3-芳苄叉基噻唑酮-氟喹啉-4-酮氧氟沙星衍生物的合成及抗肿瘤活性

目的 进一步发现氟喹诺酮的有效结构修饰策略以提高其抗肿瘤活性。方法 基于药效团拼合药物设计原理,用噻唑酮作为氧氟沙星C-3羧基的等排体、芳苄叉基为其修饰基,构建了新的3-芳苄叉噻唑酮-氟喹啉-4-酮的氧氟沙星衍生物(6a~6l),其结构经用元素分析和光谱数据确证。MTT方法评价了体外对SMMC-7721、Capan-1和HL60这3种癌细胞株的抗增值活性。结果 12个新结构的氟喹诺酮-3-噻唑不饱和酮目标化合物被合成,其活性显著强于母体氧氟沙星1,其中卤苯基化合物强于其他取代基的活性,尤其是氯苯基化合物(6k)对Capan-1细胞的活性与对照抗肿瘤药多柔比星相当。结论 芳苄叉基噻唑酮替代氟喹诺酮C-3羧基有利于提高其抗肿瘤活性。

Synthesis and Antitumor Activity of 3-Arylidenethiazolone-Fluoroquinolin-4-Ones as Ofloxacoin Derivatives

OBJECTIVE To further discover an efficiently structural modification strategy for improving antitumor activity of fluoroquinolones.CONCLUSION Based on pharmacophore combination drug design principle, novel 3-arylidenethiazolone-fluoroquinolin-4-ones as ofloxacin derivatives(6a-6l) were designed and synthesized with a thiazolone ring as an is isostere of the C-3 carboxylic group and an arylidene fragment as a functionalized modifier, respectively. The structures of the synthesized compounds were characterized by spectral data and elemental analysis, and the in vitro antitumor activity against three tumor cell lines was measured by MTT assay.RESULTS Twelve new title compounds were synthesized, and they exhibited more potent in vitro antitumor activity than parent 1. The SAR analysis exhibited that halophenyl compounds displayed better activity than the control compounds, especially the chlorophenyl compound(6k), of which the IC₅₀ against Capan-1 cell growth was comparable to doxorubicin.CONCLUSION A arylidenethiazolone scaffold appears to be a desirable isostere of the C-3 carboxylic acid group of fluoroquinolones for the improvement of antitumor activity.