Design, efficient synthesis, and anti-HIV activity of 4′-C-cyano- and 4′-C-ethynyl-2′-deoxy purine nucleosides

Some 4′-C-ethynyl-2′-deoxy purine nucleosides showed the most potent anti-HIV activity among the series of 4′-C-substituted 2′-deoxynucleosides whose 4′-C-substituents were methyl, ethyl, ethynyl and so on. Our hypothesis is that the smaller the substituent at the C-4′ position they have, the more acceptable biological activity they show. Thus, 4′-C-cyano-2′-deoxy purine nucleosides, whose substituent is smaller than the ethynyl group, will have more potent antiviral activity. To prove our hypothesis, we planned to develop an efficient synthesis of 4′-C-cyano-2′-deoxy purine nucleosides (4′-CNdNs) and 4′-C-ethynyl-2′-deoxy purine nucleosides (4′-EdNs). Consequently, we succeeded in developing an efficient synthesis of six 2′-deoxy purine nucleosides bearing either a cyano or an ethynyl group at the C-4′ position of the sugar moiety from 2′-deoxyadenosine and 2,6-diaminopurine 2′-deoxyriboside. Unfortunately, 4′-C-cyano derivatives showed lower activity against HIV-1, and two 4′-C-ethynyl derivatives suggested high toxicity in vivo.