Synthetic and structural studies on anti-HIV agents

Work described in this dissertation focuses on synthesis and biological evaluation of anti-HIV agents. The leads for the three projects discussed were obtained from the National Cancer Institute’s developmental therapeutics program.

Recently, there has been a lot of interest in compounds that target the highly conserved retroviral zinc fingers of the nucleocapsid p7 (NCp7) protein as inhibitors of HIV-1. Described here is the synthesis and anti-HIV-1 evaluation of analogs of the lead compounds, cis- and trans-4,5-dihydroxy-1,2-hithiane 1,1-dioxides. Also, described here is the resolution of the most active compound, (±)-cis-4,5-4,5-dihydroxy-l,2-dithiane 1,1- dioxide, into its enantiomers using an optically active ancillary group and evaluation of their anti-HIV-1 activity. Finally, the absolute configuration of these enantiomers was established by obtaining a single-crystal X-ray structure of the bis-‘Mosher’ ester of the (-)-enantiomer.

Calanolide A is a potent non-nucleoside reverse transcriptase inhibitor of HIV-1. Analogs of this natural product were synthesized in racemic form in our laboratory and evaluated for anti-HIV-1 activity. The 5-isoproxy analog was found to be the most active compound in this series.

The last project discussed here also deals with non-nucleoside reverse transcriptase inhibitors of HIV-1. Analogs of the lead compound, (±)-2-methyl-3-phenyl- 2,3-dihydrobenzo[d]isothiazole 1,1-dioxide, were synthesized and evaluated for anti- HIV-1 activity. The lead compound was resolved into its enantiomers using chiral HPLC and the (+)-enantiomer was found to be the active component. Also, described here is the work done towards determining the absolute configuration of the enantiomers of (±)-2-methyl-3 -phenyl-2,3-dihydrobenzo [d]isothiazole 1,1-dioxide.