氟喹诺酮C-3羧基等排体的合成及抗肿瘤活性V.环丙沙星酰腙的合成及构效关系
Synthesis and antitumor activity of fluoroquinolone C-3 isostere V: ciprofloxacin acylhydrazone derivatives
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摘要: 为发现转化抗菌氟喹诺酮到抗肿瘤氟喹诺酮的策略及其构-效关系,用酰腙作为环丙沙星C3羧基的生物电子等排体,合成了12个未见报道的环丙沙星酰腙( 3a ~ 3l )目标化合物。结果显示:体外对SMMC-7721、L1210和HL60 3种肿瘤细胞的抑制活性显著强于母体,但都低于对照药阿霉素,尤其对肝癌SMMC-7721细胞的活性与阿霉素相当。构效关系表明,取代链苯环带吸电子基团的活性强于供电子基团的活性,酰腙还原产物酰肼取代物的活性消失。结果说明酰腙可作为C-3羧基的等排体,酰腙亚胺双键是抗肿瘤活性所必需的药效团部位。Abstract: To explore an efficient strategy for the transformation of antibacterial fluoroquinoles into antitumor fluoroquinolones and their structure-activity relationship, an acylhydrazone as bioisostere of the C-3 carboxylic group, twelve novel fluoroquinolone C-3 acylhydrazones 3a - 3l were synthesized from ciprofloxacin, respectively. The structures were characterized by element analysis and spectral data. The in vitro antitumor activity against SMMC- 7721, L1210 and HL60 cell lines exhibited more significantly inhibitory activity than the parent, in which compounds with electron-withdrawing group were comparable to doxorubicin. SAR showed that compounds with electron-withdrawing group had more potency than those with electron-donating group, after reduction of acylhydrazone moiety, antitumor activity disappeared. Thus, it is necessary for an acylhydrazone as a bioisostere of the C-3 carboxylic group to develop antitumor fluoroquinolone lead compounds.
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Keywords:
- fluoroquinolone /
- acylhydrazone /
- bioisostere /
- synthesis /
- antitumor activity
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