Design, Stereoselective Synthesis, and Biological Activity of Neplanocin A Analogues

Abstract

S-Adenosyl-L-homocysteine (SAH) hydrolase is an important intracellular enzyme catalyzing SAH to homocysteine and adenosine. The inhibition of SAH hydrolase resulted in accumulation of SAH in cell, which affects biological transmethylation. Neplanocin A (1) is one of the representative natural occurring carbocyclic nucleosides as inhibitor of SAH hydrolase inhibitor. However, it is difficult to develope 1 as a clinical agent due to cytotoxic effect. To overcome this problem, fluoro-neplanocin A (3) was synthesized and it is two times more potent than compound 1 against SAH hydrolase. Recently, 7-deazaadenine was introduced in place of adenine in 2’-Me-ribonucleoside which also exhibited potent inhibition of SAH hydrolase. Based on these findings, 7-deazaneplanocin A analogues (4, 8, 9) and corresponding fluoro analogues (5, 6, 7), which combines the properties of fluoro-neplanocin A and 7-deazaneplanocin A were synthesized. For the synthesis of the target nucleosides, the ring closing metathesis (RCM), selective epoxidation, nucleophilic fluorination to epoxide and simultaneous oxidation-elimination reactions were employed as the key steps. Biological assay for anticancer and antiviral activity of these compounds (4-9) was carried out. Among them, 7-deaza-fluoroneplanocin A (5) exhibited the most potent anticancer and antiviral activity.;Neplanocin A 는 S-adenoyl-L-homocystein (SAH) hydrolase를 효과적으로 억제하여 항암효과와 항바이러스효과를 나타내는 천연물이다. 이 효과에 착안하여 Fluoroneplanocin A 와 7-Deazazneplanicin A 이 SAH hydrolase 억제제로서 합성되었다. 뛰어난 항암효과와 항바이러스효과를 가진 Fluoroneplanocin A 와 7-Deazazneplanicin A로부터 7-Deazaneplanicin A 유도체를 합성하였다. 원하는 유도체들을 합성하기 위해 ring closing methathesis, 선택적 epoxidation, nucleophilic fluorination 그리고 연속적인 산화-환원 반응이 이번 연구에서 중요하게 진행된 과정이었다. 합성된 Neplanocin A 유도체들 중에 7-Deaza-fluoroneplanocin A 이 가장 뛰어난 항암효과와 항바이러스 효과를 나타내었다.