TY - JOUR
T1 - 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 drug resistance in cancer
AU - Doshi, Jignesh M.
AU - Tian, Defeng
AU - Xing, Chengguo
PY - 2006/12/28
Y1 - 2006/12/28
N2 - 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. A series 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 with varied levels of Bcl-2 and Bcl-XL proteins and a non-small-cell lung carcinoma cell line (NCI-H460). It was found that the 6-bromo of 1 was not essential for its bioactivity and the 6-position can accommodate a 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 antiapoptotic Bcl-2 proteins and their in vitro cytotoxicities, suggesting that the antiapoptotic Bcl-2 proteins are likely to be the cellular targets of 1 and its analogues. (In this study, the binding interactions of the small molecules to antiapoptotic Bcl-2 proteins were studied by assaying their abilities to compete against a Bak peptide binding to the antiapoptotic Bcl-2 proteins. Inhibitory constants, instead of dissociation constants, were obtained in such assays. The term "binding affinity" is used in this article for simplicity.) The most active compound, 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 or Bcl-XL protein can develop resistance to standard cancer therapies, such cells failed to develop resistance to 1 based candidates. 1 also sensitizes Jurkat cells to cisplatin. These studies provide further support that 1 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 the overexpression of antiapoptotic Bcl-2 proteins.
AB - 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. A series 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 with varied levels of Bcl-2 and Bcl-XL proteins and a non-small-cell lung carcinoma cell line (NCI-H460). It was found that the 6-bromo of 1 was not essential for its bioactivity and the 6-position can accommodate a 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 antiapoptotic Bcl-2 proteins and their in vitro cytotoxicities, suggesting that the antiapoptotic Bcl-2 proteins are likely to be the cellular targets of 1 and its analogues. (In this study, the binding interactions of the small molecules to antiapoptotic Bcl-2 proteins were studied by assaying their abilities to compete against a Bak peptide binding to the antiapoptotic Bcl-2 proteins. Inhibitory constants, instead of dissociation constants, were obtained in such assays. The term "binding affinity" is used in this article for simplicity.) The most active compound, 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 or Bcl-XL protein can develop resistance to standard cancer therapies, such cells failed to develop resistance to 1 based candidates. 1 also sensitizes Jurkat cells to cisplatin. These studies provide further support that 1 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 the overexpression of antiapoptotic Bcl-2 proteins.
UR - http://www.scopus.com/inward/record.url?scp=33845940416&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33845940416&partnerID=8YFLogxK
U2 - 10.1021/jm060968r
DO - 10.1021/jm060968r
M3 - Article
C2 - 17181155
AN - SCOPUS:33845940416
SN - 0022-2623
VL - 49
SP - 7731
EP - 7739
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 26
ER -