Synthetic and structural studies on anti-HIV agents

Author

Anand Mayasundari

Date of Award

8-1998

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Chemistry

Major Professor

David C. Baker

Committee Members

George W. Kabalka, Spiro D. Alexandratos, David L. Hacker

Abstract

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.

Recommended Citation

Mayasundari, Anand, "Synthetic and structural studies on anti-HIV agents. " PhD diss., University of Tennessee, 1998.
https://trace.tennessee.edu/utk_graddiss/9310