title: 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.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Li-Fan
authors.initials: LF
authors.lastname: Zeng
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Roza
authors.initials: R
authors.lastname: Kazemi
authors.forename: Shili
authors.initials: S
authors.lastname: Xu
authors.forename: Zhong-Liang
authors.initials: ZL
authors.lastname: Xu
authors.forename: Tino W
authors.initials: TW
authors.lastname: Sanchez
authors.forename: Liu-Meng
authors.initials: LM
authors.lastname: Yang
authors.forename: Bikash
authors.initials: B
authors.lastname: Debnath
authors.forename: Srinivas
authors.initials: S
authors.lastname: Odde
authors.forename: Hua
authors.initials: H
authors.lastname: Xie
authors.forename: Yong-Tang
authors.initials: YT
authors.lastname: Zheng
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
authors.forename: Ya-Qiu
authors.initials: YQ
authors.lastname: Long
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy; D019427:HIV Integrase / Q000737:chemistry; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009287:Naphthyridines / Q000737:chemistry* / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D016662:Virus Integration / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D019428:HIV Integrase Inhibitors; C489415:L870810; D009287:Naphthyridines; D019427:HIV Integrase