Structure-Activity Relationship Studies of Ethyl 2-Amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA 14-1), an Antagonist for Antiapoptotic Bcl-2 Proteins To Overcome
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- 作者：Jignesh M. Doshi ; Defeng Tian ; Chengguo Xing
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：December 28, 2006
- 年：2006
- 卷：49
- 期：26
- 页码：7731 - 7739
- 全文大小：300K
- 年卷期：v.49,no.26(December 28, 2006)
- ISSN：1520-4804
文摘
The structure-activity relationship studies of ethyl 2-amino-6-cyclopentyl-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (1, HA 14-1), an antagonist of the antiapoptotic Bcl-2 proteins, are reported. Aseries of analogues of 1 with varied functional groups at the 6-position of the chromene ring were synthesized.These candidates were evaluated for their binding interactions with three antiapoptotic proteins: Bcl-2,Bcl-XL, and Bcl-w. They were also assayed for their in vitro cytotoxicities against a set of Jurkat cells withvaried levels of Bcl-2 and Bcl-XL proteins and a non-small-cell lung carcinoma cell line (NCI-H460). Itwas found that the 6-bromo of 1 was not essential for its bioactivity and the 6-position can accommodatea variety of alkyl groups. 1 and its analogues bind to all of the three antiapoptotic Bcl-2 proteins tested.Positive correlations were observed between the binding affinities of these candidates to the antiapoptoticBcl-2 proteins and their in vitro cytotoxicities, suggesting that the antiapoptotic Bcl-2 proteins are likely tobe the cellular targets of 1 and its analogues. (In this study, the binding interactions of the small moleculesto antiapoptotic Bcl-2 proteins were studied by assaying their abilities to compete against a Bak peptidebinding to the antiapoptotic Bcl-2 proteins. Inhibitory constants, instead of dissociation constants, wereobtained in such assays. The term "binding affinity" is used in this article for simplicity.) The most activecompound, 3g, had a >3-fold increase of binding affinity to the antiapoptotic Bcl-2 proteins and a >13-fold increase of in vitro cytotoxicity over 1. Though Jurkat cells with transgenic overexpression of Bcl-2 orBcl-XL protein can develop resistance to standard cancer therapies, such cells failed to develop resistanceto 1 based candidates. 1 also sensitizes Jurkat cells to cisplatin. These studies provide further support that1 and its analogues function as antagonists for antiapoptotic Bcl-2 proteins and that they have the potential,either as a single agent or as a combination therapy with other anticancer agents, to treat cancers with theoverexpression of antiapoptotic Bcl-2 proteins.