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1
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Li T, Jiang S, Li T, Xu H, Zhang X, Yan R, Wu X, Jin Y, Wang Z. Exploring the Potential of Cyclic Peptidyl Antitumor Agents Derived from Natural Macrocyclic Peptide Phakellistatin 13. J Med Chem 2024; 67:11789-11813. [PMID: 38990190 DOI: 10.1021/acs.jmedchem.4c00393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/12/2024]
Abstract
The exploration of novel anticancer compounds based on natural cyclopeptides has emerged as a pivotal paradigm in the contemporary advancement of macrocyclic pharmaceuticals. Phakellistatin 13 is a cycloheptapeptide derived from the brown snubby sponge and exhibits remarkable antitumor activity. In this study, we have designed and synthesized a series of chiral cyclopeptides incorporating the rigid isoindolinone moiety at various sites within the natural cycloheptapeptide Phakellistatin 13, with the aim of investigating conformationally constrained cyclopeptides as potential antitumor agents. Cyclopeptide 3, comprising alternating l-/d-amino acid residues, exhibited promising antihepatocellular carcinoma effects. Detailed biological experiments have revealed that Phakellistatin 13 analogs effectively inhibit the proliferation of tumor cells and induce apoptosis and autophagy, while also causing cell cycle arrest through the modulation of the p53 and mitogen-activated protein kinase (MAPK) signaling pathway. This study not only provides valuable insights into chemical structural modifications but also contributes to a deeper understanding of the biological mechanisms underlying the development of natural cyclopeptide-based drugs.
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Affiliation(s)
- Tong Li
- Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, College of Chemistry & Chemical Engineering, Harbin Normal University, Harbin 150025, China
| | - Shitian Jiang
- Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, College of Chemistry & Chemical Engineering, Harbin Normal University, Harbin 150025, China
| | - Tingting Li
- Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, College of Chemistry & Chemical Engineering, Harbin Normal University, Harbin 150025, China
| | - Hongyu Xu
- Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, College of Chemistry & Chemical Engineering, Harbin Normal University, Harbin 150025, China
| | - Xiong Zhang
- Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, College of Chemistry & Chemical Engineering, Harbin Normal University, Harbin 150025, China
| | - Rui Yan
- Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, College of Chemistry & Chemical Engineering, Harbin Normal University, Harbin 150025, China
| | - Xiaodan Wu
- Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, College of Chemistry & Chemical Engineering, Harbin Normal University, Harbin 150025, China
| | - Yingxue Jin
- Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, College of Chemistry & Chemical Engineering, Harbin Normal University, Harbin 150025, China
| | - Zhiqiang Wang
- Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, College of Chemistry & Chemical Engineering, Harbin Normal University, Harbin 150025, China
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Wang X, Zhao Z, Guo J, Wang J, Zhao J. Synthesis of 3-sulfonylisoindolin-1-ones from olefinic amides and sodium sulfinates via electrooxidative tandem cyclization. Org Biomol Chem 2024; 22:5897-5901. [PMID: 38967547 DOI: 10.1039/d4ob00980k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/06/2024]
Abstract
Sulfonyl groups are motifs that are widely found in biologically active compounds and drug molecules, many isolated natural products as well as pharmaceuticals contain sulfonyl groups. Herein, we present the synthesis of sulfonyl-substituted isoindolones by a electrochemical oxidative radical cascade cycloaddition reaction of olefinic amides with sodium sulfite under oxidant- and catalyst-free conditions. Various olefinic amides and sodium sulfinates were compatible and gave the desired products in yields up to 99%.
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Affiliation(s)
- Xuecheng Wang
- State Key Laboratory of New Pharmaceutical Preparations and Excipients, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Materials Science, Hebei University, Baoding, Hebei, 071002, P. R. China.
| | - Ziyue Zhao
- State Key Laboratory of New Pharmaceutical Preparations and Excipients, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Materials Science, Hebei University, Baoding, Hebei, 071002, P. R. China.
| | - Jiajie Guo
- State Key Laboratory of New Pharmaceutical Preparations and Excipients, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Materials Science, Hebei University, Baoding, Hebei, 071002, P. R. China.
| | - Jijin Wang
- State Key Laboratory of New Pharmaceutical Preparations and Excipients, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Materials Science, Hebei University, Baoding, Hebei, 071002, P. R. China.
| | - Jincan Zhao
- State Key Laboratory of New Pharmaceutical Preparations and Excipients, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Materials Science, Hebei University, Baoding, Hebei, 071002, P. R. China.
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3
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Guzmán Ramírez JE, Mancilla Percino T. Synthesis of N-aminophalimides derived from α-amino acids: Theoretical study to find them as HDAC8 inhibitors by docking simulations and in vitro assays. Chem Biol Drug Des 2023; 102:1367-1386. [PMID: 37641461 DOI: 10.1111/cbdd.14323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 08/02/2023] [Accepted: 08/03/2023] [Indexed: 08/31/2023]
Abstract
Phthalimides are valuable for synthesis and biological properties. New acetamides 3(a-c) and 4(a-c) were synthesized and characterized as precursors for novel N-aminophalimides 5(a-c) and 6(a-c). Structures of 4a, 5(a-b), and 6(a-b) were confirmed by single crystal X-ray. Docking studies identified compounds with favorable Gibbs free energy values for binding to histone deacetylase 8 (HDAC8), an enzyme targeted for anticancer drug development. These compounds bound to both the orthosteric and allosteric pockets of HDAC8, similar to Trichostatin A (TSA), an HDAC8 inhibitor. 6(a-c) contain hydroxyacetamide moiety as a zinc-binding group, a phthalimide moiety as a capping group, and aminoacetamide moiety as a linker group, which are important for ligand-receptor binding. ΔG values indicated that compounds 5b, 6b, and 6c had higher affinity for HDAC8 in the allosteric pocket compared to TSA. In vitro evaluation of inhibitory activities on HDAC8 revealed that compounds 3(a-c) and 5(a-c) showed similar inhibitory effects (IC50 ) ranging from 0.445 to 0.751 μM. Compounds 6(a-c) showed better affinity, with 6a (IC50 = 28 nM) and 6b (IC50 = 0.18 μM) showing potent inhibitory effects slightly lower than TSA (IC50 = 26 nM). These findings suggest that the studied compounds hold promise as potential candidates for further biological investigations.
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Affiliation(s)
- José Eduardo Guzmán Ramírez
- Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, Mexico
| | - Teresa Mancilla Percino
- Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, Mexico
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4
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Peng J, Xie F, Qin P, Liu Y, Niu H, Sun J, Xue H, Zhao Q, Liu J, Wu J. Recent development of selective inhibitors targeting the HDAC6 as anti-cancer drugs: Structure, function and design. Bioorg Chem 2023; 138:106622. [PMID: 37244230 DOI: 10.1016/j.bioorg.2023.106622] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 05/09/2023] [Accepted: 05/19/2023] [Indexed: 05/29/2023]
Abstract
HDAC6, a member of the histone deacetylase family, mainly is a cytosolic protein and regulates cell growth by acting on non-histone substrates, such as α -tubulin, cortactin, heat shock protein HSP90, programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), that are closely related to the proliferation, invasion, immune escape and angiogenesis of cancer tissues. The approved drugs targeting the HDACs are all pan-inhibitors and have many side effects due to their lack of selectivity. Therefore, development of selective inhibitors of HDAC6 has attracted much attention in the field of cancer therapy. In this review, we will summarize the relationship between HDAC6 and cancer, and discuss the design strategies of HDAC6 inhibitors for cancer treatment in recent years.
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Affiliation(s)
- Jie Peng
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, PR China
| | - Fei Xie
- Department of Pharmacy, Qilu Hospital of Shandong University, Jinan 250012, PR China
| | - Pengxia Qin
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, PR China
| | - Yujing Liu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, PR China
| | - Haoqian Niu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, PR China
| | - Jie Sun
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, PR China
| | - Haoyu Xue
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, PR China
| | - Qianlong Zhao
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, PR China
| | - Jingqian Liu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, PR China
| | - Jingde Wu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, PR China.
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Matore BW, Banjare P, Sarthi AS, Roy PP, Singh J. Phthalimides Represent a Promising Scaffold for Multi‐Targeted Anticancer Agents. ChemistrySelect 2023. [DOI: 10.1002/slct.202204851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2023]
Affiliation(s)
- Balaji Wamanrao Matore
- Department of Pharmacy Guru Ghasidas Vishwavidyalaya (A Central University) Bilaspur Chhattisgarh 495009 India
| | - Purusottam Banjare
- Department of Pharmacy Guru Ghasidas Vishwavidyalaya (A Central University) Bilaspur Chhattisgarh 495009 India
| | - Ajay Singh Sarthi
- Rungta College of Pharmaceutical Sciences and Research Raipur Chhattisgarh 492009 India
| | - Partha Pratim Roy
- Department of Pharmacy Guru Ghasidas Vishwavidyalaya (A Central University) Bilaspur Chhattisgarh 495009 India
| | - Jagadish Singh
- Department of Pharmacy Guru Ghasidas Vishwavidyalaya (A Central University) Bilaspur Chhattisgarh 495009 India
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Korkmaz IN, Özdemir H. Synthesis and Anticancer Potential of New Hydroxamic Acid Derivatives as Chemotherapeutic Agents. Appl Biochem Biotechnol 2022; 194:6349-6366. [PMID: 35917102 DOI: 10.1007/s12010-022-04107-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/15/2022] [Indexed: 11/25/2022]
Abstract
Histone deacetylase (HDAC) inhibitors have been shown to induce differentiation, cell cycle arrest, and apoptosis due to their low toxicity, inhibiting migration, invasion, and angiogenesis in many cancer cells. Studies show that hydroxamic acids are generally used as anticancers. For this reason, it is aimed to synthesize new derivatives of hydroxamic acids, to examine the anticancer properties of these candidate inhibitors, and to investigate the inhibition effects on some enzymes that cause multidrug resistance in cancer cells. For this reason, new (4-amino-2-methoxy benzohydroxamic acid (a), 4-amino-3-methyl benzohydroxamic acid (b), 3-amino-5-methyl benzohydroxamic acid (c)) amino benzohydroxamic acid derivatives were synthesized in this study. The effects on healthy fibroblast, lung (A549), and cervical (HeLa) cancer cells were investigated. In addition, their effects on TRXR1, GST, and GR activities, which are important for the development of chemotherapeutic strategies, were also examined. It was determined that molecule b was the most effective molecule in HeLa cancer cells with the lowest IC50 value of 0.54. It was determined that molecule c was the most effective molecules for A549 and HeLa cancer cells, with the lowest IC50 values of 0.78 mM and 0.25 mM, respectively. It was determined that b and c molecules directed cancer cells to necrosis rather than apoptosis. c molecule showed anticancer effect in A549 and HeLa cancer cells. It was found that molecule c significantly suppressed both GR and TRXR1 activities. In GST activities, however, inhibitors did not have a significant effect on cancer cells.
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Affiliation(s)
- Işıl Nihan Korkmaz
- Faculty of Science, Department of Chemistry, Atatürk University, Erzurum, 25240, Turkey
| | - Hasan Özdemir
- Faculty of Science, Department of Chemistry, Atatürk University, Erzurum, 25240, Turkey.
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7
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Xiong M, Shu Y, Tang J, Yang F, Xing D. Iridium(I)-Catalyzed Isoindolinone-Directed Branched-Selective Aromatic C-H Alkylation with Simple Alkenes. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27061923. [PMID: 35335286 PMCID: PMC8954050 DOI: 10.3390/molecules27061923] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/05/2022] [Accepted: 03/10/2022] [Indexed: 12/18/2022]
Abstract
We report an iridium(I)-catalyzed branched-selective C–H alkylation of N-arylisoindolinones with simple alkenes as the alkylating agents. The amide carbonyl group of the isoindolinone motif acts as the directing group to assist the ortho C–H activation of the N-aryl ring. With this atom-economic and highly branched-selective protocol, an array of biologically relevant N-arylisoindolinones were obtained in good yields. Asymmetric control was achieved with up to 87:13 er when a BiPhePhos-like chiral ligand was employed.
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8
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Mellah M, Zhang YF. Samarium(II)-Electrocatalyzed Chemoselective Reductive Alkoxylation of Phthalimides. Org Chem Front 2022. [DOI: 10.1039/d1qo01760h] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The unprecedented samarium-eletrocatalyzed reductive alkoxylation of phthalimides in a single step is presented. Under mild conditions, using electrogenerated Sm(II) with TMSCl (trimethyl chlorosilane), N-substituted 3-alkoxyl isoindolin-1-ones are isolated in good...
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9
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Zou Z, Cai G, Chen W, Zou C, Li Y, Wu H, Chen L, Hu J, Li Y, Huang Y. Metal-Free Cascade Formation of Intermolecular C-N Bonds Accessing Substituted Isoindolinones under Cathodic Reduction. J Org Chem 2021; 86:15777-15784. [PMID: 34699211 DOI: 10.1021/acs.joc.1c01845] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
An electrochemical protocol for the construction of substituted isoindolinones via reduction/amidation of 2-carboxybenzaldehydes and amines has been realized. Under metal-free and external-reductant-free electrolytic conditions, the reaction achieves the cascade formation of intermolecular C-N bonds and provides a series of isoindolinones in moderate to good yields. The deuterium-labeling experiment proves that the hydrogen in the methylene of the product is mainly provided by H2O in the system.
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Affiliation(s)
- Zirong Zou
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529090, P. R. China
| | - Genuo Cai
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529090, P. R. China
| | - Weihao Chen
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529090, P. R. China
| | - Canlin Zou
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529090, P. R. China
| | - Yamei Li
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529090, P. R. China
| | - Hongting Wu
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529090, P. R. China
| | - Lu Chen
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529090, P. R. China
| | - Jinhui Hu
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529090, P. R. China
| | - Yibiao Li
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529090, P. R. China
| | - Yubing Huang
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529090, P. R. China
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10
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Chen N, Zheng Q, Wan G, Guo F, Zeng X, Shi P. Impact of posttranslational modifications in pancreatic carcinogenesis and treatments. Cancer Metastasis Rev 2021; 40:739-759. [PMID: 34342796 DOI: 10.1007/s10555-021-09980-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/06/2021] [Indexed: 01/22/2023]
Abstract
Pancreatic cancer (PC) is a highly aggressive cancer, with a 9% 5-year survival rate and a high risk of recurrence. In part, this is because PC is composed of heterogeneous subgroups with different biological and functional characteristics and personalized anticancer treatments are required. Posttranslational modifications (PTMs) play an important role in modifying protein functions/roles and are required for the maintenance of cell viability and biological processes; thus, their dysregulation can lead to disease. Different types of PTMs increase the functional diversity of the proteome, which subsequently influences most aspects of normal cell biology or pathogenesis. This review primarily focuses on ubiquitination, SUMOylation, and NEDDylation, as well as the current understanding of their roles and molecular mechanisms in pancreatic carcinogenesis. Additionally, we briefly summarize studies and clinical trials on PC treatments to advance our knowledge of drugs available to target the ubiquitination, SUMOylation, and NEDDylation PTM types. Further investigation of PTMs could be a critical field of study in relation to PC, as they have been implicated in the initiation and progression of many other types of cancer.
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Affiliation(s)
- Nianhong Chen
- Center Lab of Longhua Branch and Department of Infectious Disease, Shenzhen People's Hospital, 2Nd Clinical Medical College, Jinan University, Guangzhou, People's Republic of China.
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Medicine School, Guangdong Province, Shenzhen University, Shenzhen, 518037, People's Republic of China.
- Department of Cell Biology & University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
- Laboratory of Signal Transduction, Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
| | - Qiaoqiao Zheng
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Guoqing Wan
- Center Lab of Longhua Branch and Department of Infectious Disease, Shenzhen People's Hospital, 2Nd Clinical Medical College, Jinan University, Guangzhou, People's Republic of China
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Medicine School, Guangdong Province, Shenzhen University, Shenzhen, 518037, People's Republic of China
| | - Feng Guo
- Department of Medicine, Stanford School of Medicine, Stanford, CA, 94305, USA
| | - Xiaobin Zeng
- Center Lab of Longhua Branch and Department of Infectious Disease, Shenzhen People's Hospital, 2Nd Clinical Medical College, Jinan University, Guangzhou, People's Republic of China.
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Medicine School, Guangdong Province, Shenzhen University, Shenzhen, 518037, People's Republic of China.
| | - Ping Shi
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China.
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Upadhyay SP, Thapa P, Sharma R, Sharma M. 1-Isoindolinone scaffold-based natural products with a promising diverse bioactivity. Fitoterapia 2020; 146:104722. [PMID: 32920034 DOI: 10.1016/j.fitote.2020.104722] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/03/2020] [Accepted: 09/05/2020] [Indexed: 12/21/2022]
Abstract
Isoindolin-1-one or 1-isoindolinone framework is referred to phthalimidines or benzo fused γ-lactams of the corresponding γ-amino carboxylic acids and has been of prime interest for scientists for last several decades. 1-Isoindolinone framework is found in a wide range of naturally occurring compounds with diverse biological activities and therapeutic potential for various chronic diseases. Recent developments in synthetic methods for their procurement have opened a new era of 1-isoindolinone chemistry. This review aims to provide an alphabetical quick reference guide to only 1-isoindolinone based natural products and its variable fused, oxidized and reduced state skeleton with information for advanced chemotaxonomic analyses, cellular targets/pathways and diverse biological activities and future use for medicinal chemistry.
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Affiliation(s)
- Sunil P Upadhyay
- Drug Discovery Program, KCVA Medical Center, Midwest Veterans' Biomedical Research Foundation, Kansas City, MO 64128, United States.
| | - Pritam Thapa
- Drug Discovery Program, KCVA Medical Center, Midwest Veterans' Biomedical Research Foundation, Kansas City, MO 64128, United States
| | - Ram Sharma
- Drug Discovery Program, KCVA Medical Center, Midwest Veterans' Biomedical Research Foundation, Kansas City, MO 64128, United States
| | - Mukut Sharma
- Drug Discovery Program, KCVA Medical Center, Midwest Veterans' Biomedical Research Foundation, Kansas City, MO 64128, United States
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12
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Shaaban S, Davies C, Merten C, Flegel J, Otte F, Strohmann C, Waldmann H. Rh III -Catalyzed C-H Activation of Aryl Hydroxamates for the Synthesis of Isoindolinones. Chemistry 2020; 26:10729-10734. [PMID: 32428319 PMCID: PMC7496876 DOI: 10.1002/chem.202002384] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Indexed: 01/20/2023]
Abstract
RhIII -catalyzed C-H functionalization reaction yielding isoindolinones from aryl hydroxamates and ortho-substituted styrenes is reported. The reaction proceeds smoothly under mild conditions at room temperature, and tolerates a range of functional groups. Experimental and computational investigations support that the high regioselectivity observed for these substrates results from the presence of an ortho-substituent embedded in the styrene. The resulting isoindolinones are valuable building blocks for the synthesis of bioactive compounds. They provide easy access to the natural-product-like compounds, isoindolobenzazepines, in a one-pot two-step reaction. Selected isoindolinones inhibited Hedgehog (Hh)-dependent differentiation of multipotent murine mesenchymal progenitor stem cells into osteoblasts.
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Affiliation(s)
- Saad Shaaban
- Max-Planck-Institute of Molecular PhysiologyDepartment of Chemical BiologyOtto-Hahn-Strasse 1144227DortmundGermany
| | - Caitlin Davies
- Max-Planck-Institute of Molecular PhysiologyDepartment of Chemical BiologyOtto-Hahn-Strasse 1144227DortmundGermany
- Technical University DortmundFaculty of Chemical BiologyOtto-Hahn-Strasse 4a44227DortmundGermany
| | - Christian Merten
- Ruhr University BochumOrganic Chemistry IIUniversitätsstrasse 15044801BochumGermany
| | - Jana Flegel
- Max-Planck-Institute of Molecular PhysiologyDepartment of Chemical BiologyOtto-Hahn-Strasse 1144227DortmundGermany
- Technical University DortmundFaculty of Chemical BiologyOtto-Hahn-Strasse 4a44227DortmundGermany
| | - Felix Otte
- Technical University DortmundDepartment of Inorganic ChemistryOtto-Hahn-Strasse 644227DortmundGermany
| | - Carsten Strohmann
- Technical University DortmundDepartment of Inorganic ChemistryOtto-Hahn-Strasse 644227DortmundGermany
| | - Herbert Waldmann
- Max-Planck-Institute of Molecular PhysiologyDepartment of Chemical BiologyOtto-Hahn-Strasse 1144227DortmundGermany
- Technical University DortmundFaculty of Chemical BiologyOtto-Hahn-Strasse 4a44227DortmundGermany
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14
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Cabrero-Antonino JR, Adam R, Papa V, Holsten M, Junge K, Beller M. Unprecedented selective homogeneous cobalt-catalysed reductive alkoxylation of cyclic imides under mild conditions. Chem Sci 2017; 8:5536-5546. [PMID: 28970933 PMCID: PMC5618770 DOI: 10.1039/c7sc01175j] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 06/05/2017] [Indexed: 01/02/2023] Open
Abstract
The first general and efficient non-noble metal-catalysed reductive C2-alkoxylation of cyclic imides (phthalimides and succinimides) is presented. Crucial for the success is the use of [Co(BF4)2·6H2O/triphos (L1)] combination and no external additives are required.
The first general and efficient non-noble metal-catalysed reductive C2-alkoxylation of cyclic imides (phthalimides and succinimides) is presented. Crucial for the success is the use of [Co(BF4)2·6H2O/triphos (L1)] combination and no external additives are required. Using the optimal cobalt-system, the hydrogenation of the aromatic ring of the parent phthalimide is avoided and only one of the carbonyl groups is selectively functionalized. The resulting products, N- and aryl-ring substituted 3-alkoxy-2,3-dihydro-1H-isoindolin-1-one and N-substituted 3-alkoxy-pyrrolidin-2-one derivatives, are prepared under mild conditions in good to excellent isolated yields. Intramolecular reductive couplings can also be performed affording tricyclic compounds in a one-step process. The present protocol opens the way to the development of new base-metal processes for the straightforward synthesis of functionalized N-heterocyclic compounds of pharmaceutical and biological interest.
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Affiliation(s)
- Jose R Cabrero-Antonino
- Leibniz-Institut für Katalyse e.V. an der Universität Rostock , Albert-Einstein-Straße 29a , 18059 Rostock , Germany .
| | - Rosa Adam
- Leibniz-Institut für Katalyse e.V. an der Universität Rostock , Albert-Einstein-Straße 29a , 18059 Rostock , Germany .
| | - Veronica Papa
- Leibniz-Institut für Katalyse e.V. an der Universität Rostock , Albert-Einstein-Straße 29a , 18059 Rostock , Germany .
| | - Mattes Holsten
- Leibniz-Institut für Katalyse e.V. an der Universität Rostock , Albert-Einstein-Straße 29a , 18059 Rostock , Germany .
| | - Kathrin Junge
- Leibniz-Institut für Katalyse e.V. an der Universität Rostock , Albert-Einstein-Straße 29a , 18059 Rostock , Germany .
| | - Matthias Beller
- Leibniz-Institut für Katalyse e.V. an der Universität Rostock , Albert-Einstein-Straße 29a , 18059 Rostock , Germany .
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15
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Zhao L, Zhang H, Tan G, Wang Z, Jin Y. Photo-induced synthesis and in vitro biological activity of a Sansalvamide A analog. Tetrahedron Lett 2017. [DOI: 10.1016/j.tetlet.2017.03.042] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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16
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Giofrè SV, Cirmi S, Mancuso R, Nicolò F, Lanza G, Legnani L, Campisi A, Chiacchio MA, Navarra M, Gabriele B, Romeo R. Synthesis of spiro[isoindole-1,5'-isoxazolidin]-3(2 H)-ones as potential inhibitors of the MDM2-p53 interaction. Beilstein J Org Chem 2017; 12:2793-2807. [PMID: 28144352 PMCID: PMC5238597 DOI: 10.3762/bjoc.12.278] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 12/08/2016] [Indexed: 01/05/2023] Open
Abstract
A series of spiro[isoindole-1,5-isoxazolidin]-3(2H)-ones has been synthesized by 1,3-dipolar cycloaddition of N-benzylnitrone with isoindolin-3-methylene-1-ones. The regio- and stereoselectivity of the process have been rationalized by computational methods. The obtained compounds show cytotoxic properties and antiproliferative activity in the range of 9–22 μM. Biological tests suggest that the antitumor activity could be linked to the inhibition of the protein–protein p53-MDM2 interaction. Docking measurements support the biological data.
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Affiliation(s)
- Salvatore V Giofrè
- Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali, Via S.S. Annunziata, 98168 Messina, Italy
| | - Santa Cirmi
- Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali, Via S.S. Annunziata, 98168 Messina, Italy
| | - Raffaella Mancuso
- Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, Via P. Bucci, 12/C, 87036 Arcavacata di Rende (CS), Italy
| | - Francesco Nicolò
- Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali, Università di Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy
| | - Giuseppe Lanza
- Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria, 95100 Catania, Italy
| | - Laura Legnani
- Dipartimento di Chimica, Università di Pavia, Via Taramelli 12, 27100 Pavia, Italy
| | - Agata Campisi
- Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria, 95100 Catania, Italy
| | - Maria A Chiacchio
- Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria, 95100 Catania, Italy; Dipartimento di Chimica, Università di Pavia, Via Taramelli 12, 27100 Pavia, Italy
| | - Michele Navarra
- Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali, Via S.S. Annunziata, 98168 Messina, Italy
| | - Bartolo Gabriele
- Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, Via P. Bucci, 12/C, 87036 Arcavacata di Rende (CS), Italy
| | - Roberto Romeo
- Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali, Via S.S. Annunziata, 98168 Messina, Italy
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17
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Chen T, Cai C. An efficient approach to 3-oxoisoindoline-1-difluoroalkyl derivatives via a metal triflate-catalyzed Mannich/lactamization cascade reaction. NEW J CHEM 2017. [DOI: 10.1039/c6nj03813a] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
An efficient approach for the synthesis of N-substituted 3-oxoisoindoline-1-difluoroalkyl derivatives via a one-pot cascade reaction has been developed.
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Affiliation(s)
- Tingting Chen
- College of Chemical Engineering
- Nanjing University of Science & Technology
- Nanjing
- China
| | - Chun Cai
- College of Chemical Engineering
- Nanjing University of Science & Technology
- Nanjing
- China
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18
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Kumar S, Kumar A, Kumar N, Roy P, Sondhi SM. Grinding and Microwave-assisted Synthesis of Heterocyclic Molecules in High Yields and Their Biological Evaluation. J Heterocycl Chem 2016. [DOI: 10.1002/jhet.2481] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Sandeep Kumar
- Department of Chemistry; Indian Institute of Technology-Roorkee; Roorkee 247667 Uttarakhand India
| | - Anuj Kumar
- Department of Chemistry; Indian Institute of Technology-Roorkee; Roorkee 247667 Uttarakhand India
| | - Nikhil Kumar
- Department of Biotechnology; Indian Institute of Technology-Roorkee; Roorkee 247667 Uttarakhand India
| | - Partha Roy
- Department of Biotechnology; Indian Institute of Technology-Roorkee; Roorkee 247667 Uttarakhand India
| | - Sham M. Sondhi
- Department of Chemistry; Indian Institute of Technology-Roorkee; Roorkee 247667 Uttarakhand India
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19
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Manal M, Chandrasekar M, Gomathi Priya J, Nanjan M. Inhibitors of histone deacetylase as antitumor agents: A critical review. Bioorg Chem 2016; 67:18-42. [DOI: 10.1016/j.bioorg.2016.05.005] [Citation(s) in RCA: 143] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 04/29/2016] [Accepted: 05/15/2016] [Indexed: 12/11/2022]
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20
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Yang BW, Ho SL, Lim HJ, Cho CS. Palladium-catalyzed carbonylative cyclization of 2-(2-bromovinyl)benzimidazoles leading to pyrrolone-fused benzimidazoles. J Organomet Chem 2016. [DOI: 10.1016/j.jorganchem.2015.12.040] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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21
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Mancilla-Percino T, Trejo-Muñoz CR, Díaz-Gandarilla JA, Talamás-Rohana P, Guzmán Ramírez JE, Cervantes J, Figueroa Ortíz A. Isoindoline Derivatives of α-Amino Acids as Cyclooxygenase 1 and 2 Inhibitors. Arch Pharm (Weinheim) 2016; 349:175-85. [PMID: 26762192 DOI: 10.1002/ardp.201500372] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Revised: 12/04/2015] [Accepted: 12/11/2015] [Indexed: 11/12/2022]
Abstract
IC50 values were obtained for two series of isoindolines derived from α-amino acids over cyclooxygenase 1 and 2 (COX-1 and COX-2). In order to explain the biological activity observed, a structure-activity relationship (SAR) model was achieved for the tested compounds and 19 reference compounds with known selective inhibitory activity, through the correlation of the binding energies calculated from rigid docking of the best conformations into the catalytic sites of COX-1 and COX-2, as well as their molecular descriptors: Log P, molecular weight (MW), volume (V), and solvation energy (Esol) versus their experimental IC50 values by MLR and LS-SVM methods. The model probed whether the COX-1 and COX-2 inhibitory activities of the isoindolines correlate with steric, hydrophobic, and thermodynamic parameters. The correlation values with MLR for COX-1 and COX-2 (r(2) = 0.4193 and r(2) = 0.5929) were optimized with LS-SVM until r(2) = 0.6818 for COX-1 and r(2) = 0.8985 for COX-2, resulting in a good predictive ability for COX-1 and -2 inhibition with this model. In conclusion, the data suggests that the physicochemical descriptors evaluated have an impact on the inhibitory activity and selectivity of isoindolines over COX-1 and COX-2.
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Affiliation(s)
- Teresa Mancilla-Percino
- Department of Chemistry, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico
| | - Cynthia R Trejo-Muñoz
- Department of Chemistry, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico
| | - José Alfredo Díaz-Gandarilla
- Department of Microbiology and Parasitology, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Patricia Talamás-Rohana
- Department of Infectomic and Molecular Pathogenesis, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico
| | - José Eduardo Guzmán Ramírez
- Department of Chemistry, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico
| | - Jair Cervantes
- Universidad Autónoma del Estado de México, UAEMEX-Texcoco, Estado de Mexico Mexico, Mexico
| | - Armando Figueroa Ortíz
- Instituto de Ciencias Nucleares, Universidad Nacional Autónoma de México, Mexico City, Mexico
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22
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Chen T, Cai C. Sc(OTf)3-catalyzed three-component cascade reaction: One-pot synthesis of substituted 3-oxoisoindoline-1-carbonitrile derivatives. CATAL COMMUN 2016. [DOI: 10.1016/j.catcom.2015.11.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
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23
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Gandhamsetty N, Jeong J, Park J, Park S, Chang S. Boron-Catalyzed Silylative Reduction of Nitriles in Accessing Primary Amines and Imines. J Org Chem 2015; 80:7281-7. [DOI: 10.1021/acs.joc.5b00941] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Narasimhulu Gandhamsetty
- Center
for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 305-701, Korea
- Department
of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea
| | - Jinseong Jeong
- Center
for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 305-701, Korea
- Department
of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea
| | - Juhyeon Park
- Center
for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 305-701, Korea
- Department
of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea
| | - Sehoon Park
- Center
for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 305-701, Korea
- Department
of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea
| | - Sukbok Chang
- Center
for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 305-701, Korea
- Department
of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea
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24
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Novel phenyl and pyridyl substituted derivatives of isoindolines: Synthesis, antitumor activity and DNA binding features. Eur J Med Chem 2014; 87:372-85. [DOI: 10.1016/j.ejmech.2014.09.079] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Revised: 09/15/2014] [Accepted: 09/24/2014] [Indexed: 11/23/2022]
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25
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Pharmacophore modelling, validation, 3D virtual screening, docking, design and in silico ADMET simulation study of histone deacetylase class-1 inhibitors. Med Chem Res 2014. [DOI: 10.1007/s00044-014-1057-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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26
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Nadaf RN, Seapy DG. Palladium-Catalyzed Cross-Coupling Reactions of Potassium N-Methyltrifluoroborate Isoindolin-1-one with Aryl and Heteroaryl Chlorides. SYNTHETIC COMMUN 2014. [DOI: 10.1080/00397911.2014.884591] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Affiliation(s)
- Rashid N. Nadaf
- a Department of Chemistry , Texas A&M University at Qatar , Doha , Qatar
| | - Dave G. Seapy
- a Department of Chemistry , Texas A&M University at Qatar , Doha , Qatar
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27
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28
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Kumar S, Kumar N, Roy P, Sondhi SM. Synthesis, anti-inflammatory, and antiproliferative activity evaluation of isoindole, pyrrolopyrazine, benzimidazoisoindole, and benzimidazopyrrolopyrazine derivatives. Mol Divers 2013; 17:753-766. [PMID: 23979512 DOI: 10.1007/s11030-013-9472-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Accepted: 08/12/2013] [Indexed: 12/13/2022]
Abstract
A number of isoindole (3x, 3y, 6xa-6ye), pyrrolopyrazine (3z, 6za-6ze), benzimidazoisoindole (4x, 4y, 7xa-7ye), and benzimidazopyrrolopyrazine (4z, 7za-7ze) derivatives has been synthesized in excellent yields. All these compounds were fully characterized and evaluated against five human cancer cell lines for their anti-inflammatory and antiproliferative activity. Compounds 6yc and 7zd exhibited good anti-inflammatory activity whereas compounds 6zc, 7zd (lung NCl H-522), 6ye, 7xd, 7yd, 7zc, 7zd (colon HCT-15), 6xc, 7zc (ovary PA-1), 6xc, 6yb, 6zc (liver HepG-2) exhibited good antiproliferative activity.
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Affiliation(s)
- Sandeep Kumar
- Department of Chemistry, Indian Institute of Technology-Roorkee, Roorkee , 247667, UK, India
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29
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Foster RW, Tame CJ, Hailes HC, Sheppard TD. Highly Regioselective Synthesis of Substituted Isoindolinones via Ruthenium-Catalyzed Alkyne Cyclotrimerizations. Adv Synth Catal 2013; 355:2353-2360. [PMID: 24124414 PMCID: PMC3793232 DOI: 10.1002/adsc.201300055] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Revised: 05/23/2013] [Indexed: 11/08/2022]
Abstract
(Cyclooctadiene)(pentamethylcyclopentadiene)ruthenium chloride [Cp*RuCl(cod)] has been used to catalyze the regioselective cyclization of amide-tethered diynes with monosubstituted alkynes to give polysubstituted isoindolinones. Notably, the presence of a trimethylsilyl group on the diyne generally led to complete control over the regioselectivity of the alkyne cyclotrimerization. The cyclization reaction worked well in a sustainable non-chlorinated solvent and was tolerant of moisture. The optimized conditions were effective with a diverse range of alkynes and diynes. The 7-silylisoindolinone products could be halogenated, protodesilylated or ring opened to access a range of usefully functionalized products.
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Affiliation(s)
- Robert W Foster
- Department of Chemistry, University College London, Christopher Ingold LaboratoriesLondon, WC1H 0AJ, U.K. Fax: (+44)-(0)20-7679-7463; phone: (+44)-(0)20-7679-2467
| | - Christopher J Tame
- GlaxoSmithKline, Medicines Research CentreGunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
| | - Helen C Hailes
- Department of Chemistry, University College London, Christopher Ingold LaboratoriesLondon, WC1H 0AJ, U.K. Fax: (+44)-(0)20-7679-7463; phone: (+44)-(0)20-7679-2467
| | - Tom D Sheppard
- Department of Chemistry, University College London, Christopher Ingold LaboratoriesLondon, WC1H 0AJ, U.K. Fax: (+44)-(0)20-7679-7463; phone: (+44)-(0)20-7679-2467
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30
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Koutsounas I, Giaginis C, Patsouris E, Theocharis S. Current evidence for histone deacetylase inhibitors in pancreatic cancer. World J Gastroenterol 2013; 19:813-28. [PMID: 23430136 PMCID: PMC3574878 DOI: 10.3748/wjg.v19.i6.813] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Revised: 10/18/2011] [Accepted: 01/05/2013] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most aggressive human cancers, with more than 200 000 deaths worldwide every year. Despite recent efforts, conventional treatment approaches, such as surgery and classic chemotherapy, have only slightly improved patient outcomes. More effective and well-tolerated therapies are required to reverse the current poor prognosis of this type of neoplasm. Among new agents, histone deacetylase inhibitors (HDACIs) are now being tested. HDACIs have multiple biological effects related to acetylation of histones and many non-histone proteins that are involved in regulation of gene expression, apoptosis, cell cycle progression and angiogenesis. HDACIs induce cell cycle arrest and can activate the extrinsic and intrinsic pathways of apoptosis in different cancer cell lines. In the present review, the main mechanisms by which HDACIs act in pancreatic cancer cells in vitro, as well as their antiproliferative effects in animal models are presented. HDACIs constitute a promising treatment for pancreatic cancer with encouraging anti-tumor effects, at well-tolerated doses.
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Abstract
Hydroxamic acid is a potent moiety not only in the field of cancer therapy but also as a mutagenic agent. Among the various derivatives of hydroxamic acid, SAHA (Suberoylanilide Hydroxamic Acid) is considered as a potent anticancer agent. Scientists from the different corner synthesized different hydroxamic acid moieties with some straight chain oxazole, thiadiazole, biphenyl moieties in the terminal position. Acetylation and deacetylation of histones of the core proteins of nucleosomes in chromatin play an important role in the regulation of gene expression. The level of acetylation of histones is established and maintained by two classes of enzymes, histone acetyltransferase and histone deacetylases, which have been identified as transcriptional coactivators and transcriptional corepressors, respectively. There is increasing evidence that aberrant histone acetylation has been linked to various malignant diseases. Great efforts are currently underway for the design of more potent and less toxic candidates for the treatment of cancer. In recent years, hydroxamic acid derivatives have attracted increasing attention for their potential as highly efficacious in combating various etiological factors associated with cancer. Our main intention to draw an attention is that this single functional moiety has not only fit in the receptor but also create a diversified activity.
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Affiliation(s)
- Dilipkumar Pal
- Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Guru GhasidashVishwavidyalaya (A Central University), Koni, Bilashpur, India
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32
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Das S, Addis D, Knöpke LR, Bentrup U, Junge K, Brückner A, Beller M. Selective Catalytic Monoreduction of Phthalimides and Imidazolidine-2,4-diones. Angew Chem Int Ed Engl 2011; 50:9180-4. [DOI: 10.1002/anie.201104226] [Citation(s) in RCA: 106] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2011] [Indexed: 11/07/2022]
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Das S, Addis D, Knöpke LR, Bentrup U, Junge K, Brückner A, Beller M. Selective Catalytic Monoreduction of Phthalimides and Imidazolidine-2,4-diones. Angew Chem Int Ed Engl 2011. [DOI: 10.1002/ange.201104226] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Rajak H, Agarawal A, Parmar P, Thakur BS, Veerasamy R, Sharma PC, Kharya MD. 2,5-Disubstituted-1,3,4-oxadiazoles/thiadiazole as surface recognition moiety: design and synthesis of novel hydroxamic acid based histone deacetylase inhibitors. Bioorg Med Chem Lett 2011; 21:5735-8. [PMID: 21875796 DOI: 10.1016/j.bmcl.2011.08.022] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2011] [Revised: 07/31/2011] [Accepted: 08/03/2011] [Indexed: 01/04/2023]
Abstract
The enzymatic inhibition of histone deacetylase activity has come out as a novel and effectual means for the treatment of cancer. Two novel series of 2-[5-(4-substitutedphenyl)-[1,3,4]-oxadiazol/thiadiazol-2-ylamino]-pyrimidine-5-carboxylic acid (tetrahydro-pyran-2-yloxy)-amides were designed and synthesized as novel hydroxamic acid based histone deacetylase inhibitors. The antiproliferative activities of the compounds were investigated in vitro using histone deacetylase inhibitory assay and MTT assay. The synthesized compounds were also tested for antitumor activity against Ehrlich ascites carcinoma cells in Swiss albino mice. The efforts were also made to establish structure-activity relationships among synthesized compounds. The results of the present studying indicates 2,5-disubstituted 1,3,4-oxadiazole/thiadiazole as promising surface recognition moiety for development of newer hydroxamic acid based histone deacetylase inhibitor.
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Affiliation(s)
- Harish Rajak
- Medicinal Chemistry Research Laboratory, SLT Institute of Pharmaceutical Sciences, Guru Ghasidas University, Bilaspur 495 009, CG, India.
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35
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Unexpected formation of (Z)-3-(halomethylene)isoindolinones from gem-dihalovinylbenzonitriles: efficient synthesis of enyne-containing isoindolinones. Tetrahedron Lett 2011. [DOI: 10.1016/j.tetlet.2011.03.143] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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36
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Efficient access to (1H)-isoindolin-1-one-3-carboxylic acid derivatives by orthopalladation and carbonylation of methyl arylglycinate substrates. Tetrahedron 2011. [DOI: 10.1016/j.tet.2011.04.064] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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37
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Bertrand P. Inside HDAC with HDAC inhibitors. Eur J Med Chem 2010; 45:2095-116. [PMID: 20223566 DOI: 10.1016/j.ejmech.2010.02.030] [Citation(s) in RCA: 264] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2009] [Revised: 02/09/2010] [Accepted: 02/10/2010] [Indexed: 11/17/2022]
Abstract
Histone deacetylase inhibitors are a large group of diverse molecules intrinsically able to inhibit cell proliferation in various cancer cell lines. Their apoptotic effects have been linked to the modulation in the expression of several regulatory tumor suppressor genes caused by the modified status of histone acetylation, a key event in chromatin remodelling. As the initial histone deacetylase activity of HDAC has been extended to other proteins, the possible other biological mechanisms modified by HDAC inhibitor treatments are still to be clarified. The need for HDAC isoform selective inhibitors is an important issue to serve this goal. This review discusses the approaches proposed by several research groups working on the synthesis of HDAC inhibitors, based on modelling studies and the way these findings were used to obtain new HDAC inhibitors with possible isoform selectivity.
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Affiliation(s)
- Philippe Bertrand
- Laboratoire Synthèse et Réactivité des Substances Naturelles, Université de Poitiers, CNRS-UMR 6514, 40 Avenue du Recteur Pineau, Poitiers, F-86022, France.
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Abstract
IMPORTANCE OF THE FIELD Following FDA approval of vorinostat in 2006, several novel HDAC inhibitors (HDACis) have entered clinical trials, and there are numerous published patent applications claiming novel HDACis which were optimized as potential drug candidates, designed for regional or systemic release, and created as dual or multifunctional inhibitors. Given the breadth and depth of recent reporting of novel HDACis, there has emerged a need to review the field from a chemist's perspective in one compact article. AREAS COVERED IN THIS REVIEW This review provides a summary of published patent applications claiming novel HDACis from 2007 until mid-2009, covering mainly classes I, II and IV anticancer HDACis including those that have recently advanced to the clinic. WHAT THE READER WILL GAIN Readers will rapidly gain an overview of the majority of HDACi scaffolds with representative structure-activity relationships; they will learn how these new compounds were created, how their drug like properties were improved and which companies are the main players in the field. TAKE HOME MESSAGE Although competition in this field is intense, the future application of HDACis to treat human disease either as single agents or in combination with existing drugs holds real promise.
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Affiliation(s)
- Haishan Wang
- Chemistry Discovery, S*BIO Pte Ltd, The Capricorn, Singapore Science Park II, Singapore, Singapore.
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39
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Huang X, Xu J. One-Pot Facile Synthesis of Substituted Isoindolinones via an Ugi Four-Component Condensation/Diels−Alder Cycloaddition/ Deselenization−Aromatization Sequence. J Org Chem 2009; 74:8859-61. [DOI: 10.1021/jo901628a] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Xian Huang
- Department of Chemistry, Zhejiang University (Xixi Campus), Hangzhou 310028, People’s Republic of China
- State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People’s Republic of China
| | - Jianfeng Xu
- Department of Chemistry, Zhejiang University (Xixi Campus), Hangzhou 310028, People’s Republic of China
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Hashimoto Y. Thalidomide as a Multi-Template for Development of Biologically Active Compounds. Arch Pharm (Weinheim) 2008; 341:536-47. [DOI: 10.1002/ardp.200700217] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Salcedo A, Neuville L, Zhu J. Palladium-Catalyzed Intramolecular C-Arylation of Benzylic Carbon: Synthesis of 3-Benzoxazolylisoindolinones by a Sequence of Ugi-4CR/Postfunctionalization. J Org Chem 2008; 73:3600-3. [DOI: 10.1021/jo800266y] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
- Angela Salcedo
- Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
| | - Luc Neuville
- Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
| | - Jieping Zhu
- Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
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