The anti-HIV agent (+/-)-calanolide A (1) has been synthesized in a five-step approach starting with phloroglucinol [-->5-->6-->11-->18-->(+/-)-1], which includes Pechmann reaction, Friedel-Crafts acylation, chromenylation with 4,4-dimethoxy-2-methylbutan-2-ol, cyclization, and Luche reduction. Cyclization of chromene 11 to chromanone 18 was achieved by employing either acetaldehyde diethyl acetal or paraldehyde in the presence of trifluoroacetic acid and pyridine or PPTS. Luche reduction of chromanone 18 at lower temperature preferably yielded (+/-)-1. Reduction of chromone 12, synthesized by Kostanecki-Robinson reaction from chromene 11, failed to afford (+/-)-1. The synthetic (+/-)-1 has been chromatographically resolved into its optically active forms, (+)- and (-)-1. The anti-HIV activities for synthetic (+/-)-1, as well as resultant (+)- and (-)-1, have been determined. Only (+)-1 accounted for anti-HIV activity, which was similar to the data reported for the natural product, and (-)-1 was inactive.
(+)-Calanolide A is a potent inhibitor of reverse transcriptase from human immunodeficiency virus type 1 (HIV-1), which was isolated from an extract of Calophyllum lanigerum, along with seven related compounds. In order to examine the structure-activity relationships of the trans-10,11-dimethyldihydropyran-12-ol ring (designated ring C), a series of structural analogues were prepared and evaluated using a whole cell cytopathicity assay (XTT). Removal of the 10-methyl group resulted in decreased activity, with only one epimer exhibiting anti-HIV activity. Substituting the 10-methyl group with an ethyl chain maintained anti-HIV activity, with only a 4-fold reduction in potency relative to racemic calanolide A. Substitution of the 10-methyl group with an isopropyl moiety completely eliminated the anti-HIV activity. Addition of an extra methyl group at either the 10- or 11-position maintained the basic stereochemical features of the parent calanolide system while removing the chirality at the respective carbon, but resulted in decreased activity relative to calanolide A. In all the above examples, analogues containing a cis relationship between the 10- and 11-alkyl moieties were completely devoid of activity. Synthetic intermediates in which the 12-hydroxyl group was in the ketone oxidation state exhibited suppressing anti-HIV activity, with EC50 values only 5-fold less potent than that of calanolide A for both the 10,11-cis (6) and -trans (5) series. These ketones represent the first derivatives in the calanolide series to exhibit anti-HIV activity while not containing a 12-hydroxyl group. Likewise, ketone derivative 6 was the first example of a compound in the calanolide series having a cis relationship between the 10- and 11-methyl groups found to exhibit anti-HIV activity. Analogues which showed anti-HIV activity in the CEM-SS cytoprotection assay were further confirmed to be inhibitors of HIV-1 reverse transcriptase.
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