Synthesis and biological evaluation of novel Guanine-containing compounds as potential HIV-1 non-nucleoside reverse transcriptase or integrase inhibitors

Abstract

The global epidemic of HIV/AIDS has become one of the most pressing public health emergencies of this century. Various chemotherapy approaches towards the treatment of HIV-1 have been developed. These approaches were based on targets identified in the life-cycle of HIV-1. In this research work the synthesis of novel guanine compounds is described which were tested for their activities towards reverse transcriptase and integrase enzymes. Initial attempts to synthesise Boc and Cbz protected guan-9-ylacetic acids from commercially available 2-amino-6-chloropurine were inspired by the work of Dey and Garner. Their approach was extended to the synthesis N2-mono-Boc-guan-9-ylacetic acid in 55% yield. Furthermore, a novel route was designed to the latter compound involving the activation of the exocyclic amino group of the purine ring with triphosgene, followed by addition of tert-butanol. This approach gave the desired product in 55% yield. Although the yields of the two strategies were similar, the time taken for completion of the second route was much shorter (3 days cf 7 days). An attempt to synthesize N2-diBoc-guan-9-ylacetic acid only afforded this compound in 20% yield. The activation of the exocyclic amino group of 2-amino-6-chloropurine with triphosgene was also explored for the synthesis of N2-Cbz protected guan-9-ylacetic acid. This gave the desired Cbz-protected N2-guanyl-9-ylacetic acid in yields ranging from 50% to 90% depending on whether ethylbromoacetate or tert-butylbromoacetate was used. The synthesis of orthogonally protected guanine-PNA monomers is described. Boc- and Fmoc-protected aminoethylglycine (PNA backbones) were efficiently prepared using established procedures. The various intermediates were screened for their biological activities and it was found out that N2-benzyloxycarbonylguan-9-ylacetic acid derivatives inhibited HIV-1 reverse transcriptase by interacting with the non-nucleoside binding pocket and they showed a reduced loss of potency towards common drug resistant HIV-1 mutant strains. Various structural modifications of N2-benzyloxycarbonylguan-9-ylacetic acid derivatives were also prepared. Finally, attempts were made to synthesize guanine-PNA dimers and guanine-rich PNA oligomers containing guanine and thymine bases.