Improved synthesis and pharmacological evaluation of racemic 11 -demethylcalanolide A.
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.
Wang
Lin
L
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Zhang
Xing-quan
XQ
Chen
Hong-shan
HS
Tao
Pei-zhen
PZ
Li
Yan
Y
Bai
Yu
Y
Hu
Jin-ping
JP
Ma
Tao
T
Xing
Zhen-tang
ZT
Peng
Zong-gen
ZG
Zhou
Chun-mei
CM
Gao
Qi
Q
Liu
Gang
G
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
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