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

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.

• Authors: Li-Fan Zeng, 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 22 Pg. 9492-509 (Nov 26 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 23098137 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• HIV Integrase Inhibitors
• L870810
• Naphthyridines
• HIV Integrase

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Drug Design
• HIV Infections (drug therapy)
• HIV Integrase (chemistry)
• HIV Integrase Inhibitors (chemistry, pharmacology)
• HIV-1 (drug effects)
• Humans
• Models, Molecular
• Molecular Structure
• Naphthyridines (chemistry, pharmacology)
• Neoplasms (drug therapy)
• Structure-Activity Relationship
• Tumor Cells, Cultured
• Virus Integration (drug effects)