氟喹诺酮(绕丹宁不饱和酮)酰胺衍生物的合成与抗肿瘤活性

Synthesis and anti-proliferative activity of fluoroquinolone(rhodanine unsaturated ketone) amide derivatives

为发现新型抗肿瘤绕丹宁不饱和酮衍生物,以氟喹诺酮酰胺骨架作为载体,设计合成了氟喹诺酮(绕丹宁α,β-不饱和酮)酰胺类目标化合物5a^5r,其结构经元素分析、1H NMR、MS确证。采用MTT法评价了目标化合物对人肝癌Hep-3B细胞、人Capan-1胰腺癌细胞及人HL60白血病细胞的体外增值抑制活性。结果表明,18个目标化合物对3种实验癌细胞的抗增殖活性均显著高于母体环丙沙星1的活性,其中对Capan-1细胞的活性最强,尤其是芳杂环或苯环带有吸电子羧基及磺酰氨基类化合物的活性与对照抗肿瘤药物阿霉素相当。为此,氟喹诺酮(绕丹宁不饱和酮)酰胺衍生物是一类有发展前景的抗肿瘤活性先导物。

To discover novel antitumor rhodanine unsaturated ketones, a series of fluoroquinolone （rhodanine a, fl-unsaturated ketone） amine derivatives （Sa-Sr） were designed and synthesized with fluoroquinolone amide scaffold as a carrier. The structures of eighteen title compounds were characterized by elemental analysis, 1H NMR and MS. The in vitro anti-proliferative activity against Hep-3B, Capan-1 and HL60 cells was evaluated by MTT assay. The results showed that the title compounds not only had more significant anti-proliferative activity against three tested cancer cell lines than that of the parent ciprofloxacin 1, but also exhibited the highest activity against Capan-1 cells. The SAR revealed that some compounds carrying aromatic heterocyclic rings or phenyl attached to an electron-withdrawing carboxyl or sulfonamide substituent were comparable to or better than comparison doxorubicin against Capan-1 cells. As such, it suggests that fluoroquinolone （rhodanine α,β-unsaturated ketone） amines are promising leads for the development of novel antitumor fluoroquinolones or rhodanine analogues.