Molecular Topology Applied to the Discovery of 1-Benzyl-2-(3-fluorophenyl)-4-hydroxy-3-(3-phenylpropanoyl)-2H-pyrrole-5-one as a Non-Ligand-Binding-Pocket Antiandrogen

被引：9
|
作者：
Caboni, Laura [1 ]
Galvez-Llompart, Maria [2 ]
Galvez, Jorge [2 ]
Blanco, Fernando [1 ]
Rubio-Martinez, Jaime [3 ,4 ]
Fayne, Darren [1 ]
Lloyd, David G. [1 ]
机构：
[1] Trinity Coll Dublin, Trinity Biomed Sci Inst, Sch Biochem & Immunol, Mol Design Grp, Dublin 2, Ireland
[2] Univ Valencia, Fac Pharm, Dept Phys Chem, Drug Design & Mol Connect Res Unit, Valencia, Spain
[3] Univ Barcelona, Dept Phys Chem, Barcelona, Spain
[4] Univ Barcelona, Inst Quim Teor & Computac IQTCUB, Barcelona, Spain
来源：
JOURNAL OF CHEMICAL INFORMATION AND MODELING | 2014年 / 54卷 / 10期
关键词：
3; BF3; SITE; ANDROGEN RECEPTOR; ANTIHISTAMINIC COMPOUNDS; ACTIVE-DRUGS; PREDICTION; SEARCH; VALIDATION; CHEMISTRY; TOXICITY; PATTERN;
D O I：
10.1021/ci500324f
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
We report the discovery of 1-benzyl-2-(3-fluorophenyl)-4-hydroxy-3-(3-phenylpropanoyl)-2H-pyrrole-5-one as a novel non-ligand binding pocket (non-LBP) antagonist of the androgen receptor (AR) through the application of molecular topology techniques. This compound, validated through time-resolved fluorescence resonance energy transfer and fluorescence polarization biological assays, provides the basis for lead optimization and structureactivity relationship analysis of a new series of non-LBP AR antagonists. Induced-fit docking and molecular dynamics studies have been performed to establish a consistent hypothesis for the interaction of the new active molecule on the AR surface.
引用
收藏
页码：2953 / 2966
页数：14
相关论文
共 50 条
  • [21] Five-membered 2,3-dioxoheterocycles: LXXXVI. Spiro-heterocyclization of 1-aryl-4-aroyl-5-methoxycarbonyl-1H-pyrrole-2,3-diones under the action of 3-arylamino-1H-inden-1-ones. Crystal and molecular structure of 4′-hydroxy-3′-(2,4-dimethylbenzoyl)-1,1′-diphenyl-1H-spiro[indeno[1,2-b]pyrrole-3,2′-pyrrole]-2,4,5′(1′H)-trione
    N. V. Bubnov
    E. S. Denislamova
    P. S. Silaichev
    P. A. Slepukhin
    A. N. Maslivets
    Russian Journal of Organic Chemistry, 2012, 48 : 694 - 698
  • [22] Five-membered 2,3-dioxoheterocycles: LXXXVI. Spiro-heterocyclization of 1-aryl-4-aroyl-5-methoxycarbonyl-1H-pyrrole-2,3-diones under the action of 3-arylamino-1H-inden-1-ones. Crystal and molecular structure of 4′-hydroxy-3′-(2,4-dimethylbenzoyl)-1,1′-diphenyl-1H-spiro[indeno[1,2-b]pyrrole-3,2′-pyrrole]-2,4,5′(1′H)-trione
    Bubnov, N. V.
    Denislamova, E. S.
    Silaichev, P. S.
    Slepukhin, P. A.
    Maslivets, A. N.
    RUSSIAN JOURNAL OF ORGANIC CHEMISTRY, 2012, 48 (05) : 694 - 698
  • [23] Synthesis, characterization and cytotoxicity of a new palladium(II) complex with a coumarin-derived ligand. Crystal structure of 4-hydroxy-3-(1-(p-tolylimino)ethyl)-2H-chromen-2-one-palladium(II) complex
    Jevtic, Verica V.
    Pesic, Milica
    Radic, Gordana P.
    Vukovic, Nenad
    Sukdolak, Slobodan
    Klisuric, Olivera
    Podolski-Renic, Ana
    Tanic, Nikola
    Trifunovic, Srecko R.
    JOURNAL OF MOLECULAR STRUCTURE, 2013, 1040 : 216 - 220
  • [24] Discovery and Preclinical Evaluation of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic Acid, (3S)-3-Morpholinylmethyl Ester (BMS-599626), a Selective and Orally Efficacious Inhibitor of Human Epidermal Growth Factor Receptor 1 and 2 Kinases
    Gavai, Ashvinikumar V.
    Fink, Brian E.
    Fairfax, David J.
    Martin, Gregory S.
    Rossiter, Lana M.
    Holst, Christian L.
    Kim, Soong-Hoon
    Leavitt, Kenneth J.
    Mastalerz, Harold
    Han, Wen-Ching
    Norris, Derek
    Goyal, Bindu
    Swaminathan, Shankar
    Patel, Bharat
    Mathur, Arvind
    Vyas, Dolatrai M.
    Tokarski, John S.
    Yu, Chiang
    Oppenheimer, Simone
    Zhang, Hongjian
    Marathe, Punit
    Fargnoli, Joseph
    Lee, Francis Y.
    Wong, Tai W.
    Vite, Gregory D.
    JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (21) : 6527 - 6530
  • [25] Synthesis, Spectroscopic Studies and Antifungal Activity of 2-[(4(3-Chlorophenyl) piperazine-1-yl)methyl]-3-[8-hydroxy quinolin-5-yl]-3(H)-quinazolin-4-one Ligand and its Chelates
    Vashi, R. T.
    Shelat, C. D.
    Patel, Himanshu
    E-JOURNAL OF CHEMISTRY, 2010, 7 : S163 - S168
  • [26] Synthesis and crystal structure of (S,E)-4-hydroxy-3-(2-((4aR,6aS,7R,10aS,10bR)-3,3,6a,10b-tetramethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethylidene)dihydrofuran-2(3H)-one, C23H34O5
    Li, Shi-Qing
    Zhou, Jian
    Dong, Zhang-Chao
    Pan, Bo Wen
    Shi, Yang
    Zhou, Ying
    ZEITSCHRIFT FUR KRISTALLOGRAPHIE-NEW CRYSTAL STRUCTURES, 2023, 238 (04): : 735 - 737
  • [27] Interaction of 3-p-toluoyl-1,2-dihydro-4H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-trione with benzylamine. Synthesis and crystal and molecular structure of Z-3-(1-benzyl-2-hydroxy-4,5-dioxo-2-p-tolyltetrahydropyrrol-3-idene)-3,4-dihydro-2H-1,4-benzoxazin-2-one
    Aliev, ZG
    Maslivets, AN
    Mashevskaya, IV
    Andreichikov, YS
    Atovmyan, LO
    RUSSIAN CHEMICAL BULLETIN, 1997, 46 (03) : 546 - 549
  • [28] Interaction of 3-p-toluoyl-1,2-dihydro-4H-pyrrolo-[2,1-c][1,4]benzoxazine-1,2,4-trione with benzylamine. Synthesis and crystal and molecular structure ofZ-3-(1-benzyl-2-hydroxy-4,5-dioxo-2-p-tolyltetrahydropyrrol-3-idene)-3,4-dihydro-2H-1,4-benzoxazin-2-one
    Z. G. Aliev
    A. N. Maslivets
    I. V. Mashevskaya
    Yu. S. Andreichikov
    L. O. Atovmyan
    Russian Chemical Bulletin, 1997, 46 : 546 - 549
  • [29] COMPLEXES OF THE METHYL TRIS (3,5-DIMETHYLPYRAZOL-1-YL) GALLATE LIGAND, MEGA(N2C5H7)3-, AND ITS HYDROXY DERIVATIVE, MEGA(N2C5H7)2(OH)- - CRYSTAL AND MOLECULAR-STRUCTURE OF [MEGA(N2C5H7)2(OH)]MO(CO)2(ETA-3-C4H7)
    BREAKELL, KR
    RETTIG, SJ
    STORR, A
    TROTTER, J
    CANADIAN JOURNAL OF CHEMISTRY-REVUE CANADIENNE DE CHIMIE, 1979, 57 (02): : 139 - 146
  • [30] Five-membered 2,3-dioxo heterocycles: LXXXV. Synthesis of methyl 1-aryl-4,5-dioxo-3-(1-oxo-3-phenylprop-2-en-1-yl)-4,5-dihydro-1H-pyrrole-2-carboxylates and their reaction with 3-amino-5,5-dimethylcyclohex-2-en-1-ones. Molecular and crystalline structure of 4′-hydroxy-1′-(4-methoxyphenyl)-6,6-dimethyl-3′-(1-oxo-3-phenylprop-2-en-1-yl)-1-phenyl-6,7-dihydrospiro[indole-3,2′-pyrrole]-2,4,5′(1H,1′H,5H)-trione
    Silaichev, P. S.
    Filimonov, V. O.
    Slepukhin, P. A.
    Maslivets, A. N.
    RUSSIAN JOURNAL OF ORGANIC CHEMISTRY, 2012, 48 (04) : 561 - 565
12345