions. By contrast, the enediyne C-1027 was nearly 3-fold more cytotoxic to hypoxic than to normoxic cells. Like other radiomimetics, C-1027 induced DNA breaks to a lesser extent in cell-free, or cellular hypoxic, compared with normoxic environments. However, the unique DNA interstrand cross-linking ability of C-1027 was markedly enhanced under the same hypoxic conditions that reduced its DNA break induction. Although the unique chemistry of C-1027 allows it to concurrently generate both DNA breaks and cross-links in normoxic cells, a low oxygen environment represses the former and promotes the latter. Thus, treatment with C-1027 offers a facile approach for overcoming the radioresistance associated with poorly oxygenated cells.
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Affiliation(s)
- Terry A Beerman
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
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42
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Chen J, Wu SY, Ou-Yang ZG, Zhen YS. Synergy of gemcitabine and lidamycin associated with NF-kappaB downregulation in pancreatic carcinoma cells. Acta Pharmacol Sin 2008; 29:614-9. [PMID: 18430374 DOI: 10.1111/j.1745-7254.2008.00774.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
AIM To investigate the effects on human pancreatic cancer PANC-1 and SW1990 cells using a combination of lidamycin (LDM) and gemcitabine. METHODS A 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to determine the growth inhibition of drugs in PANC-1 and SW1990 cells. The effects on apoptosis were measured by terminal uridine deoxynucleotidyl transferase dUTP nick end labeling assay and flow cytometry combined with fluorescein- isothiocyanate-Annexin V/propidium iodide staining. The activity of caspase-3 was measured with a special assay kit. The mitochondrial membrane potential was determined by confocal microscopy analyses. The level of mRNA encoding K-ras in the cells was determined by RT-PCR analysis. The expression of K-ras, NF-kappaB, and Bcl-2 was detected by Western blotting analysis. RESULTS There was a significant reduction in proliferation in the pancreatic cancer cell lines treated with a combination of gemcitabine and LDM. The overall growth inhibition directly correlated with apoptotic cell death. LDM potentiated the gemcitabine-induced cell killing by reducing mitochondrial membrane potential and increasing the caspase-3 activity. Notably, the K-ras mRNA level was significantly reduced with the combination of gemcitabine and LDM. The results for K-ras, NF-kappaB, and Bcl-2 proteins also showed downregulation in the combination group relative to the single-agent treatment and the untreated control. CONCLUSION LDM can potentiate the growth inhibition induced by gemcitabine in human pancreatic cancer cells, and the synergy may be associated with NF-kappaB downregulation.
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Affiliation(s)
- Jing Chen
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
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43
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Iso K, Inoue M, Kato N, Hirama M. Synthesis of the Bicyclo[7.3.0]dodecadiyne Core of the Maduropeptin Chromophore. Chem Asian J 2008; 3:447-53. [DOI: 10.1002/asia.200700310] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Reddy GJ, Rao ΚS. SYNTHESIS OF METHYL-(3-OXO-2H-[1,4]-BENZOXA /THIAZIN-6-YL)-PYRAZOLE-5-CARBOXYLATES & ISOXAZOLE-3-CARBOXYLATES AS POSSIBLE COX-2 / 5-LOX INHIBITORS. HETEROCYCL COMMUN 2008. [DOI: 10.1515/hc.2008.14.1-2.83] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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45
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Van Lanen SG, Oh TJ, Liu W, Wendt-Pienkowski E, Shen B. Characterization of the maduropeptin biosynthetic gene cluster from Actinomadura madurae ATCC 39144 supporting a unifying paradigm for enediyne biosynthesis. J Am Chem Soc 2007; 129:13082-94. [PMID: 17918933 PMCID: PMC2529154 DOI: 10.1021/ja073275o] [Citation(s) in RCA: 123] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The biosynthetic gene cluster for the enediyne antitumor antibiotic maduropeptin (MDP) from Actinomadura madurae ATCC 39144 was cloned and sequenced. Cloning of the mdp gene cluster was confirmed by heterologous complementation of enediyne polyketide synthase (PKS) mutants from the C-1027 producer Streptomyces globisporus and the neocarzinostatin producer Streptomyces carzinostaticus using the MDP enediyne PKS and associated genes. Furthermore, MDP was produced, and its apoprotein was isolated and N-terminal sequenced; the encoding gene, mdpA, was found to reside within the cluster. The biosynthesis of MDP is highlighted by two iterative type I PKSs--the enediyne PKS and a 6-methylsalicylic acid PKS; generation of (S)-3-(2-chloro-3-hydroxy-4-methoxyphenyl)-3-hydroxypropionic acid derived from L-alpha-tyrosine; a unique type of enediyne apoprotein; and a convergent biosynthetic approach to the final MDP chromophore. The results demonstrate a platform for engineering new enediynes by combinatorial biosynthesis and establish a unified paradigm for the biosynthesis of enediyne polyketides.
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Affiliation(s)
| | | | - Wen Liu
- Division of Pharmaceutical Sciences
| | | | - Ben Shen
- Division of Pharmaceutical Sciences
- University of Wisconsin National Cooperative Drug Discovery Group
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53705
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Miao Q, Shang B, Ouyang Z, Liu X, Zhen Y. Generation and antitumor effects of an engineered and energized fusion protein VL-LDP-AE composed of single-domain antibody and lidamycin. ACTA ACUST UNITED AC 2007; 50:447-56. [PMID: 17653664 DOI: 10.1007/s11427-007-0058-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2006] [Accepted: 02/13/2007] [Indexed: 10/23/2022]
Abstract
Type IV collagenase plays a pivotal role in invasion, metastasis and angiogenesis of tumor. Single domain antibodies are attractive as tumor-targeting vehicle because of their much smaller size compared with antibody molecules produced by conventional methods. Lidamycin (LDM) is a potent enediyne-containing antitumor antibiotic. In this study an engineered and energized fusion protein VL-LDP-AE composed of lidamycin and VL domain of mAb 3G11 directed against type IV collagenase was prepared using a novel two-step method. First a VL-LDP fusion protein was constructed by DNA recombination. Secondly VL-LDP-AE was obtained by molecular reconstitution. In MTT assay, VL-LDP-AE showed potent cytotoxicity to HT-1080 cells and KB cells with IC(50) values of 8.55 x 10(-12) and 1.70 x 10(-11) mol/L, respectively. VL-LDP-AE showed antiangiogenic activity in chick chrorioallantoic membrane (CAM) assay and tube formation assay. In in vivo experiments, VL-LDP-AE was proved to be more effective than free LDM against the growth of subcutaneously transplanted hepatoma 22 in mice. Drugs were given intravenously on day 3 and 10 after tumor transplantation. Compared in terms of maximal tolerated doses, VL-LDP-AE at 0.25 mg/kg suppressed the tumor growth by 89.5%, LDM at 0.05 mg/kg by 69.9%, and mitomycin at 1 mg/kg by 35%. Having a molecular weight of 25.2 kDa, VL-LDP-AE was much smaller than other reported antibody-based drugs. The results suggested that VL-LDP-AE would be a promising candidate for tumor targeting therapy. And the 2-step approach could serve as a new technology platform for making a series of highly potent engineered antibody-based drugs for a variety of cancers.
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Affiliation(s)
- QingFang Miao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050, China
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Abstract
This review is a comprehensive survey of acetylenic lipids and their derivatives, obtained from living organisms, that have anticancer activity. Acetylenic metabolites belong to a class of molecules containing triple bond(s). They are found in plants, fungi, microorganisms, and marine invertebrates. Although acetylenes are common as components of terrestrial plants, fungi, and bacteria, it is only within the last 30 years that biologically active polyacetylenes having unusual structural features have been reported from plants, cyanobacteria, algae, invertebrates, and other sources. Naturally occurring aquatic acetylenes are of particular interest since many of them display important biological activities and possess antitumor, antibacterial, antimicrobial, antifouling, antifungal, pesticidal, phototoxic, HIV-inhibitory, and immunosuppressive properties. There is no doubt that they are of great interest, especially for the medicinal and/or pharmaceutical industries. This review presents structures and describes cytotoxic and anticancer activities only for more than 300 acetylenic lipids and their derivatives isolated from living organisms.
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Affiliation(s)
- Valery M Dembitsky
- Department of Medicinal Chemistry and Natural Products, School of Pharmacy, P.O. Box 12065, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
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Miao QF, Liu XY, Shang BY, Ouyang ZG, Zhen YS. An enediyne-energized single-domain antibody-containing fusion protein shows potent antitumor activity. Anticancer Drugs 2007; 18:127-37. [PMID: 17159599 DOI: 10.1097/cad.0b013e3280112779] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Single-domain antibodies are attractive as tumor-targeting vehicles because of their much smaller size than intact antibody molecules. Lidamycin is a macromolecular antitumor antibiotic, which consists of a labile enediyne chromophore (AE) and a noncovalently bound apoprotein (LDP). An enediyne-energized fusion protein VH-LDP-AE composed of single-domain antibody directed against type IV collagenase and lidamycin was prepared by a novel two-step method including DNA recombination and molecular reconstitution. VH-LDP-AE demonstrated extremely potent cytotoxicity to cancer cells and marked antiangiogenic activity in vitro. In the mouse hepatoma 22 model, drugs were administered intravenously as a single dose on day 1 with maximal tolerated doses. VH-LDP-AE (0.25 mg/kg) suppressed the tumor growth by 95.9%, whereas lidamycin (0.05 mg/kg) and mitomycin (1 mg/kg) by 79.6 and 51.1%, respectively. In the HT-1080 xenograft model in nude mice, drugs were given intravenously as a single dose on day 4 after tumor implantation. VH-LDP-AE at 0.25 mg/kg suppressed tumor growth by 76% (P<0.05) compared with that of lidamycin at 0.05 mg/kg (53%) on day 18. No obvious toxic effects were observed in all groups during treatments. The results showed that energized fusion protein VH-LDP-AE was more effective than lidamycin and mitomycin. These properties, together with its much smaller size than conventional antibody-based agents, suggested that VH-LDP-AE would be a promising candidate for cancer-targeting therapy. In addition, the two-step approach could serve as a new technology platform for making a series of highly potent engineered antibody-based drugs for a variety of cancers.
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Affiliation(s)
- Qing-fang Miao
- Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, #1 Tiantan Xili, Beijing 100050, PRC
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Inoue M, Usuki T, Lee N, Hirama M, Tanaka T, Hosoi F, Ohie S, Otani T. Antitumor Enediyne Chromoprotein C-1027: Mechanistic Investigation of the Chromophore-Mediated Self-Decomposition Pathway. J Am Chem Soc 2006; 128:7896-903. [PMID: 16771503 DOI: 10.1021/ja060724w] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
C-1027 is an extremely potent antitumor agent that causes double-stranded DNA cleavages. It is a unique small molecule-protein complex composed of a highly reactive enediyne chromophore, which upon binding reacts with its target molecule DNA through radical-mediated hydrogen abstraction and an apoprotein that encapsulates the chromophore serving as its carrier to reach DNA. Although C-1027 has favorable properties as an effective drug delivery system, it slowly self-decomposes due to the reactivity of the chromophore toward the apoprotein. Understanding how the C-1027 destroys itself may enable design of its analogues that overcome this limitation. In this paper, mechanistic insights into the self-reactivity of C-1027 that facilitates its own decomposition are described. We provide evidence that the formation of the Gly96 radical, which promotes the oxidative protein scission and the subsequent chromophore release, is the major pathway for the self-decomposition of C-1027. On the basis of the newly isolated products of the self-decomposition, we propose that the apoprotein effectively protects two different structural elements of the chromophore that are essential for its biological activity: the nine-membered enediyne moiety (necessary for DNA cleavage) and the benzoxazine moiety (necessary for DNA intercalation). Using an engineered apoprotein analogue kinetically more stable toward the chromophore radical, we show that enhanced overall properties can be achieved for the natural C-1027 with respect to stability and antitumor activities. The results present the first example of a rationally designed C-1027 analogue reported to display superior in vitro antitumor activity to the natural C-1027. Our findings may have implications for design of proteins that can stably encapsulate highly reactive small molecules.
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Affiliation(s)
- Masayuki Inoue
- Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan.
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Inoue M. Exploring the Chemistry and Biology of Antitumor Enediyne Chromoprotein C-1027. BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN 2006. [DOI: 10.1246/bcsj.79.501] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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