Department of Medicinal Chemistry, Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
J Biochem Mol Toxicol. 2023 Jun;37(6):e23334. doi: 10.1002/jbt.23334. Epub 2023 Feb 27.
Levofloxacin, the optical S-(-) isomer of ofloxacin, is a broad-spectrum antibacterial agent widely used to control various infections caused by Gram-positive and Gram-negative bacteria. While the COOH group is necessary for antibacterial activity, its modification can offer anticancer activity to the fluoroquinolone framework. Therefore, several levofloxacin carboxamides 11a-j and 12 containing 5-substituted-1,3,4-thiadiazole residue were synthesized and screened in vitro for their anticancer activity. The in vitro MTT viability assay revealed that the most compounds had significant activity against cancer cells MCF-7, A549, and SKOV3. In particular, the 3-chloro- and 4-fluoro- benzyl derivatives (11b and 11h), with IC values of 1.69-4.76 μM were as potent as or better than doxorubicin. It should be noted that the mother quinolone levofloxacin showed no activity on the tested cancer cell lines. The SAR analysis demonstrated that the 3-chloro or 4-fluoro substituent on the S-benzyl moiety had positive effect on the activity. Further in vitro evaluations of the most promising compounds 11b and 11h by flow cytometric analysis and comet test revealed the ability of compounds in the induction of apoptosis and blockage of the cell proliferation at the G1-phase by nuclear fragmentation and DNA degradation in cancer cells. The obtained results demonstrated that the alteration of 6-COOH functional group in the levofloxacin structure and conjugation with a proper heterocyclic pharmacophore is a good strategy to obtain new anticancer agents.
左氧氟沙星，氧氟沙星的光学 S-（-）对映异构体，是一种广谱抗菌剂，广泛用于控制革兰氏阳性和革兰氏阴性细菌引起的各种感染。虽然 COOH 基团是抗菌活性所必需的，但它的修饰可以为氟喹诺酮骨架提供抗癌活性。因此，合成了几种含有 5-取代-1,3,4-噻二唑残基的左氧氟沙星羧酰胺 11a-j 和 12，并在体外筛选其抗癌活性。体外 MTT 活力测定显示，大多数化合物对 MCF-7、A549 和 SKOV3 癌细胞具有显著的活性。特别是 3-氯-和 4-氟-苄基衍生物（11b 和 11h），IC 值为 1.69-4.76μM，与阿霉素相当或更好。值得注意的是，母喹诺酮左氧氟沙星对测试的癌细胞系没有活性。SAR 分析表明，S-苄基部分的 3-氯或 4-氟取代基对活性有积极影响。进一步通过流式细胞术分析和彗星试验对最有前途的化合物 11b 和 11h 进行体外评价，发现化合物具有诱导癌细胞凋亡和通过核碎裂和 DNA 降解在 G1 期阻止细胞增殖的能力。获得的结果表明，在左氧氟沙星结构中改变 6-COOH 官能团并与适当的杂环药效团缀合是获得新型抗癌剂的一种很好的策略。
