Design, Synthesis, and Antiviral Evaluation of Some 3′-Carboxymethyl-3′-Deoxyadenosine Derivatives

Abstract

3′-Carboxymethyl-3′-deoxyadenosine derivatives were prepared from 2′-O-TBDMS-3′-[(ethoxycarbonyl)methyl]-3′-deoxyadenosine (1) via simple and efficient procedures. Conversion of 1 to its 5′-azido-5′-deoxy derivative 5 was accomplished via a novel one-pot method employing 5′-activation (TosCl) followed by efficient nucleophilic displacement with tetramethylguanidinium azide. Compound 5 was converted to 5′-[(N-methylcarbamoyl)amino] derivative 8 via one-pot reduction/acylation employing H₂/Pd-C followed by treatment with p-nitrophenyl N-methylcarbamate. N ⁶-phenylcarbamoyl groups were introduced by treatment with phenylisocyanate, and an efficient new method for lactonization of 2′-O-TBDMS-3′-[(ethoxycarbonyl)methyl]-3′-deoxyadenosines to give corresponding 2′,3′-lactones was also developed. Target compounds were evaluated for anti-HIV and anti-HIV integrase activities, but were not active at the concentrations tested.

Keywords:

• HIV
• HIV integrase
• Antivirals
• 3′-C-Branched nucleotides

This work was supported in part by a grant from the Public Health Service (1RO1-AI063973 to WER). Generous support from the BYU Cancer Research Center is also gratefully acknowledged.

Notes

^a Inhibitory concentration required to protect MT-2 cells from 50% viral induced cell death.

^b Cytotoxic concentration required to inhibit cell growth by 50%.

^c Cytotoxic concentration required to inhibit cell growth by 5%.

^d Inhibitory concentration required to inhibit IN 3′-end processing (EP) or strand transfer (ST)by 50%.

^e 3′-End processing.

^f Strand transfer.