Synthesis of 5′-substituted fluoro-neplanocin A analogues: Importance of a hydrogen bonding donor at 5′-position for the inhibitory activity of S-adenosylhomocysteine hydrolase

Abstract

Four 5′-substituted fluoro-neplanocin A analogues 1a-d were designed and synthesized to study structure-activity relationship against SAH. The inhibitory activity against SAH was in the following order: NH 2 > SH > F, N 3, indicating a hydrogen bonding donor such as OH or NH 2 was essential for inhibitory activity. Four 5′-substituted fluoro-neplanocin A analogues 1a-d were designed and synthesized, using cyclopentenone derivative 2 as a key intermediate. The inhibitory activity against SAH was in the following order: NH 2 > SH > F, N 3, indicating a hydrogen bonding donor such as OH or NH 2 was essential for inhibitory activity. All the final compounds showed much less decreased cytotoxicity in two cancer cell lines (Col2 and A549), implying that phosphorylation of the 5′-hydroxyl group of fluoro-neplanocin A is closely related to its high cytotoxicity. © 2004 Elsevier Ltd. All rights reserved.