左氧氟沙星3-芳苄叉基-喹啉-4-酮衍生物的合成及抗肿瘤活性

为进一步发现提高氟喹诺酮抗肿瘤活性的有效结构修饰策略,基于片段药物设计原理,通过喹啉-4(1H)-酮与芳香醛缩合反应合成了(S)-6-氟-7-(4-甲基-哌嗪-基)-8,1-(1,3-氧丙基)-3-芳苄叉基-2,3-二氢-喹啉-4(1H)-酮(3a-3l)目标化合物。 体外抗肿瘤活性结果表明,所合成的12个新化合物的活性均强于母体左氧氟沙星,其中F、Cl、Br取代的卤苯基化合物对人肝癌细胞株(SMMC-7721)和人胰腺癌细胞株(Capan-1)的半数抑制浓度(IC₅₀)低于其它取代基化合物,尤其是氯苯基化合物(3k)与对照抗肿瘤药阿霉素活性相当。 为此,芳苄叉基替代C-3羧基构建的3-芳苄叉基-喹啉-4-酮化合物有助于提高氟喹诺酮的抗肿瘤活性,提示α,β-不饱和酮片段作为一个有发展前景的氟喹诺酮的候选修饰基团值得进一步发展。

Synthesis and Antitumor Activity of 3-Arylidene-Quinolin-4-Ones Derivatives of Levofloxacin

To further explore an efficient structural modification strategy, a fragment-based drug design, for improving the antitumor activity of fluoroquinolones, twelve novel 3-arylidene-quinolin-4(1H)-ones as levofloxacin derivatives (3a-3l) were synthesized by a condensation reaction of dihydroquinolin-4(1H)-one with aromatic aldehydes. The measured half inhibition concentration(IC₅₀) values using human hepatocellular carcinoma cell lines (SMMC-7721), human pancreatic cancer cell lines (Capan-1) and human leukemia cell line (HL60) cell lines reveal that the antitumor activities of the synthesized compounds are more potent than that of levofloxacin. Meanwhile, the halophenyl compounds such as fluorophenyl (3i, 3j), chlorophenyl (3k) or bromophenyl compounds (3l) display better activities than the control compounds, especially the IC₅₀ value of chlorophenyl (3k) against SMMC-7721 and Capan-1 cell is comparable to that of doxorubicin. Thus, 3-arylidene-quinolin-4(1H)-one skeleton instead of quinolin-4(1H)-one-3-carboxylic acid is beneficial to improve the antitumor activities of fluoroquinolones. Furthermore, an α,β-unsaturated ketone fragment as a promising candidate pharmacophore for an alternative modified group of fluoroquinolone needs to be developed.