Asymmetric Synthesis and Anti-HIV-I Activity of Hydroxy-Substituted Apio Dideoxynucleosides

Abstract

Apio dideoxynucleosides (apio ddNs) which belong to novel class of nucleosides in that oxygen of the furanose and C2'-methylene are transposed, were reported to show anti-HIV activity and better profile about enzymatic deamination and glycosyl bond hydrolysis than 2',3'-dideoxynucleosides (ddNs). On the other hand, many L-nucleosides were found to be less cytotoxic than the corresponding D-nucleosides while maintaining their antiviral activities or sometimes possessing better antiviral activities. On the basis of these findings, we synthesized D- and L-apio cytidine derivatives were synthesized to compare their antiviral activity with that of parent nucleosides. Novel n- and L-2'-hydroxy substituted apio cytidines have been synthesized, starting from D-galactose via exocyclic methylene sugar 4 as a key intermediate. Stereocontrol (S-configuration) of the C3'position for D-nucleosides was accomplished using stereoselective dihydroxylation of 4 followed by stereoselective deoxygenation. Stereocontrol (R-cofiguration) of the C3'position for L-nucleosides was achieved using stereoselective hydroboration of 4 with bulky 9-BBN followed by oxidation with sodium perborate. The glycosyl donors, 2 and 6 were condensed with N^(4)-benzoylcytosine in the presence of TMSOTf to give the protected nucleosides, respectively. Deprotection of D- and L-anomers afforded D-apio analogue 1 and L-apio analogues 5a and 5b, respectively. The final nucleosides 1,5a and 5b were tested against HIV-1 in MT-4 cells. They were found to be neither active nor cytotoxic up to 100μM.;Apio dideoxynucleosides는 furanose ring의 산소와 C2'의 methylene기의 위치가 바꿔 새로운 계열의 nucleosides에 속하는 물질로서 항 HIV활성이 있으며 기존의 dideoxynucleosides 보다 바이러스 효소에 의한 deamination 및 glycosyl bond의 가수분해 작용이 적은 것으로 알려져있다. 최근에는 천연의 D-nucleosides 보다 독성이 적은 L-nucleosides가 보다 뛰어난 항바이러스 효과를 가지고 있음이 보고되고 있기 때문에 D체 뿐만 아니라 L체의 apio cytidine 유도체들을 합성하였다. D-galactose로부터 D체와 L체의 공통 중간체인 olefine 4를 합성하고 1,2-acetonide의 steric effect를 이용하여 C3에서 수산화 메틸기의 위치 선택성을 결정하였다. D-nucleoside를 유도하기 위해서 4로부터 dihydroxylation과 deoxygenation을 거쳐서 12 (s-configuration)를 합성하였고 L-nucleosides를 얻기 위해 4로 부터 hydroration과 산화과정을 거쳐서 7(R-configuration)을 합성하였다. 이들을 Ν^(4)-benzoylcytosine과 축합하여 D체인 1과 L체인 5a 및 5b를 얻을 수 있었다. 이들은 MT-4 세포에서 100 μM까지 항 HIV-1 효과가 없는 것으로 나타났으며 다른 항바이러스 활성을 측정중에 있다.