Syntheses and structure-activity relationships of novel apio and thioapio dideoxydidehydronucleosides as anti-HCMV agents

On the basis of the fact that apio dideoxynucleosides, in which the furanos e oxygen and the C2 of the 2,3-dideoxyribose are transposed, exhibited pote nt anti-HIV activity and 2',3'-dideoxy-2',3'-didehydronucleosides also show ed potent anti-HIV activity, we synthesized apio dideoxydidehydronucleoside s in which the oxygen atom and the double bond of the 2,3-dideoxy-2,3-dideh ydroribose are exchanged. The thioapio dideoxydidehydronucleosides were als o synthesized since sulfur serves as a bioisostere of oxygen. Apio dideoxyd idehydronucleosides 13a-f were synthesized starting from 1,3-dihydroxyaceto ne, utilizing phenylselenenyl chemistry as a key step. The ratio of the ano meric mixture was variable from 1:1 to 5:1 during the condensation of nucle osidic bases with the phenylselenyl acetate 11 in the presence of a Lewis a cid. This is in contrast with other glycosyl donors such as 5-O-(tert-butyl diphenylsilyl)-2-phenylselenyl- 2,3-dideoxyribosyl acetate which shows exce llent neighboring group effect (alpha:beta = 1:99). Thioapio dideoxydidehyd ronucleosides 22a,b were synthesized from the lactone 9 via thiolactone 17 as a key intermediate which was synthesized from dicyclohexylcarbodiimide c oupling of the mercapto acid produced from the basic hydrolysis of thioacet ate 16. The majority of apio analogues synthesized in this study exhibited moderate to potent anti-HCMV activity, among which the 5-fluorouracil deriv ative 13c was found to be the most potent against HCMV, while thioapio anal ogues showed no activity against HCMV. However, all synthesized compounds d id not exhibit any significant activities against HIV-1, HSV-1, and HSV-2. The fact that apio dideoxydidehydronucleosides were active against HCMV sug gests that the apio dideoxydidehydro sugar moiety can serve as a novel temp late for the development of new antiviral agents.