Synthesis and antiviral activity of azido or amino substituted acyclic nucleosides

Abstract

HCMV(Human cytomegalovirus) is lethal virus, which causes blindness to AIDS patients. Ganciclovir is a nucleoside analogue and has been a drug of choice for HCMV although it exhibited many problems such as low solubility. Since then, a number of compounds have been synthesized and evaluated for anti-HCMV activity in order to find new anti-HCMV drugs to overcome side effects of ganciclovir. Based on the structure of ganciclovir, novel acyclic nucleoside analogues to introduce N₃ or NH₂ on the acyclic moiety were synthesized from 2-methylene-propane-1, 3-diol(6) as a starting material via acid-catalyzed 1,4-addition as a key step. 1, 3-dihydroxyacetone dimmer (6) was protected with benzyl bromide to give 7. Ozonolysis of 7 gave 8. Honer-emmons olefination of 8 gave the α,β-unsaturated ester 9. Azide was inserted into 9 using acid-catalyzed 1,4-addition. Ester 10 was reduced with diisobutylaluminum hydride (DIBAL-H) to give azido aldehyde 11a which was further reduced by the treatment with NaBH_4 to give azido alchol 12a. The mesylate 13 was condensed with 2-amino-6-chloropurine to give the 14a. Deprotection of 14a with BBr₃ afforded the final nucleoside 1. Compound 1 was hydrolyzed using 1N-NaOH to give the guanine nucleoside analogue 2. Another target nucleoside, 3 was synthesized from the catalytic hydrogenation of 1 using Pd/C under H₂ gas. Among these nucleosides, compound 1 exhibited neither anti-HIV, anti-HSV, anti-Poliovirus, anti-Cox. B3, anti-VSV and anti-HBV activities nor toxicity. Compound 2 exhibited anti-HSV-1 activity, but exhibited neither anti-HIV, anti-Poliovirus, anti-Cox. B3, anti-VSV and anti-HBV activities nor toxicity. Anti-HCMV activity of compound 1 and 2 and antiviral activity of compound 3 are being investigated.;HCMV (Human cytomegalovirus)는 AIDS 환자들에게 많이 감염되는 바이러스로서 실명을 유발한다. HCMV 치료제로는 Ganciclovir가 현재 drug of choice로 사용되고 있는데, Ganciclovir는 난용성등 부작용이 크기 때문에 부작용이 경감된 항바이러스 물질을 도출하는 연구가 전세계적으로 많이 진행되고 있다. 따라서 Ganciclovir를 바탕으로 당의 위치에 N₃나 NH₂를 도입한 물질을 합성하여 부작용이 경감되고, 또한Guanine의 난용성을 해결하기 위해 2-amino-6-chloro-purine을 도입한 뉴클레오사이드 유도체를 합성하여 항바이러스 효과가 높은 새로운 항바이러스제를 개발하고자 했다. 2-methylene-propane-1,3-diol (6)을 출발물질로 해서 acid-catalyzed 1,4-addition 를 key step 으로 하여 Azido 중간체인 10번을 합성하여, 최종 뉴클레오사이드 1, 2, 그리고 3을 합성하였다. 뉴클레오사이드 1 는 항HIV, 항HSV, 항Poliovirus, 항Cox. B3, 항VSV 그리고 항HBV 활성을 가지고 있지 않았으며, 뉴클레오사이드2 는 항HSV-1 활성을 나타냈으나 항HIV, 항HSV, 항Poliovirus, 항Cox. B3, 항VSV 그리고 항HBV 활성을 가지고 있지 않았다. 1 과 2 의 항 HCMV 활성과 3 의 항바이러스 효과는 조사중이다.