Zhang Ya-Zhou, Liu Hai-Lin, He Qian-Song, Xu Zhi
College of Pharmaceutical Sciences, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China.
Curr Top Med Chem. 2020;20(16):1493-1498. doi: 10.2174/1568026620666200310123723.
Development of 1-[(1R, 2S)-2-fluorocyclopropyl]ciprofloxacin-1,2,4-triazole-5(4H)- thione hybrids as potential dual-acting mechanism anticancer agent to overcome the drug resistance.
Chemotherapy is an essential tool for the treatment of lung and female breast cancers, and numerous anticancer agents have been launched for this purpose. However, the clinical outcomes of chemotherapy are usually far from satisfactory due to the side effects and resistance to chemotherapeutic drugs. Thus, it is urgent to develop novel anti-lung and anti-breast cancer agents.
The primary objective of this study was to evaluate the potential of bis-isatin scaffolds with alkyl/ether linkers between the two isatin moieties against different human breast cancer cell lines including A549, MCF-7 and their drug-resistant counterparts A549/CDDP, MCF-7/ADM cells.
The 1-[(1R, 2S)-2-fluorocyclopropyl]ciprofloxacin-(4-methyl/phenyl/benzyl-3-aryl)-1,2,4- triazole-5(4H)-thione hybrids were screened for their in vitro activity against drug-sensitive lung (A549), breast (MCF-7) and their drug-resistant counterparts A549/CDDP (cisplatin-resistant), MCF- 7/ADM (doxorubicin-resistant) cancer cell lines by MTT assay. The inhibitory activity of these hybrids against topoisomerase II and EGFR was also evaluated to investigate the potential mechanism of action of these hybrids.
The most prominent hybrid 7k (IC50: 37.28-49.05 µM) was comparable to Vorinostat against A549 and A549/CDDP lung cancer cells, and was 2.79-2.94 times more active than Vorinostat against MCF-7 and MCF-7/ADM breast cancer cell lines. Moreover, hybrid 7k (IC50: 8.6 and 16.4 µM) also demonstrated dual inhibition against topoisomerase II and EGFR.
The 1-[(1R, 2S)-2-fluorocyclopropyl]ciprofloxacin-1,2,4-triazole-5(4H)-thione hybrids possess equally activity against both drug-sensitive cancer cells and their drug-resistant counterparts, and the majority of them were no inferior to the reference Vorinostat. The mechanistic study revealed that these hybrids could inhibit both topoisomerase II and EGFR, so these hybrids can be developed as dual-acting mechanism anticancer agents.
开发1-[(1R, 2S)-2-氟环丙基]环丙沙星-1,2,4-三唑-5(4H)-硫酮杂化物作为具有潜在双重作用机制的抗癌剂以克服耐药性。
化疗是治疗肺癌和女性乳腺癌的重要手段，为此已推出众多抗癌药物。然而，由于副作用和对化疗药物的耐药性，化疗的临床效果通常远不尽人意。因此，迫切需要开发新型抗肺癌和抗乳腺癌药物。
本研究的主要目的是评估在两个异吲哚酮部分之间带有烷基/醚连接基的双异吲哚酮支架对不同人类乳腺癌细胞系的潜力，这些细胞系包括A549、MCF-7及其耐药对应细胞系A549/CDDP、MCF-7/ADM细胞。
通过MTT法筛选1-[(1R, 2S)-2-氟环丙基]环丙沙星-(4-甲基/苯基/苄基-3-芳基)-1,2,4-三唑-5(4H)-硫酮杂化物对药物敏感的肺癌(A549)、乳腺癌(MCF-7)及其耐药对应细胞系A549/CDDP(顺铂耐药)、MCF-7/ADM(阿霉素耐药)癌细胞系的体外活性。还评估了这些杂化物对拓扑异构酶II和表皮生长因子受体(EGFR)的抑制活性，以研究这些杂化物的潜在作用机制。
最突出的杂化物7k(IC50：37.28 - 49.05 μM)对A549和A549/CDDP肺癌细胞的活性与伏立诺他相当，对MCF-7和MCF-7/ADM乳腺癌细胞系的活性比伏立诺他高2.79 - 2.94倍。此外，杂化物7k(IC50：8.6和16.4 μM)还对拓扑异构酶II和EGFR表现出双重抑制作用。
1-[(1R, 2S)-2-氟环丙基]环丙沙星-1,2,4-三唑-5(4H)-硫酮杂化物对药物敏感癌细胞及其耐药对应细胞系均具有同等活性，且它们中的大多数不逊色于对照药物伏立诺他。机制研究表明，这些杂化物可同时抑制拓扑异构酶II和EGFR，因此这些杂化物可开发为具有双重作用机制的抗癌剂。
