N-(5-芳苄叉基饶丹宁)左氧氟沙星酰胺的合成及抗肿瘤活性

为进一步发现氟喹诺酮药物向抗肿瘤活性转化的结构修饰新策略,用酰氨基为左氧氟沙星(1)C-3羧基的电子等排体,5-芳苄叉基饶丹宁为其功能修饰基,设计合成了N-(5-芳苄叉基饶丹宁)左氧氟沙星酰胺类目标化合物(6a-6n)。 体外抗肿瘤活性结果表明,所合成的14个化合物的活性均强于母体左氧氟沙星,且对正常细胞表现出较低的细胞毒性作用。 构效关系表明,增大芳基取代基的体积或供电性均导致抗肿瘤活性的明显降低,反之,吸电子取代苯基或芳香杂环类目标化合物的抗肿瘤活性强于其他取代基类。 其中,硝基化合物6l、呋喃6m和吡啶6n对人胰腺癌细胞株(Capan-1)的半数抑制浓度(IC₅₀) 与对照抗肿瘤药阿霉素(1.6 μmol/L)相当,分别为1.8、0.8和1.3 μmol/L。 因此,芳苄叉基饶丹宁修饰的酰氨基替代C-3羧基有利于提高氟喹诺酮的抗肿瘤活性。

Synthesis and Antitumor Activity of N-Arylidene-Rhodanine Levofloxacin Amides

To develope an efficiently structural modification strategy for transforming antibacterial fluoroquinolone into antitumor agent, novel N-arylidene arylidene rhodanine levofloxacin amide derivatives(6a-6n) were synthesized via amide modification with functionalized arylidene rhodanine scaffold as the bioisostere of the C-3 carboxylic group. The in vitro antitumor assay indicated that the title compounds exhibited more significant potency against three test cancer cell lines than levofloxacin, but with lower cytotoxicity against the normal cells than doxorubicin as a comparison. The SAR(structure-activity relationship) reveals that the increase in the bulky or electron-donating substituents bearing phenyl ring obviously reduces the antitumor activity. Conversely, compounds with electron-withdrawing nitro- or fluorophenyl or heteroaromatic rings such as furan or pyridine ring display comparable activity to doxorubicin. Thus, an amide group modified by arylidene rhodanine scaffold as an isostere of the C-3 carboxylic acid group appears to an alternative route for further design of antitumor fluoroquinolone.