饶丹宁甲叉基取代左氧氟沙星衍生物的合成与抗肿瘤活性

Synthesis and Antitumor Activity of Rhodanine Methylene-Substituted Levofloxacin Derivatives

为寻找提高氟喹诺酮肿瘤活的有效结构修饰策略,左氧氟沙星(3)的衍生物(S)-(-)-9-氟-2,3-二氢-3-甲基-10-(4-甲基-1-哌嗪基)-[1,4]噁嗪并[2,3,4-ij]-喹啉-7(4 H)-酮-6-甲醛(5)与饶丹宁类(2a-2l)通过Claisen-Schmid缩合反应构建了饶丹宁甲叉基取代左氧氟沙星衍生物(6a-6l)目标化合物,其结构经元素分析和光谱数据确证。体外初步抗细胞增殖活性筛选结果表明,12个新目标化合物对人非小细胞肺癌细胞(A549)、人肝癌细胞(Hep-3B)、人胰腺癌细胞(Capan-1)和人白血病细胞(HL60)的活性高于母体左氧氟沙星,且对正常细胞Vero表现出较低细胞毒作用。构效关系表明,卤代苯基或饶丹宁或环丙基饶丹宁化合物的活性强于其它取代,尤其环丙基化合物对A549的活性与对照阿霉素相当。因此,饶丹宁甲叉基替代C-3羧基有利于提高氟喹诺酮的抗肿瘤活性,发展了氟喹诺酮结构修饰的新途径。

To explore an efficient structural modification strategy to enhance the antitumor activity of fluoroquinolones,a methane-rhodanine fragment was used as the bioisosteric replacement of the C-3 carboxylic acid group and consequently twelve new C-3α,β-unsaturated thiazolone derivatives(6a-6l)were designed and synthesized by Claisen-Schmid condensation reaction with oxazinoquinolin-7-one-6-carbaldehyde(5)derived from levofloxacin(1)and N-substituted rhodanines(2a-2l),respectively.The in vitro antitumor activity of the synthesized compounds is more potent than that of levofloxacin along with lower cytotoxicity against Vero cells.Meanwhile,the structure-activity relationship(SAR)reveals that halophenyl,N-unsubstituted or cyclopropyl rhodaninec ompounds display a better activity than those of the control compounds,especially the IC 50 values of cyclopropyl rhodanine compound(6j)against A549 cell growth is comparable to doxorubicin.Thus,an unsaturated ketone annulated rhodanine scaffold as a bioisostere of the C-3 carboxylic acid group is found to be an alternative proposal for improving the antitumor activity of fluoroquinolones.Furthermore,whether anα,β-unsaturated ketone fragment is a promising bioisostere of the C-3 carboxylic acid group is worth further developing.