Synthesis of Carbocyclic Nucleosides as Potent Antiviral and Antitumor Agents

Abstract

Neplanocin A, isolated from Ampullariella regularis, has been introduced as a potent antiviral and antitumor agent. On the basis of potent antiviral and antitumor activity of adenosine and cytosine analogues, 3-deazaneplanosine A (DZNep) 2 and fluorocyclopentenyl cytosine 5 were designed and synthesized from D-ribose. 3-deazaneplanocin A (DZNep) 2 was synthesized from commercially available D-ribose via Wittig reaction, Swern oxidation, stereoselective Grignard reaction, ring-closing metathesis (RCM) reaction, oxidative rearrangement, and Mitsunobu condensation as key steps. For the synthesis of fluorocyclopentenyl cytosine 5, Wittig reaction, Swern oxidation, stereoselective Grignard reaction, ring-closing metathesis (RCM) reaction, oxidative rearrangement, iodination, and electrophilic fluorination as key steps. This cytosine derivative 5 was found to show high growth inhibition against a broad range of human tumor cell lines.;Ampullariella regularis에서 추출된 neplanocin A는 강력한 항바이러스, 항암효과를 가지고 있다. 또한 adenosine과 cytosine analogue 역시 항바이러스, 항암효과를 보인다는 결과를 근거로 하여, 3-deazaneplanocin A (DZNep)와 fluorocyclopentenyl cytosine을 설계하고 합성하였다. D-Ribose를 출발물질로 사용하고 Wittig 반응, Swern oxidation, stereoselective Grignard 반응, ring-closing metathesis (RCM) 반응 등의 핵심 반응을 적용하여, 주요 중간체인 glycosyl donor를 합성하였다. 이 중간체를 N6,N6-di-Boc-3-deazaadenine과 Mitunobu 반응을 이용해 DZNep을 합성하였고, fluorocyclopentenyl cytosine은 동일한 중간체를 benzoyluracil과 축합하여 만들어내었다. Fluorocyclopentenyl cytosine은 다양한 human tumor cell line에 대해 높은 성장 억제 효과를 나타내었다.