Pyranochromone Derivatives (DCPs) as Novel Anti-HIV

Agents
DCP (3’,4’-di-O-(-)-camphanoyl-2’,2’-dimethyldihydropyrano[2,3-f]chromone, 65)
was developed from DCK with the intention to further extend the SAR study.28, 29 In
order to introduce structural variety, the 2H–pyran-2-one system in DCK was
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replaced with a 4H-pyran-4-one in DCP. Diverse substitutions (mostly alkyl groups)
were introduced on the pyranochromone ring skeleton. Compared with DCK analogs,
the synthesized DCP analogs, not only showed high potency against a wild-type
HIV-IIIB strain, but most of them also exhibited activity against a multi-drug resistant
HIV RTMDR-1 strain. (Table 3)
The initial SAR study of DCPs suggested that DCP analogs are more promising
than DCK analogs due to their potential to inhibit the replication of HIV RTMDR-1,
which is resistant to DCKs. Methyl and ethyl groups at the 2- or 3-position (66, 68,
69) of the DCP chromone ring system were critical for anti-HIV activity against both
HIV strains. In fact, 2-EDCP (69) presented the best anti-HIV activity against both
wild-type and drug-resistant HIV-1 strains. Larger substituents at the 2-, 3-, and 6-
positions of the chromone ring dramatically decreased the anti-HIV activity against
both wild-type and drug-resistant strains.
Table 2-3. Anti-HIV activity of DCP analogs

Compound 1 contains two chiral centers at the 3’ and 4’ positions on the pyrano
ring system, both with R configurations. Fourteen different dihydroseselin
(khellactone) derivatives, including all four stereochemical isomers, were designed,
synthesized, and evaluated for anti-HIV activity (Table 2-1).11, 12 These compounds
included khellactone itself (12), various acetyl-khellactones (1, 11, 22, 24), and
khellactone diesters (13–21). The ester groups introduced at the 4’ and (or) 3’
positions included simple and branched alkyl systems, aromatic rings and large
bulky groups. 3’,4’-Di-(O)-(-)-camphanoyl-(+)-cis-khellactone (DCK, 18)
demonstrated the most promising inhibitory activity against HIV replication in H9
cells. With an EC50 value of 2.56 x 10-4 µM, DCK was 100-fold more potent than AZT
(0.045 µM) in the same assay. The anti-HIV activity of DCK was highly sterospecific
as the (-)-cis, (-)-trans, and (+)-trans isomers were much less active.12, 20 In addition,
other racemic khellactone analogs with diverse ester groups at the 3’ and 4’
positions were inactive or 10,000 times less active.