Design, Efficient Synthesis, and Anti‐HIV Activity of 4′‐C‐Cyano‐ and 4′‐C‐Ethynyl‐2′‐deoxy Purine Nucleosides

Abstract

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.

Development of modified nucleosides that have supremely high anti-HIV activity and low toxicity and prevent the emergence of resistant HIV mutants

“…25,26) These results showed that the actual toxicity of 4′EdA and 4′Ed2AA to animals is hard to estimate.…”

“…25) Although 4′SdN s in our project had been synthesized by the glycosidation of 4- C -substituted- d - ribo -furanose derivatives and nucleobases, this synthetic route incurred some problems, as follows:…”

A New Paradigm for Developing Antiviral Drugs Exemplified by the Development of Supremely High Anti-HIV Active EFdA

“…While we were working on our project, the anti-HIV activity of several 4'SdNs was reported by the Syntex group [16][17][18][19][20][21][22] and others [23,24]. Therefore, the anti-HIV activities of 4'SdNs that we studied together with those reported by other groups are listed in Table 2.…”

“…The L-isomers of 4'SdN have no anti-HIV activity, 13) although it is known that the L-enantiomer of 2',3'-dideoxy-3'-thia-Lcytidine (3TC) is as active as the D-enantiomer and less toxic than the D-isomer [24]. This may be due to that the L-isomers are too much modified to be recognized by RT as its substrates.…”

Developments in Antiviral Drug Design, Discovery and Development in 2004

“…Studies with the triphosphate derivative of racemic 100 revealed it to be similar in potency to zidovudine triphosphate as an inhibitor of HIV RT, leading to the suggestion that 100 was a poor substrate for cellular kinases [343]. The 4'-cyano-diamino purine nucleoside derivative 102 is a potent HIV inhibitor but also expresses significant cytotoxicity, in contrast to the corresponding C4'-ethynyl analogue [344].…”