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

Title
Asymmetric Synthesis and Anti-HIV-I Activity of Hydroxy-Substituted Apio Dideoxynucleosides
Authors
권성희
Issue Date
2002
Department/Major
대학원 약학과
Keywords
Asymmetric SynthesisAnti-HIV-IHydroxy-Substituted ApioDideoxynucleosides
Publisher
The Graduate School of Ewha Womans University
Degree
Master
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.
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