作为选择性雌激素受体β调节剂的3-芳基喹唑啉酮和3-芳基喹唑啉硫酮衍生物的合成与表征

Synthesis and characterization of 3-arylquinazolinone and 3-arylquinazolinethione derivatives as selective estrogen receptor beta modulators.

作者信息

Güngör Timur, Chen Ying, Golla Rajasree, Ma Zhengping, Corte James R, Northrop John P, Bin Bin, Dickson John K, Stouch Terry, Zhou Rong, Johnson Susan E, Seethala Ramakrishna, Feyen Jean H M

机构信息

Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, NJ 08543-4000, USA.

出版信息

J Med Chem. 2006 Apr 20;49(8):2440-55. doi: 10.1021/jm0509389.

DOI:10.1021/jm0509389

PMID:16610787

Abstract

On the basis of the stucture of genistein, a new series of 3-arylquinazolines was prepared and tested for their estrogen receptor (ER) alpha and beta affinities. 5,7-Dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinone (1aa) acts as an agonist on both ER subtypes. It has 62-fold higher binding affinity [IC(50)(ERbeta) = 179 nM] and 38-fold higher functional potency in a transcription assay [EC(50)(ERbeta) = 76 nM] with ERbeta than with ERalpha, thus improving upon the selectivity of genistein. All of the analogues showed preferential binding affinity for ERbeta. Many are also more potent in activating transcription by ERbeta than by ERalpha. Transformation of the C=O functionality at position 4 into a C=S group provided 5,7-dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinethione (1ba), which acts as an agonist on both ER subtypes but has 56-fold higher binding affinity for ERbeta over ERalpha [IC(50)(ERbeta) = 47 nM] and 215-fold higher potency in the transcription assay [EC(50)(ERbeta) = 13 nM]. These ERbeta-selective compounds may represent valuable tools in understanding the differences in structure and biological function of ERbeta and ERalpha.

摘要

基于染料木黄酮的结构，制备了一系列新的3-芳基喹唑啉，并测试了它们对雌激素受体（ER）α和β的亲和力。5,7-二羟基-3-(4-羟基苯基)-4(3H)-喹唑啉酮（1aa）对两种ER亚型均起激动剂作用。与ERα相比，它与ERβ的结合亲和力高62倍[IC(50)(ERβ)=179 nM]，在转录试验中功能效力高38倍[EC(50)(ERβ)=76 nM]，从而提高了染料木黄酮的选择性。所有类似物对ERβ均表现出优先结合亲和力。许多类似物在通过ERβ激活转录方面也比通过ERα更有效。将4位的C=O官能团转化为C=S基团得到5,7-二羟基-3-(4-羟基苯基)-4(3H)-喹唑啉硫酮（1ba），它对两种ER亚型均起激动剂作用，但与ERα相比，对ERβ的结合亲和力高56倍[IC(50)(ERβ)=47 nM]，在转录试验中的效力高215倍[EC(50)(ERβ)=13 nM]。这些ERβ选择性化合物可能是理解ERβ和ERα在结构和生物学功能上差异的有价值工具。