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,-dihydroxy-4-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 NaBH<,4> with CeCl3·7H2O 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 735.65mg·kg-1 and 525.10mg·kg-1, respectively. The C<,max> and AUC<,0-∞> were 0.54μg·mL-1 and 1.08(μg·mL-1)·h, respectively. The dynamics study of the inhibition of mice sera on HIV-1 RT showed that mice treated with 100mg·kg-1 (±)-1 once intraperitoneally were similar to that of 5mg·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.