title: Chemical library and structure-activity relationships of 11-demethyl-12-oxo calanolide A analogues as anti-HIV-1 agents.
abstract: (+)-Calanolide A ( 1) as a natural product was previously found as an inhibitor of HIV-1 reverse transcriptase. In our further investigation of its template, racemic 11-demethyl-12-oxo calanolide A ( 15), which had two fewer chiral carbon centers at the C-11 and C-12 positions than (+)-calanolide A, had a comparably inhibitory activity and better therapeutic index (EC 50 = 0.11 microM, TI = 818) against HIV-1 in vitro. A library based on its structural core was then designed and synthesized with introduction of nine diversity points in this article. The evaluations of anti-HIV-1 activity in vitro concluded their structure-activity relationships (SARs). A novel compound (10-bromomethyl-11-demethyl-12-oxo calanolide A, 123) was identified to have much higher inhibitory potency and therapeutic index (EC 50 = 2.85 nM, TI > 10,526) than those of the class compound against HIV-1. This finding provided a very important clue that modifications of the C ring at the C-10 position may be conducted to obtain drug candidates with better activity against HIV-1.
authors.affiliation: Department of Synthetic Medicinal Chemistry, Chinese Academy of Medical Sciences, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Ma
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Hai
authors.initials: H
authors.lastname: Xue
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Chunyan
authors.initials: C
authors.lastname: Han
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Chen
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D039681:Pyranocoumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C529298:10-bromomethyl-11-demethyl-12-oxocalanolide A; D019380:Anti-HIV Agents; D002867:Chromones; D003374:Coumarins; D039681:Pyranocoumarins; C075959:calanolide A