Improved synthesis and pharmacological evaluation of racemic 11 -demethylcalanolide A / 药学学报
Acta Pharmaceutica Sinica
;
(12): 707-718, 2008.
Article
in English
| WPRIM
| ID: wpr-277808
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.
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Pharmacology
/
Zidovudine
/
HIV-1
/
Reverse Transcriptase Inhibitors
/
Indinavir
/
Anti-HIV Agents
/
Pyranocoumarins
/
Drug Synergism
/
Allergy and Immunology
/
Toxicity
Limits:
Animals
/
Humans
/
Male
Language:
English
Journal:
Acta Pharmaceutica Sinica
Year:
2008
Type:
Article
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