STRUCTURAL ANALOGS OF THE CALANOLIDE ANTI-HIV AGENTS - MODIFICATION OF THE TRANS-10,11-DIMETHYLDIHYDROPYRAN-12-OL RING (RING-C)

(+)-Calanolide A is a potent inhibitor of reverse transcriptase from h uman 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 o f 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 race mic calanolide A. Substitution of the 10-methyl group with an isopropy l moiety completely eliminated the anti-HIV activity. Addition of an e xtra methyl group at either the 10- or 11-position maintained the basi c stereochemical features of the parent calanolide system while removi ng the chirality at the respective carbon, but resulted in decreased a ctivity relative to calanolide A. In all the above examples, analogues containing a cis relationship between the 10- and 11-alkyl moieties w ere completely devoid of activity. Synthetic intermediates in which th e 12-hydroxyl group was in the ketone oxidation state exhibited surpri sing anti-HIV activity, with EC(50) values only 5-fold less potent tha n that of calanolide A for both the 10,11-cis (6) and -trans (5) serie s. These ketones represent the first derivatives in the calanolide ser ies to exhibit anti-HIV activity while not containing a 12-hydroxyl gr oup. Likewise, ketone derivative 6 was the first example of a compound in the calanolide series having a cis relationship between the 10- an d 11-methyl groups found to exhibit anti-HIV activity. Analogues which showed anti-HIV activity in the CEM-SS cytoprotection assay were furt her confirmed to be inhibitors of HIV-1 reverse transcriptase.