Novel N-3 Substituted TSAO-T Derivatives: Synthesis and Anti-HIV-Evaluation

Abstract

Novel derivatives of the anti-HIV-1 agent, TSAO-T, bearing at the N-3 position alkylating groups or photoaffinity labels were prepared and evaluated for their anti-HIV activity. All of these compounds demonstrated pronounced anti-HIV-1 activity and inhibited HIV-1 RT; however, we were unable to detect stable covalent linkages between inhibitor and enzyme. In addition, compounds with an alcohol functional group connected to the N-3 position through a cis or trans double bond have been prepared. These compounds have been useful to study how the conformational restriction of the linker affects in the interaction between the N-3 substituent and the HIV-1 RT enzyme.

Keywords:

• AIDS
• HIV-1 reverse transcriptase
• TSAO-T

We thank Dr. Francisco Amat for his help and advise with the photochemical experiments. We thank the Ministery of Education of Spain for a grant to María-Cruz Bonache. The Spanish MEC (project SAF2006–12713-C02) is also acknowledged for financial support. NSC was supported by grants GM068406 and R21 AI060393 from the National Institutes of Health (USA).

Notes

^a 50% effective concentration, or the compound concentration required to inhibit HIV-induced cytopathicity by 50%.

^b 50% cytostatic concentration, or the compound concentration required to inhibit cell proliferation (CEM) or to reduce cell viability (MT-4) by 50%.

^c 50% inhibitory concentration, or the compound concentration required to inhibit recombinant HIV-1 RT activity by 50%.

^d Data taken from ref. [13]

^e Data taken from ref. [23].