Improved synthesis and pharmacological evaluation of racemic 11 -demethylcalanolide A.
- Author:
Lin WANG
1
;
Xing-quan ZHANG
;
Hong-shan CHEN
;
Pei-zhen TAO
;
Yan LI
;
Yu BAI
;
Jin-ping HU
;
Tao MA
;
Zhen-tang XING
;
Zong-gen PENG
;
Chun-mei ZHOU
;
Qi GAO
;
Gang LIU
Author Information
1. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
- Publication Type:Journal Article
- MeSH:
Animals;
Anti-HIV Agents;
chemical synthesis;
immunology;
pharmacology;
toxicity;
Drug Synergism;
HIV Reverse Transcriptase;
metabolism;
HIV-1;
drug effects;
enzymology;
Humans;
Immune Sera;
pharmacology;
Indinavir;
pharmacology;
Lethal Dose 50;
Male;
Mice;
Pyranocoumarins;
chemical synthesis;
immunology;
pharmacology;
toxicity;
Reverse Transcriptase Inhibitors;
chemical synthesis;
immunology;
pharmacology;
toxicity;
Zidovudine;
pharmacology
- From:
Acta Pharmaceutica Sinica
2008;43(7):707-718
- CountryChina
- Language:English
-
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.
