Repositioning HIV-1 integrase inhibitors for cancer therapeutics: 1,6-naphthyridine-7-carboxamide as a promising scaffold with drug-like properties - PubMed (original) (raw)

. 2012 Nov 26;55(22):9492-509.

doi: 10.1021/jm300667v. Epub 2012 Nov 7.

Yong Wang, Roza Kazemi, Shili Xu, Zhong-Liang Xu, Tino W Sanchez, Liu-Meng Yang, Bikash Debnath, Srinivas Odde, Hua Xie, Yong-Tang Zheng, Jian Ding, Nouri Neamati, Ya-Qiu Long

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Repositioning HIV-1 integrase inhibitors for cancer therapeutics: 1,6-naphthyridine-7-carboxamide as a promising scaffold with drug-like properties

Li-Fan Zeng et al. J Med Chem. 2012.

Abstract

Among a large number of HIV-1 integrase (IN) inhibitors, the 8-hydroxy-[1,6]naphthyridines (i.e., L-870,810) were one of the promising class of antiretroviral drugs developed by Merck Laboratories. In spite of its remarkable potency and efficacy, unfortunately upon completion of phase I clinical studies, development of L-870,810 was halted. Because of its desirable pharmacological and pharmaceutical properties we were intrigued to design novel analogues of L-870,810 with goals to (1) improve upon limitations of naphthyridine-7-carboxamides as antiviral agents and (2) to reposition their use as innovative cytotoxic agents for cancer therapeutics. Herein, we report on the design and synthesis of a series of 1,6-naphthyridine-7-carboxamides with various substitutions at the 5- and 8-positions. All the new 5-substituted-8-hydroxy-[1,6]naphthyridines were potent IN inhibitors and the 5-substituted-8-amino-[1,6]naphthyridines were significantly cytotoxic. Further optimization of the 5,8-disubstituted-[1,6]naphthyridines with structural variation on 7-carboxamide delivered novel compounds with significant cytotoxicity in a panel of cancer cell lines and effective inhibition against select oncogenic kinases.

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