新型N~6-哌嗪取代腺苷衍生物的合成及其抗肿瘤活性

以腺苷为母体,对其N6-位进行结构改造,首先经邻位双羟基保护,N6-位氯代,再在N6-位引入哌嗪环制得中间体2',3'-异丙叉-6-哌嗪嘌呤核苷(4);4与N-氯乙酰苯胺类似物(6a~6h)偶联后脱除邻位双羟基保护合成了8个新型的N6-哌嗪取代腺苷衍生物(8a~8h),其结构经1H NMR,13C NMR和HR-ESI-MS表征。采用MTT法研究了8a~8h对Hela肿瘤细胞的抑制活性。结果表明:大部分目标化合物对Hela肿瘤细胞具有较好的抑制活性,其中2-{4-9-(3,4-二羟基-5-羟甲基-四氢呋喃-2-基)-9H-嘌呤-6-基]-哌嗪-1-基}-N-(3-氟苯基)-乙酰胺(8e)的活性最好,IC50为21.74μmol·L-1。

Synthesis and Antitumor Activities of Novel N6-Piperazine Substituted Adenosine Analogues

The intermediate,{(3R,4R,6R,6R)-2,2-dimethyl-6-6-( piperazin-1-yl)-9H-purin-9-yl] tetrahydrofuro3,4-d]1,3]dioxol-4-yl}methanol(4), was synthesized by three steps including adja-cent hydroxyl protection, chlorination and introduction of piperazine at N6 position, using adenosine as starting material.Eight novel N6-piperazine substituted adenosine analogues(8a~8h) were synthe-sized by coupling reaction of 4 with 6a~6h, then deprotection of hydroxyl.The structures were char-acterized by 1 H NMR, 13 C NMR and HR-ESI-MS.Biological evaluation showed that 8a~8h exhibited antitumor activities on Hela cells, especially, 2-{4-9-(3,4-dihydroxy-5-hydroxymethyl-tetrahydro-fu-ran-2-yl)-9H-purin-6-yl]-piperazin-1-yl}-N-(3-fluoro-phenyl)-acetamide(8e) exhibited the strongest inhibitory activity with IC50 of 21.74 μmol· L-1 .