Abstract:
:While nonsteroidal androgen receptor (AR) antagonists have been known for many years, and used in the clinic for the treatment of hormone dependent prostate cancer, very little is known about nonsteroidal AR agonists. We designed and synthesized a series of chiral bicalutamide analogs, which bear electron-withdrawing groups (either a cyano or a nitro group at the 4-position and a trifluoromethyl group at the 3-position) in the aromatic A ring, and different substituents at the para position in the aromatic B ring of the parent molecule. We also synthesized a series of racemic bicalutamide analogs, which have a trifluoromethyl group instead of a methyl group at the R(2) position. We examined AR binding affinities of our compounds in a competitive binding assay with a radiolabeled high affinity AR ligand, 3H-mibolerone, and also measured their abilities to stimulate AR-mediated transcriptional activation in a cotransfection assay. These studies demonstrated that (1) nonsteroidal ligands can be structurally modified from known nonsteroidal antiandrogens to generate ligands capable of activating AR-mediated transcriptional activation. (2) R-isomer analogs exhibit higher AR binding affinity and more potent functional activity than their corresponding S-isomers in all cases. (3) All sulphide analogs show higher AR binding affinity and more potent functional activity than their corresponding sulphone analogs, with the exception of ligand R-8. Those ligands which exhibit high AR binding affinity and potent functional activity for human AR may provide effective clinical uses for male fertility, male contraception, and hormone replacement therapy.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
He Y,Yin D,Perera M,Kirkovsky L,Stourman N,Li W,Dalton JT,Miller DDdoi
10.1016/s0223-5234(02)01335-1subject
Has Abstractpub_date
2002-08-01 00:00:00pages
619-34issue
8eissn
0223-5234issn
1768-3254pii
S0223523402013351journal_volume
37pub_type
杂志文章abstract::The synthesis and vascular 5-HT(1B) receptor activity of a novel series of substituted 3-amido phenylpiperazine and 4-(4-methyl-1-piperazinyl)-1-benzo[b]thiophene derivatives is described. Modifications to the amido linked sidechains of the 3-amidophenyl-piperazine derivatives and to the 2-sidechain of the 1-benzo[b]t...
journal_title:European journal of medicinal chemistry
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abstract::In an effort to develop multipotent agents against β-secretase (BACE-1) and acetylcholinesterase (AChE), able to counteract intracellular ROS formation as well, the structure of the fluorinated benzophenone 3 served as starting point for the synthesis of a small library of 3-fluoro-4-hydroxy- analogues. Among the seri...
journal_title:European journal of medicinal chemistry
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journal_title:European journal of medicinal chemistry
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abstract::Naphthoquinoidal compounds are of great interest in medicinal chemistry. In recent years, several synthetic routes have been developed to obtain bioactive molecules derived from lapachones. In this mini-review, we focus on the synthetic aspects and strategies used to design these compounds and on the biological activi...
journal_title:European journal of medicinal chemistry
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journal_title:European journal of medicinal chemistry
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journal_title:European journal of medicinal chemistry
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journal_title:European journal of medicinal chemistry
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journal_title:European journal of medicinal chemistry
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journal_title:European journal of medicinal chemistry
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abstract::Epidermal growth factor receptor inhibitors (EGFR-TKIs) represent a class of compounds widely used in anticancer therapy. An increasing number of studies reports on combination therapies in which the block of the EGFR-TK activity is associated with inhibition of its downstream pathways, as PI3K-Akt. Sulforaphane targe...
journal_title:European journal of medicinal chemistry
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journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2007.01.006
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journal_title:European journal of medicinal chemistry
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journal_title:European journal of medicinal chemistry
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journal_title:European journal of medicinal chemistry
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journal_title:European journal of medicinal chemistry
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doi:10.1016/j.ejmech.2009.12.042
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journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
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journal_title:European journal of medicinal chemistry
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abstract::Herein, we report on the synthesis, spectral, crystallographic and electrochemical properties of a small library of N-substituted 2-ferrocenyl-1,3-thiazolidin-4-ones, designed as novel GABAA benzodiazepine-binding site ligands. The anxiolytic properties of the title compounds were evaluated in several different in viv...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
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journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2010.05.070
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abstract::The increasing development of targeted cancer therapy provides extensive possibilities in clinical trials, and numerous strategies have been explored. The prodrug is one of the most promising strategies in targeted cancer therapy to improve the selectivity and efficacy of cytotoxic compounds. Compared with normal tiss...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1016/j.ejmech.2017.08.010
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abstract::In line of a scaffold hopping strategy of pyrazole structures, especially known as potent CB(2) receptor antagonists, we exploited an original and convergent synthesis of a new class of C4-benzyl pyrazolines and derivatives from readily available hydrazones and enones (two or three steps). Making use of a mixture of r...
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pub_type: 杂志文章
doi:10.1016/j.ejmech.2012.10.031
更新日期:2012-12-01 00:00:00