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1
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Martins MS, Almeida IF, Cruz MT, Sousa E. Chronic pruritus: from pathophysiology to drug design. Biochem Pharmacol 2023; 212:115568. [PMID: 37116666 DOI: 10.1016/j.bcp.2023.115568] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 04/17/2023] [Accepted: 04/18/2023] [Indexed: 04/30/2023]
Abstract
Pruritus, the most common symptom in dermatology, is an innate response capable of protecting skin against irritants. Nonetheless, when it lasts more than six weeks it is assumed to be a chronic pathology having a negative impact on people's lives. Chronic pruritus (CP) can occur in common and rare skin diseases, having a high prevalence in global population. The existing therapies are unable to counteract CP or are associated with adverse effects, so the development of effective treatments is a pressing issue. The pathophysiological mechanisms underlying CP are not yet completely dissected but, based on current knowledge, involve a wide range of receptors, namely neurokinin 1 receptor (NK1R), Janus kinase (JAK), and transient receptor potential (TRP) ion channels, especially transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1). This review will address the relevance of these molecular targets for the treatment of CP and molecules capable of modulating these receptors that have already been studied clinically or have the potential to possibly alleviate this pathology. According to scientific and clinical literature, there is an increase in the expression of these molecular targets in the lesioned skin of patients experiencing CP when compared with non-lesioned skin, highlighting their importance for the development of potential efficacious drugs through the design of antagonists/inhibitors.
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Affiliation(s)
- Márcia S Martins
- CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Novo Edifício do Terminal de Cruzeiros do Porto de Leixões, 4450-208 Matosinhos, Portugal; Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
| | - Isaobel F Almeida
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; UCIBIO-Applied Molecular Biosciences Unit, MedTech, Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
| | - Maria T Cruz
- CNC-Center for Neuroscience and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Emília Sousa
- CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Novo Edifício do Terminal de Cruzeiros do Porto de Leixões, 4450-208 Matosinhos, Portugal; Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
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2
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Trammel GL, Kannangara PB, Vasko D, Datsenko O, Mykhailiuk P, Brown MK. Arylboration of Enecarbamates for the Synthesis of Borylated Saturated N-Heterocycles. Angew Chem Int Ed Engl 2022; 61:e202212117. [PMID: 36250954 PMCID: PMC9643676 DOI: 10.1002/anie.202212117] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Indexed: 11/09/2022]
Abstract
Two catalytic systems have been developed for the arylboration of endocyclic enecarbamates to deliver synthetically versatile borylated saturated N-heterocycles in good regio- and diastereoselectivities. A Cu/Pd dual catalytic reaction enables the synthesis of borylated, α-arylated azetidines, while a Ni-catalysed arylboration reaction efficiently functionalizes 5-, 6-, and 7-membered enecarbamates. In the case of the Cu/Pd-system, a remarkable additive effect was identified that allowed for broader scope. The products are synthetically useful, as demonstrated by manipulations of the boronic ester to access biologically active compounds.
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Affiliation(s)
- Grace L. Trammel
- Department of ChemistryIndiana University800 E. Kirkwood Ave.BloomingtonIN, 47401USA
| | | | | | | | - Pavel Mykhailiuk
- Enamine Ltd.Chervonotkatska 6002094KyivUkraine
- Taras Shevchenko National University of KyivChemistry DepartmentVolodymyrska 6401601KyivUkraine
| | - M. Kevin Brown
- Department of ChemistryIndiana University800 E. Kirkwood Ave.BloomingtonIN, 47401USA
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3
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Trammel GL, Kannangara PB, Vasko D, Datsenko O, Mykhailiuk P, Brown MK. Arylboration of Enecarbamates for the Synthesis of Borylated Saturated N‐Heterocycles. Angew Chem Int Ed Engl 2022. [DOI: 10.1002/ange.202212117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Grace L. Trammel
- Department of Chemistry Indiana University 800 E. Kirkwood Ave. Bloomington IN, 47401 USA
| | | | - Dmytro Vasko
- Enamine Ltd. Chervonotkatska 60 02094 Kyiv Ukraine
| | | | - Pavel Mykhailiuk
- Enamine Ltd. Chervonotkatska 60 02094 Kyiv Ukraine
- Taras Shevchenko National University of Kyiv Chemistry Department Volodymyrska 64 01601 Kyiv Ukraine
| | - M. Kevin Brown
- Department of Chemistry Indiana University 800 E. Kirkwood Ave. Bloomington IN, 47401 USA
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4
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Yamamoto K, Kuriyama M, Onomura O. Shono-Type Oxidation for Functionalization of N-Heterocycles. CHEM REC 2021; 21:2239-2253. [PMID: 33656281 DOI: 10.1002/tcr.202100031] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 02/24/2021] [Accepted: 02/24/2021] [Indexed: 01/05/2023]
Abstract
The development of facile synthetic methods for stereodefined aliphatic cyclic amines is an important research field in synthetic organic chemistry since such scaffolds constitute a variety of natural products and biologically active compounds. N-Acyl cyclic N,O-acetals which prepared by electrochemical oxidation of the corresponding cyclic amines have proven to be useful and versatile precursors for the synthesis of such skeletons. In this Personal Account, we introduce our efforts toward the development of synthetic strategies for the diastereo- and/or enantioselective synthesis of cyclic amines by using electrochemically prepared cyclic N,O-acetals. In addition, the investigation of the "memory of chirality" in the electrooxidative methoxylation of N-acyl amino acid derivatives, the strategy for the synthesis of chiral azabicyclic compounds by utilizing electrochemical oxidation, and halogen cation-mediated synthesis of nitrogen-containing heterocycles are also described.
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Affiliation(s)
- Kosuke Yamamoto
- Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, 852-8521, Japan
| | - Masami Kuriyama
- Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, 852-8521, Japan
| | - Osamu Onomura
- Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, 852-8521, Japan
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5
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Anand PS, Sethukumar A, Kumar CU, Krishnasamy K, Senthan S, Manikandan G, Prakasam BA. Synthesis, stereochemical, single crystal X-ray structural and antimicrobial studies of some isobutyl-1,2,6-triaryl-4-(arylamino)-1,2,5,6-tetrahydropyridine-3-carboxylates: Exploring RAHB with S(6) graph set. J Mol Struct 2021. [DOI: 10.1016/j.molstruc.2020.129563] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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6
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Yamamoto K, Kuriyama M, Onomura O. Anodic Oxidation for the Stereoselective Synthesis of Heterocycles. Acc Chem Res 2020; 53:105-120. [PMID: 31872753 DOI: 10.1021/acs.accounts.9b00513] [Citation(s) in RCA: 139] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Stereodefined aliphatic heterocycles are one of the fundamental structural motifs observed in natural products and biologically active compounds. Various strategies for the synthesis of these building blocks based on transition metal catalysis, organocatalysis, and noncatalytic conditions have been developed. Although electrosynthesis has also been utilized for the functionalization of aliphatic heterocycles, stereoselective transformations under electrochemical conditions are still a challenging field in electroorganic chemistry. This Account consists of four main topics related to our recent efforts on the diastereo- and/or enantioselective synthesis of aliphatic heterocycles, especially N-heterocycles, using anodic oxidations as key steps. The first topic is the development of stereoselective synthetic methods for multisubstituted piperidines and pyrrolidines from anodically prepared α-methoxy cyclic amines. Our strategies were based primarily on N-acyliminium ion chemistry, and the key electrochemical transformations were diastereoselective anodic methoxylation, diastereoselective arylation, and anodic deallylative methoxylation. Furthermore, we found a unique property of the N-cyano protecting group that enabled the electrochemical α-methoxylation of α-substituted cyclic amines. The second topic of investigation is memory of chirality in electrochemical decarboxylative methoxylation. We observed that the electrochemical decarboxylative methoxylation of oxazolidine and thiazolidine derivatives with the appropriate N-protecting group occurred in a stereospecific manner even though the reaction proceeded through an sp2 planar carbon center. Our findings demonstrated the first example of memory of chirality in N-acyliminium ion chemistry. The third topic is the synthesis of chiral azabicyclo-N-oxyls and their application to chiral organocatalysis in the electrochemical oxidative kinetic resolution of secondary alcohols. The final topic is stereoselective transformations utilizing anodically generated halogen cations. We investigated the oxidative kinetic resolution of amino alcohol derivatives using anodically generated bromo cations. We also developed an intramolecular C-C bond formation of keto amides, a diastereoselective bromoiminolactonization of α-allyl malonamides, and an oxidative ring expansion reaction of allyl alcohols. It is noteworthy that most of the electrochemical reactions were performed in undivided cells under constant-current conditions, which avoided a complicated reaction setup and was beneficial for a large-scale reaction. In addition, we developed some enantioselective electrochemical transformations that are still challenges in electroorganic chemistry. We hope that our research will contribute to the further development of diastereo- and/or enantioselective transformations and the construction of valuable heterocyclic compounds using an electrochemical approach.
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Affiliation(s)
- Kosuke Yamamoto
- Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
| | - Masami Kuriyama
- Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
| | - Osamu Onomura
- Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
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7
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Ushakov PY, Khatuntseva EA, Nelyubina YV, Tabolin AA, Ioffe SL, Sukhorukov AY. Synthesis of Isoxazolines from Nitroalkanes
via
a [4+1]‐Annulation Strategy. Adv Synth Catal 2019. [DOI: 10.1002/adsc.201901000] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Pavel Yu. Ushakov
- N. D. Zelinsky Institute of Organic ChemistryRussian Academy of Sciences 119991 Leninsky prospect, 47 Moscow Russian Federation
- Department of ChemistryM. V. Lomonosov Moscow State University 119991 Leninskie gory, 1, str. 3 Moscow Russian Federation
| | - Elizaveta A. Khatuntseva
- N. D. Zelinsky Institute of Organic ChemistryRussian Academy of Sciences 119991 Leninsky prospect, 47 Moscow Russian Federation
| | - Yulia V. Nelyubina
- A. N. Nesmeyanov Institute of Organoelement Compounds 119991 Vavilov str. 28 Moscow Russian Federation
| | - Andrey A. Tabolin
- N. D. Zelinsky Institute of Organic ChemistryRussian Academy of Sciences 119991 Leninsky prospect, 47 Moscow Russian Federation
| | - Sema L. Ioffe
- N. D. Zelinsky Institute of Organic ChemistryRussian Academy of Sciences 119991 Leninsky prospect, 47 Moscow Russian Federation
| | - Alexey Yu. Sukhorukov
- N. D. Zelinsky Institute of Organic ChemistryRussian Academy of Sciences 119991 Leninsky prospect, 47 Moscow Russian Federation
- D. Mendeleev University of Chemical Technology of Russia 125047 Miusskaya sq., 9 Moscow Russian Federation
- Plekhanov Russian University of Economics 117997 Stremyanny per. 36 Moscow Russian Federation
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8
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Velasco M, Hernández U, Terán JL, Gnecco D, Orea ML, Aparicio DM, Gómez-Calvario V, Bernès S, Juárez JR. Stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine. Tetrahedron Lett 2019; 60:820-824. [DOI: 10.1016/j.tetlet.2019.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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9
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Zhong F, Yue WJ, Zhang HJ, Zhang CY, Yin L. Catalytic Asymmetric Construction of Halogenated Stereogenic Carbon Centers by Direct Vinylogous Mannich-Type Reaction. J Am Chem Soc 2018; 140:15170-15175. [DOI: 10.1021/jacs.8b09484] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Affiliation(s)
- Feng Zhong
- CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
| | - Wen-Jun Yue
- CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
| | - Hai-Jun Zhang
- CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
| | - Cheng-Yuan Zhang
- CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
| | - Liang Yin
- CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
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10
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Trost BM, Gnanamani E, Tracy JS, Kalnmals CA. Zn-ProPhenol Catalyzed Enantio- and Diastereoselective Direct Vinylogous Mannich Reactions between α,β- and β,γ-Butenolides and Aldimines. J Am Chem Soc 2017; 139:18198-18201. [PMID: 29198100 DOI: 10.1021/jacs.7b11361] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
We report a Zn-ProPhenol catalyzed reaction between butenolides and imines to obtain tetrasubstituted vinylogous Mannich products in good yield and diastereoselectivity with excellent enantioselectivity (97 to >99.5% ee). Notably, both α,β- and β,γ-butenolides can be utilized as nucleophiles in this transformation. The imine partner bears the synthetically versatile N-Cbz group, avoiding the use of the specialized aryl directing groups previously required in related work. Additionally, the reaction can be performed on gram scale with reduced catalyst loading as low as 2 mol %. The functional group-rich products can be further elaborated using a variety of methods.
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Affiliation(s)
- Barry M Trost
- Department of Chemistry, Stanford University , Stanford, California 94305, United States
| | - Elumalai Gnanamani
- Department of Chemistry, Stanford University , Stanford, California 94305, United States
| | - Jacob S Tracy
- Department of Chemistry, Stanford University , Stanford, California 94305, United States
| | - Christopher A Kalnmals
- Department of Chemistry, Stanford University , Stanford, California 94305, United States
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11
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Su RH, Ding XF, Wu SX, Zhao JH, Deng WP. Secondary amine-catalyzed asymmetric formal aza [3 + 3] cycloaddition to construct enantioenriched piperidines derivatives. Tetrahedron 2017. [DOI: 10.1016/j.tet.2017.08.049] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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12
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Divergent syntheses of L-733, 060 and CP-122721 from functionalized pieridinones made by one-pot tandem cyclization. Tetrahedron 2017. [DOI: 10.1016/j.tet.2017.02.057] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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13
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Gieuw MH, Ke Z, Yeung YY. Lewis Base Catalyzed Stereo- and Regioselective Bromocyclization. CHEM REC 2016; 17:287-311. [PMID: 27701807 DOI: 10.1002/tcr.201600088] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Indexed: 01/01/2023]
Abstract
Oxygen- and nitrogen-containing heterocyclic compounds are widely recognized as key components in many natural products and biologically relevant molecules, but often the problem comes down to methodologies in synthesizing them. Halocyclization of olefinic substrates is a promising strategy in the construction of O- and N-heterocyclic compounds, which further signifies the development of their asymmetric variants. Over the past years, our group has been devoted to this particular area of asymmetric electrophilic halocyclization with chalcogen-containing molecules as catalysts. In this account, the main focus is on the development of our novel chiral catalysts and applications derived from the reaction products.
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Affiliation(s)
- Matthew H Gieuw
- Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, SAR China
| | - Zhihai Ke
- Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, SAR China
| | - Ying-Yeung Yeung
- Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, SAR China
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14
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Huang WX, Wu B, Gao X, Chen MW, Wang B, Zhou YG. Iridium-Catalyzed Selective Hydrogenation of 3-Hydroxypyridinium Salts: A Facile Synthesis of Piperidin-3-ones. Org Lett 2015; 17:1640-3. [DOI: 10.1021/acs.orglett.5b00276] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Wen-Xue Huang
- State Key Laboratory of Fine Chemicals, School of Pharmaceutical
Science and Technology, Dalian University of Technology, 2 Linggong
Road, Dalian 116024, P. R. China
- State Key Laboratory of Catalysis, Dalian
Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan
Road, Dalian 116023, P. R. China
| | - Bo Wu
- State Key Laboratory of Catalysis, Dalian
Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan
Road, Dalian 116023, P. R. China
| | - Xiang Gao
- State Key Laboratory of Catalysis, Dalian
Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan
Road, Dalian 116023, P. R. China
| | - Mu-Wang Chen
- State Key Laboratory of Catalysis, Dalian
Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan
Road, Dalian 116023, P. R. China
| | - Baomin Wang
- State Key Laboratory of Fine Chemicals, School of Pharmaceutical
Science and Technology, Dalian University of Technology, 2 Linggong
Road, Dalian 116024, P. R. China
| | - Yong-Gui Zhou
- State Key Laboratory of Catalysis, Dalian
Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan
Road, Dalian 116023, P. R. China
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15
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Abstract
Since its first use in the steroid field in the late 1950s, the use of fluorine in medicinal chemistry has become commonplace, with the small electronegative fluorine atom being a key part of the medicinal chemist's repertoire of substitutions used to modulate all aspects of molecular properties including potency, physical chemistry and pharmacokinetics. This review will highlight the special nature of fluorine, drawing from a survey of marketed fluorinated pharmaceuticals and the medicinal chemistry literature, to illustrate key concepts exploited by medicinal chemists in their attempts to optimize drug molecules. Some of the potential pitfalls in the use of fluorine will also be highlighted.
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16
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Murakami K, Sasano Y, Tomizawa M, Shibuya M, Kwon E, Iwabuchi Y. Highly Enantioselective Organocatalytic Oxidative Kinetic Resolution of Secondary Alcohols Using Chiral Alkoxyamines as Precatalysts: Catalyst Structure, Active Species, and Substrate Scope. J Am Chem Soc 2014; 136:17591-600. [DOI: 10.1021/ja509766f] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- Keiichi Murakami
- Department of Organic Chemistry,
Graduate School of Pharmaceutical
Sciences and ‡Research and Analytical Center for Giant Molecules, Graduate School
of Science, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
| | - Yusuke Sasano
- Department of Organic Chemistry,
Graduate School of Pharmaceutical
Sciences and ‡Research and Analytical Center for Giant Molecules, Graduate School
of Science, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
| | - Masaki Tomizawa
- Department of Organic Chemistry,
Graduate School of Pharmaceutical
Sciences and ‡Research and Analytical Center for Giant Molecules, Graduate School
of Science, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
| | - Masatoshi Shibuya
- Department of Organic Chemistry,
Graduate School of Pharmaceutical
Sciences and ‡Research and Analytical Center for Giant Molecules, Graduate School
of Science, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
| | - Eunsang Kwon
- Department of Organic Chemistry,
Graduate School of Pharmaceutical
Sciences and ‡Research and Analytical Center for Giant Molecules, Graduate School
of Science, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
| | - Yoshiharu Iwabuchi
- Department of Organic Chemistry,
Graduate School of Pharmaceutical
Sciences and ‡Research and Analytical Center for Giant Molecules, Graduate School
of Science, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
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17
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Hardy S, Martin SF. Multicomponent, Mannich-type assembly process for generating novel, biologically-active 2-arylpiperidines and derivatives. Tetrahedron 2014; 70:7142-7157. [PMID: 25267860 PMCID: PMC4175438 DOI: 10.1016/j.tet.2014.06.045] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
A multicomponent, Mannich-type assembly process commencing with commercially available bromobenzaldehydes was sequenced with [3+2] dipolar cycloaddition reactions involving nitrones and azomethine ylides to generate collections of fused, bicyclic scaffolds based on the 2-arylpiperidine subunit. Use of the 4-pentenoyl group, which served both as an activator in the Mannich-type reaction and a readily-cleaved amine protecting group, allowed sub-libraries to be prepared through piperidine N-functionalization and cross-coupling of the aryl bromide. A number of these derivatives displayed biological activities that had not previously been associated with this substructure. Methods were also developed that allowed rapid conversion of these scaffolds to novel, polycyclic dihydroquinazolin-2-ones, 2-imino-1,3-benzothiazinanes, dihydroisoquinolin-3-ones and bridged tetrahydroquinolines.
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Affiliation(s)
- Simon Hardy
- Department of Chemistry, The University of Texas at Austin, Austin, TX 78712
| | - Stephen F. Martin
- Department of Chemistry, The University of Texas at Austin, Austin, TX 78712
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18
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A concise diastereoselective approach to enantioenriched substituted piperidines and their in vitro cytotoxicity evaluation. Bioorg Med Chem Lett 2014; 24:4439-4443. [PMID: 25172418 DOI: 10.1016/j.bmcl.2014.08.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 07/12/2014] [Accepted: 08/02/2014] [Indexed: 11/21/2022]
Abstract
A library of diversely stereo-oriented, highly substituted 2,6-cis piperidine derivatives were synthesized, and evaluated for their anticancer activity in cancer cells that included A549 (lung cancer, CCL-185), MCF7 (breast cancer (HTB-22), DU145 (prostate cancer (HTB-81), and HeLa (cervical cancer, CCL-2). One stereo-variant emerged as a promising candidate for further design based structure-activity studies.
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19
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Wu YJ, He H, Gao Q, Wu D, Bertekap R, Westphal RS, Lelas S, Newton A, Wallace T, Taber M, Davis C, Macor JE, Bronson J. Discovery of a cyclopentylamine as an orally active dual NK1 receptor antagonist-serotonin reuptake transporter inhibitor. Bioorg Med Chem Lett 2014; 24:1611-4. [PMID: 24507922 DOI: 10.1016/j.bmcl.2014.01.036] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Revised: 01/10/2014] [Accepted: 01/14/2014] [Indexed: 11/15/2022]
Abstract
Cyclopentylamine 4 was identified as a potent dual NK1R antagonist-SERT inhibitor. This compound demonstrated significant oral activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders.
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Affiliation(s)
- Yong-Jin Wu
- Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
| | - Huan He
- Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA
| | - Qi Gao
- Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA
| | - Dedong Wu
- Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA
| | - Robert Bertekap
- Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA
| | - Ryan S Westphal
- Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA
| | - Snjezana Lelas
- Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA
| | - Amy Newton
- Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA
| | - Tanya Wallace
- Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA
| | - Matthew Taber
- Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA
| | - Carl Davis
- Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA
| | - John E Macor
- Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA
| | - Joanne Bronson
- Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA
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20
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Muñoz M, Coveñas R. Involvement of substance P and the NK-1 receptor in pancreatic cancer. World J Gastroenterol 2014; 20:2321-2334. [PMID: 24605029 PMCID: PMC3942835 DOI: 10.3748/wjg.v20.i9.2321] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/23/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is the fourth leading cause of cancer related-death for both men and women and the 1- and 5-year relative survival rates are 25% and 6%, respectively. Thus, it is urgent to investigate new antitumor drugs to improve the survival of pancreatic cancer patients. The peptide substance P (SP) has a widespread distribution throughout the body. After binding to the neurokinin-1 (NK-1) receptor, SP regulates biological functions related to cancer, such as tumor cell proliferation, neoangiogenesis, the migration of tumor cells for invasion, infiltration and metastasis, and it exerts an antiapoptotic effects on tumor cells. It is known that the SP/NK-1 receptor system is involved in pancreatic cancer progression: (1) pancreatic cancer cells and samples express NK-1 receptors; (2) the NK-1 receptor is overexpressed in pancreatic cancer cells in comparison with non-tumor cells; (3) nanomolar concentrations of SP induce pancreatic cancer cell proliferation; (4) NK-1 receptor antagonists inhibit pancreatic cell proliferation in a concentration-dependent manner, at a certain concentration, these antagonists inhibit 100% of tumor cells; (5) this antitumor action is mediated through the NK-1 receptor, and tumor cells die by apoptosis; and (6) NK-1 receptor antagonists inhibit angiogenesis in pancreatic cancer xenografts. All these data suggest that the SP/NK-1 receptor system could play an important role in the development of pancreatic cancer; that the NK-1 receptor could be a new promising therapeutic target in pancreatic cancer, and that NK-1 receptor antagonists could improve the treatment of pancreatic cancer.
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21
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Huy PH, Westphal JC, Koskinen AMP. Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxypiperidines - development of a phosphite-driven cyclodehydration. Beilstein J Org Chem 2014; 10:369-83. [PMID: 24605158 PMCID: PMC3943667 DOI: 10.3762/bjoc.10.35] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 01/16/2014] [Indexed: 12/21/2022] Open
Abstract
A concise (5 to 6 steps), stereodivergent, highly diastereoselective (dr up to >19:1 for both stereoisomers) and scalable synthesis (up to 14 g) of cis- and trans-2-substituted 3-piperidinols, a core motif in numerous bioactive compounds, is presented. This sequence allowed an efficient synthesis of the NK-1 inhibitor L-733,060 in 8 steps. Additionally, a cyclodehydration-realizing simple triethylphosphite as a substitute for triphenylphosphine is developed. Here the stoichiometric oxidized P(V)-byproduct (triethylphosphate) is easily removed during the work up through saponification overcoming separation difficulties usually associated to triphenylphosphine oxide.
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Affiliation(s)
- Peter H Huy
- Aalto University, School of Chemical Technology, Laboratory of Organic Chemistry, Kemistintie 1, 02015 Espoo, Finland
| | - Julia C Westphal
- University of Cologne, Department of Chemistry, Organic Chemistry, Greinstrasse 4, 50939 Cologne, Germany
| | - Ari M P Koskinen
- Aalto University, School of Chemical Technology, Laboratory of Organic Chemistry, Kemistintie 1, 02015 Espoo, Finland
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22
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Rojas C, Raje M, Tsukamoto T, Slusher BS. Molecular mechanisms of 5-HT3 and NK1 receptor antagonists in prevention of emesis. Eur J Pharmacol 2014; 722:26-37. [DOI: 10.1016/j.ejphar.2013.08.049] [Citation(s) in RCA: 106] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Revised: 07/01/2013] [Accepted: 08/03/2013] [Indexed: 11/26/2022]
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23
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The Orthoester Johnson-Claisen Rearrangement in the Synthesis of Bioactive Molecules, Natural Products, and Synthetic Intermediates - Recent Advances. European J Org Chem 2013. [DOI: 10.1002/ejoc.201301033] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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24
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Huy PH, Koskinen AMP. Efficient, stereodivergent access to 3-piperidinols by traceless P(OEt)3 cyclodehydration. Org Lett 2013; 15:5178-81. [PMID: 24090120 DOI: 10.1021/ol4026588] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
A stereodivergent and highly diastereoselective (dr up to >19:1 for both isomers), step economic (5-6 steps), and scalable synthesis (up to 14 g) of cis- and trans-2-substituted 3-piperidinols, the core motif of numerous bioactive compounds, providing efficient access to the NK-1 inhibitor L-733,060 is presented. Additionally, a "traceless" (referring to the simplified byproduct separation) cyclodehydration realizing simple P(OEt)3 as a substitute for PPh3 is developed.
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Affiliation(s)
- Peter H Huy
- Aalto University , School of Chemical Technology, Laboratory of Organic Chemistry, Kemistintie 1, 00076 Espoo, Finland
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25
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Hoecker J, Rudolf GC, Bächle F, Fleischer S, Lindner BD, Helmchen G. Enantio- and Diastereoselective Syntheses of 3-Hydroxypiperidines through Iridium-Catalyzed Allylic Substitution. European J Org Chem 2013. [DOI: 10.1002/ejoc.201300445] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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26
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Wu YJ, He H, Bertekap R, Westphal R, Lelas S, Newton A, Wallace T, Taber M, Davis C, Macor JE, Bronson J. Discovery of disubstituted piperidines and homopiperidines as potent dual NK 1 receptor antagonists–serotonin reuptake transporter inhibitors for the treatment of depression. Bioorg Med Chem 2013; 21:2217-2228. [DOI: 10.1016/j.bmc.2013.02.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Revised: 02/01/2013] [Accepted: 02/11/2013] [Indexed: 10/27/2022]
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27
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28
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Zhou L, Tay DW, Chen J, Leung GYC, Yeung YY. Enantioselective synthesis of 2-substituted and 3-substituted piperidines through a bromoaminocyclization process. Chem Commun (Camb) 2012; 49:4412-4. [PMID: 23072774 DOI: 10.1039/c2cc36578b] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
A catalytic enantioselective bromocyclization of olefinic amides using amino-thiocarbamates as the catalysts has been developed. The resulting enantioenriched 2-substituted 3-bromopiperidines can readily be transformed to 3-substituted piperidines through a silver salt-mediated rearrangement. This process has been applied to the synthesis of a dopaminergic drug, Preclamol.
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Affiliation(s)
- Ling Zhou
- Department of Chemistry, NUS, 3 Science Drive 3, Singapore11754
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29
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Rosso M, Muñoz M, Berger M. The role of neurokinin-1 receptor in the microenvironment of inflammation and cancer. ScientificWorldJournal 2012; 2012:381434. [PMID: 22545017 PMCID: PMC3322385 DOI: 10.1100/2012/381434] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2011] [Accepted: 11/20/2011] [Indexed: 12/11/2022] Open
Abstract
The recent years have witnessed an exponential increase in cancer research, leading to a considerable investment in the field. However, with few exceptions, this effort has not yet translated into a better overall prognosis for patients with cancer, and the search for new drug targets continues. After binding to the specific neurokinin-1 (NK-1) receptor, the peptide substance P (SP), which is widely distributed in both the central and peripheral nervous systems, triggers a wide variety of functions. Antagonists against the NK-1 receptor are safe clinical drugs that are known to have anti-inflammatory, analgesic, anxiolytic, antidepressant, and antiemetic effects. Recently, it has become apparent that SP can induce tumor cell proliferation, angiogenesis, and migration via the NK-1 receptor, and that the SP/NK-1 receptor complex is an integral part of the microenvironment of inflammation and cancer. Therefore, the use of NK-1 receptor antagonists as a novel and promising approach for treating patients with cancer is currently under intense investigation. In this paper, we evaluate the recent scientific developments regarding this receptor system, its role in the microenvironment of inflammation and cancer, and its potentials and pitfalls for the usage as part of modern anticancer strategies.
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Affiliation(s)
- Marisa Rosso
- Research Laboratory on Neuropeptides, Hospital Infantil Universitario Virgen del Rocío, Avenida Manuel Siurot s/n, 41013 Seville, Spain.
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30
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Eleventh international symposium on radiopharmaceutical chemistry: Abstracts. J Labelled Comp Radiopharm 2012. [DOI: 10.1002/jlcr.2580370601] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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31
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Cossy J, Gomez Pardo D, Cochi A. Synthesis of Two Neurokinin NK1 Receptor Antagonists: (+)-L-733,060 and (-)-L-733,061. HETEROCYCLES 2012. [DOI: 10.3987/rev-12-sr(n)2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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32
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Mizuta S, Onomura O. Diastereoselective addition to N-acyliminium ions with aryl- and alkenyl boronic acids via a Petasis-type reaction. RSC Adv 2012. [DOI: 10.1039/c2ra01254e] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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33
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A concise enantioselective synthesis of l-(−)-733,061 and (2S,3S)-methyl 3-aminopiperidine-2-carboxylate using catalytic enantioselective aza-Henry reaction as key step. Tetrahedron 2011. [DOI: 10.1016/j.tet.2011.02.031] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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34
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Muñoz M, Rosso M, Robles-Frias MJ, Salinas-Martín MV, Rosso R, González-Ortega A, Coveñas R. The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines. J Transl Med 2010; 90:1259-69. [PMID: 20458280 DOI: 10.1038/labinvest.2010.92] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Melanoma, the most deadly form of skin cancer, is aggressive and resistant to current therapies. It has been previously reported that the substance P and neurokinin-1 (NK-1) receptor antagonists induce cell proliferation and cell inhibition, respectively, in human melanoma cell lines. Aprepitant is a selective high-affinity antagonist of the human NK-1 receptor. Until now, this drug has been used as an anxiolytic, antidepressant and antiemetic. Moreover, the antitumor action of aprepitant has been previously reported. However, the presence of NK-1 receptors in human melanomas and whether the antitumor action of the NK-1 receptor antagonist aprepitant is exerted on human malignant melanomas have not been previously described. The aims of this study are to show the presence of NK-1 receptors in human malignant melanomas and the antitumoral action of aprepitant against several human melanoma cell lines. Immunoblot analysis was used to determine the presence of NK-1 receptors in human melanoma cell lines, and immunohistochemistry was used to demonstrate NK-1 receptors in human melanoma samples. We performed an in vitro study of the cytotoxicity of the NK-1 receptor antagonist aprepitant on human melanoma cell lines. A coulter counter was used to determine viable cell numbers, followed by application of the tetrazolium compound MTS. The DAPI method was applied to demonstrate apoptosis. We observed that NK-1 receptors were present in all the melanoma samples studied as well as in human melanoma cell lines. We also showed that melanoma cell lines expressed mRNA for the NK-1 receptor. Moreover, after using a knockdown method, we showed that NK-1 receptors are involved in the viability of tumor cells. In this study, we also report that aprepitant, at 10-60 microM concentrations, elicits cell growth inhibition in a concentration-dependent manner in all melanoma cell lines studied, that the specific antitumor action of aprepitant occurs through the NK-1 receptor and that melanoma cell death is due to apoptosis. These findings show for the first time that the NK-1 receptor may be a promising new target and that the NK-1 receptor antagonist aprepitant could be a candidate as a new antitumor drug in the treatment of human melanoma.
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Affiliation(s)
- Miguel Muñoz
- Research Laboratory on Neuropeptides, Virgen del Rocío University Hospital, Sevilla, Spain.
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35
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Botuha C, Chemla F, Ferreira F, Louvel J, Pérez-Luna A. Allenylzincs and tert-butylsulfinylimines: a fruitful marriage for synthesis. ACTA ACUST UNITED AC 2010. [DOI: 10.1016/j.tetasy.2010.04.044] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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36
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Muñoz M, Rosso M, González-Ortega A, Coveñas R. The NK-1 Receptor Antagonist L-732,138 Induces Apoptosis and Counteracts Substance P-Related Mitogenesis in Human Melanoma Cell Lines. Cancers (Basel) 2010; 2:611-23. [PMID: 24281084 PMCID: PMC3835094 DOI: 10.3390/cancers2020611] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2010] [Revised: 04/14/2010] [Accepted: 04/19/2010] [Indexed: 01/17/2023] Open
Abstract
It has been recently demonstrated that substance P (SP) and neurokinin-1 (NK-1) receptor antagonists induce cell proliferation and cell inhibition in human melanoma cells, respectively. However, the antitumor action of the NK-1 receptor antagonist L-732,138 on such cells is unknown. The aim of this study was to demonstrate an antitumor action of L-732,138 against three human melanoma cell lines (COLO 858, MEL HO, COLO 679). We found that L-732,138 elicits cell growth inhibition in a concentration dependent manner in the melanoma cells studied. Moreover, L-732,138 blocks SP mitogen stimulation. The specific antitumor action of L-732,138 occurred through the NK-1 receptor and melanoma cell death was by apoptosis. These findings indicate that the NK-1 receptor antagonist L-732,138 could be a new antitumor agent in the treatment of human melanoma.
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Affiliation(s)
- Miguel Muñoz
- Research Laboratory on Neuropeptides, Virgen del Rocío University Hospital, Sevilla, Spain; E-Mails: (M.R.); (A.G.-O.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +34-955012965; Fax: +34-955012921
| | - Marisa Rosso
- Research Laboratory on Neuropeptides, Virgen del Rocío University Hospital, Sevilla, Spain; E-Mails: (M.R.); (A.G.-O.)
| | - Ana González-Ortega
- Research Laboratory on Neuropeptides, Virgen del Rocío University Hospital, Sevilla, Spain; E-Mails: (M.R.); (A.G.-O.)
| | - Rafael Coveñas
- Institute of Neurosciences of Castilla y León (INCYL), Laboratory of Neuroanatomy of the Peptidergic Systems (Laboratory 14), Salamanca, Spain; E-Mail: (R.C.)
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37
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Prévost S, Phansavath P, Haddad M. A stereoselective synthesis of (+)-L-733,060 from ethyl (R)-(+)-2,3-epoxypropanoate. ACTA ACUST UNITED AC 2010. [DOI: 10.1016/j.tetasy.2009.12.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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38
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Bilke JL, Moore SP, O’Brien P, Gilday J. Catalytic Asymmetric Synthesis of Piperidines from Pyrrolidine: Concise Synthesis of L-733,060. Org Lett 2009; 11:1935-8. [DOI: 10.1021/ol900366m] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Julia L. Bilke
- Department of Chemistry, University of York, Heslington, York YO10 5DD, United Kingdom, and AstraZeneca, Process R & D, Avlon Works, Severn Road, Hallen, Bristol, BS10 7ZE, United Kingdom
| | - Stephen P. Moore
- Department of Chemistry, University of York, Heslington, York YO10 5DD, United Kingdom, and AstraZeneca, Process R & D, Avlon Works, Severn Road, Hallen, Bristol, BS10 7ZE, United Kingdom
| | - Peter O’Brien
- Department of Chemistry, University of York, Heslington, York YO10 5DD, United Kingdom, and AstraZeneca, Process R & D, Avlon Works, Severn Road, Hallen, Bristol, BS10 7ZE, United Kingdom
| | - John Gilday
- Department of Chemistry, University of York, Heslington, York YO10 5DD, United Kingdom, and AstraZeneca, Process R & D, Avlon Works, Severn Road, Hallen, Bristol, BS10 7ZE, United Kingdom
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39
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Organocatalyzed highly atom economic one pot synthesis of tetrahydropyridines as antimalarials. Bioorg Med Chem 2008; 17:625-33. [PMID: 19095455 DOI: 10.1016/j.bmc.2008.11.062] [Citation(s) in RCA: 163] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2008] [Revised: 11/24/2008] [Accepted: 11/25/2008] [Indexed: 11/20/2022]
Abstract
A highly atom economic one pot synthesis of tetrahydropyridines was achieved by L-proline/TFA catalysed multicomponent reaction of beta-keto-esters, aromatic aldehydes and anilines. The synthesized compounds were screened against Plasmodium falciparum in vitro and one of them showed antimalarial activity with MIC as low as 0.09 microg/mL.
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40
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A short enantioselective synthesis of (+)-L-733,060 via Shi epoxidation of a homoallylic carboxylate. Tetrahedron Lett 2008. [DOI: 10.1016/j.tetlet.2008.07.086] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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41
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Wee AGH, Fan GJ. Asymmetric Synthesis of (+)-Isofebrifugine and (−)-Sedacryptine from a Common Chiral Nonracemic Building Block. Org Lett 2008; 10:3869-72. [DOI: 10.1021/ol8013864] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Andrew G. H. Wee
- Department of Chemistry and Biochemistry, University of Regina, Regina, Saskatchewan, Canada S4S 0A2
| | - Gao-Jun Fan
- Department of Chemistry and Biochemistry, University of Regina, Regina, Saskatchewan, Canada S4S 0A2
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42
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Lin GQ, Xu MH, Zhong YW, Sun XW. An advance on exploring N-tert-butanesulfinyl imines in asymmetric synthesis of chiral amines. Acc Chem Res 2008; 41:831-40. [PMID: 18533688 DOI: 10.1021/ar7002623] [Citation(s) in RCA: 242] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Although catalytic asymmetric synthesis has undergone tremendous growth in the last 30 years, chiral auxiliary-aided asymmetric synthesis continues to attract considerable attention. Chiral N- tert-butanesulfinamide, as pioneered by Ellman and co-workers, is undoubtedly one of the most efficient auxiliaries developed to date; it allows the preparation, through simple conversion, of a diverse range of enantiopure amines, which are ubiquitous in natural products and biologically active molecules. Following on from our studies of the SmI(2)-mediated asymmetric syntheses of alpha,gamma-substituted gamma-butyrolactones, we found that simple homocoupling of chiral N- tert-butanesulfinyl imines in the presence of SmI(2) produced enantiopure vicinal C2-symmetric diamines in high yield. In addition, C2-unsymmetric chiral diamines are readily prepared through SmI(2)-mediated cross-couplings of N- tert-butanesulfinyl imines and nitrones; these transformations represented the first successful examples of asymmetric cross-coupling between two different imine species. Subsequently, we discovered another useful reaction induced by SmI(2), the efficient cross-coupling of N- tert-butanesulfinyl imines and aldehydes, which provides ready access to enantiopure anti-1,2-amino alcohols. The synthetic applicability of this reaction was demonstrated through its use in the facile total syntheses of (3R,4S)-statine, d- erythro-sphinganine, (+)-CP-99,994, and (+)-L-733,060. The Zn/In-mediated allylation of chiral N- tert-butanesulfinyl imines yields homoallylic amines. After pondering the reaction mechanism, we developed optimal reaction conditions for reversing the stereogenic outcome, thereby allowing the preparation of enantiopure homoallylic amines of either handedness from single enantiomers of the (R)- or (S)-sulfinyl imine. When a benzoyl-substituted allyl bromide is used for allylation, the reaction proceeds smoothly to give 2-vinyl-substituted anti-1,2-amino alcohols in high yields and diastereoselectivities, another simple method for preparing enantiopure amino alcohols. We employed these reactions in the syntheses of enantiopure allylglycine, 3-allyl-isoindolinones, and (-)-cytoxazone. Further studies led to the discovery that the allylations of N- tert-butanesulfinyl aldimines can be performed in water. The reactions described in this Account are among the simplest and most efficient synthetic methods available for preparing enantio-enriched diamines, amino alcohols, homoallylic amines, and other amine derivatives. These reactions are additionally attractive because of the ready availability of the starting materials, the simplicity of the reaction conditions, and the high degree of stereochemical control. Their applications in the total syntheses of several biologically interesting molecules illustrate the versatility of these transformations; we hope that they will stimulate the development of new synthetic methods.
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Affiliation(s)
- Guo-Qiang Lin
- Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Feng Lin Road, Shanghai 200032, China
| | - Ming-Hua Xu
- Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Feng Lin Road, Shanghai 200032, China
| | - Yu-Wu Zhong
- Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Feng Lin Road, Shanghai 200032, China
| | - Xing-Wen Sun
- Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Feng Lin Road, Shanghai 200032, China
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43
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Synthesis of trans-4-aryl-3-(3-chloropropyl)azetidin-2-ones and their transformation into trans- and cis-2-arylpiperidine-3-carboxylates. Tetrahedron 2008. [DOI: 10.1016/j.tet.2008.03.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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44
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Liu RH, Fang K, Wang B, Xu MH, Lin GQ. Concise Asymmetric Synthesis of (+)-CP-99,994 and (+)-L-733,060 via Efficient Construction of Homochiral syn-1,2-Diamines and syn-1,2-Amino Alcohols. J Org Chem 2008; 73:3307-10. [DOI: 10.1021/jo8002979] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Run-Hua Liu
- Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, Institutes of Biomedical Sciences, Fudan University, 138 Yixueyuan Road, Shanghai 200032, and Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
| | - Kai Fang
- Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, Institutes of Biomedical Sciences, Fudan University, 138 Yixueyuan Road, Shanghai 200032, and Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
| | - Bing Wang
- Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, Institutes of Biomedical Sciences, Fudan University, 138 Yixueyuan Road, Shanghai 200032, and Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
| | - Ming-Hua Xu
- Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, Institutes of Biomedical Sciences, Fudan University, 138 Yixueyuan Road, Shanghai 200032, and Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
| | - Guo-Qiang Lin
- Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, Institutes of Biomedical Sciences, Fudan University, 138 Yixueyuan Road, Shanghai 200032, and Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
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45
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Carruthers NI, Kaminski JJ. Patent Update Pulmonary-Allergy, Dermatological, Gastrointestinal & Arthritis: Neurokinin receptor antagonists for the treatment of inflammation. Expert Opin Ther Pat 2008. [DOI: 10.1517/13543776.6.2.169] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Morgan IR, Yazici A, Pyne SG. Diastereoselective borono-Mannich reactions on cyclic N-acyliminium ions. Tetrahedron 2008. [DOI: 10.1016/j.tet.2007.11.046] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Synthesis of pharmaceutically active compounds containing a disubstituted piperidine framework. Bioorg Med Chem 2008; 16:601-35. [DOI: 10.1016/j.bmc.2007.10.018] [Citation(s) in RCA: 177] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2007] [Accepted: 10/09/2007] [Indexed: 11/18/2022]
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48
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Davis FA, Ramachandar T. alpha-Amino 1,3-Dithioketal Mediated Asymmetric Synthesis of Piperidines (L-733,060) and Tetrahydrofuran Glycines. Tetrahedron Lett 2008; 49:870-872. [PMID: 19180171 DOI: 10.1016/j.tetlet.2007.11.170] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Sulfinimine-derived alpha-amino 1,3-dithianes, alpha-amino carbonyl chiral building blocks, are utilized in asymmetric syntheses of (+)-(tetrahydrofuran-2-yl)glycine and the 2,3-disubstituted piperidine (+)-L-733,060.
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Affiliation(s)
- Franklin A Davis
- Department of Chemistry, Temple University, Philadelphia, PA 19122 USA
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49
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Shishido Y, Ito F, Morita H, Ikunaka M. Stereoselective synthesis of a novel 2-aza-7-oxabicyclo[3.3.0]octane as neurokinin-1 receptor antagonist. Bioorg Med Chem Lett 2007; 17:6887-90. [PMID: 17967540 DOI: 10.1016/j.bmcl.2007.10.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2007] [Revised: 09/28/2007] [Accepted: 10/03/2007] [Indexed: 11/17/2022]
Abstract
A novel neurokinin-1 receptor antagonist, (+/-)-(1R( *),3S( *),4S( *),5S( *))-4-[(N-(2-methoxy-5-trifluoromethoxybenzyl)amino]-3-phenyl-2-aza-7-oxabicyclo[3.3.0]octane (1), was synthesized stereoselectively using Padwa's intramolecular 1,3-dipolar cycloaddition methodology as the key step. Compound (+/-)-1 showed high affinity for the NK-1 receptors in human IM-9 cells with an IC(50) value of 0.22 nM. This new structural scaffold demonstrated significant in vivo antagonistic activity in the guinea pig ureter capsaicin-induced plasma extravasation model with an ED(50) value of 1-10mg/kg, po.
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Affiliation(s)
- Yuji Shishido
- Pfizer Global Research & Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2394, Japan
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Muñoz M, Rosso M, Aguilar FJ, González-Moles MA, Redondo M, Esteban F. NK-1 receptor antagonists induce apoptosis and counteract substance P-related mitogenesis in human laryngeal cancer cell line HEp-2. Invest New Drugs 2007; 26:111-8. [PMID: 17906845 DOI: 10.1007/s10637-007-9087-y] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2007] [Accepted: 08/27/2007] [Indexed: 01/21/2023]
Abstract
It has been demonstrated that substance P (SP) induces cell proliferation and neurokinin-1 (NK-1) receptor antagonists inhibit growth in several human cancer cell lines, but it is currently unknown whether such actions are exerted on human laryngeal carcinoma cell line HEp-2. In addition, the presence of NK-1 receptor has not been demonstrated in this cell line. We carried out an in vitro study of the growth inhibitory capacity of the NK-1 receptor antagonists L-733,060 and L-732,138 against human laryngeal carcinoma cell line HEp-2. Coulter counter was used to determine viable cell numbers followed by application of the tetrazolium compound MTS. Furthermore, an immunoblot analysis was used to determine the NK-1 receptor, and the 4',6-diamidino-2-phenylindole (DAPI) method was applied to demonstrate apoptosis of the laryngeal carcinoma cells. We observed the presence of several NK-1 receptors isoforms (34, 46, 58 and 75 kDa). Nanomolar concentrations of SP increased the growth rate of the cell line and micromolar concentrations of L-733,060 and L-732,138 inhibited the growth of the HEp-2 cells in a dose-dependent manner, with and without previous administration of SP. The 50% inhibition concentration values were 21.34 microM and 37.97 (48 h) respectively for HEp-2. NK-1 receptor presence on HEp-2 cells was confirmed by western blotting. DAPI staining revealed the presence of apoptosis following NK-1 receptor antagonists treatment. We demonstrated that NK-1 receptors were present in this laryngeal cancer cell line; these findings demonstrate that SP acts as a mitogen on the human laryngeal carcinoma cell line HEp-2 through the NK-1 receptor, and also indicate that both NK-1 receptors antagonists induced apoptosis of the tumour cells. This new action, reported here for the first time, suggests that the NK-1 receptor is a new and promising target in the treatment of human laryngeal carcinoma.
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Affiliation(s)
- Miguel Muñoz
- Hospital Universitario Virgen del Rocío, Seville, Spain.
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