title: Improved synthesis and pharmacological evaluation of racemic 11 -demethylcalanolide A.
abstract: An improved and practical synthesis of racemic 11-demethylcalanolide A [(+/-)-1] was developed. This improved process involved Pechmann reaction on phloroglucinol with ethyl butyrylacetate to give 5,7,-dihydroxy4-n-propylcoumarin (3). Poly phosphoric acid (PPA) catalyzed acylation of compound (3) with crotonic acid, then intramolecular cyclization was achieved simultaneously in one step to afford the key intermediate chromanone (4). A microwave assisted synthetic method preparing chromene (6) using chromenynation of chromanone (4) with 1, 1-diethoxy-methyl-2-butene was conducted. Luche reduction of chromene (6) using NaBH4 with CeCl3 x 7H2O preferably gave (+/-)-1. The overall yield of this four step synthesis of (+/-)-1 was around 32% increasing one fold more than that of the previous method. An in vitro investigation showed that (+/-)-1 exhibited inhibitory activities against both wild-type and drug-resistant HIV-1 in HIV-1 RT and cell culture assay, and significant synergistic effects in combination with AZT, T-20, and indinavir. Its LD50 of acute toxicity in mice by intragastric administration and by intraperitoneal injection were 735.65 mg kg(-1) and 525.10 mg x kg(-1), respectively. The Cmax and AUC(0-infinity) were 0.54 microg x mL(-1) and 1.08 (microg x mL(-1) x h, respectively. The dynamics study of the inhibition of mice sera on HIV-1 RT showed that mice treated with 100 mg x kg(-1 (+/-)-1 once intraperitoneally were similar to that of 5 mg x kg(-1) of known clinical effective anti-HIV-1 drug neverapine. The results suggested that further investigation of the anti-HIV candidate (+/-)-1 was warranted.
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Xing-quan
authors.initials: XQ
authors.lastname: Zhang
authors.forename: Hong-shan
authors.initials: HS
authors.lastname: Chen
authors.forename: Pei-zhen
authors.initials: PZ
authors.lastname: Tao
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Bai
authors.forename: Jin-ping
authors.initials: JP
authors.lastname: Hu
authors.forename: Tao
authors.initials: T
authors.lastname: Ma
authors.forename: Zhen-tang
authors.initials: ZT
authors.lastname: Xing
authors.forename: Zong-gen
authors.initials: ZG
authors.lastname: Peng
authors.forename: Chun-mei
authors.initials: CM
authors.lastname: Zhou
authors.forename: Qi
authors.initials: Q
authors.lastname: Gao
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000276:immunology / Q000494:pharmacology / Q000633:toxicity; D004357:Drug Synergism; D054303:HIV Reverse Transcriptase / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D019469:Indinavir / Q000494:pharmacology; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D039681:Pyranocoumarins / Q000138:chemical synthesis* / Q000276:immunology / Q000494:pharmacology / Q000633:toxicity; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000276:immunology / Q000494:pharmacology / Q000633:toxicity; D015215:Zidovudine / Q000494:pharmacology
chemical_list: C543509:11-demethylcalanolide A; D019380:Anti-HIV Agents; D007106:Immune Sera; D039681:Pyranocoumarins; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D019469:Indinavir; D054303:HIV Reverse Transcriptase