Novel Hybrids of 3-Substituted Coumarin and Phenylsulfonylfuroxan as Potent Antitumor Agents with Collateral Sensitivity against MCF-7/ADR,Journal of Medicinal Chemistry

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Novel Hybrids of 3-Substituted Coumarin and Phenylsulfonylfuroxan as Potent Antitumor Agents with Collateral Sensitivity against MCF-7/ADR
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-06-23 , DOI: 10.1021/acs.jmedchem.2c00608
Zhihui Yu ₁ , Mengru Li ₂ , Ke Wang _{1,

3} , Yuting Gu ₂ , Shiqi Guo ₁ , Weijie Wang ₁ , Yulei Ma ₂ , Hongrui Liu ₂ , Ying Chen ₁

Affiliation

Twenty-three new coumarin-furoxan hybrids were synthesized, which exhibited nanomole antiproliferation activities in A2780, A2780/CDDP, MCF-7/ADR, and MDA-MB-231. Among them, compound 9 showed the strongest collateral sensitivity to MCF-7/ADR with 499-fold potency compared with MCF-7. Notably, the solubility of compound 9 increased 70-fold compared with the lead 2. And preliminary pharmacological studies displayed that compound 9 obviously increased Rh123 accumulation in MCF-7/ADR and released NO to produce ROS in lysosomes, which were able to damage lysosomal membrane and induce apoptosis. These results reasonably explained that the collateral sensitivity of compound 9 to MCF-7/ADR was closely related to P-gp-mediated lysosome damage and apoptosis. Additionally, compound 9 showed a very weak cytotoxicity both in MCF-10A and hERG potassium channels and had a desirable safety in ion cyclotron resonance (ICR) mice. Hence, compound 9 was merited to further study for developing a desirable candidate against MDR MCF-7/ADR via a potential mechanism of collateral sensitivity in MDR cancer cell lines.

中文翻译：

3-取代香豆素和苯磺酰呋喃的新型混合物作为对 MCF-7/ADR 具有附带敏感性的强效抗肿瘤剂

合成了 23 个新的香豆素-呋喃杂化物，它们在 A2780、A2780/CDDP、MCF-7/ADR 和 MDA-MB-231 中表现出纳摩尔抗增殖活性。其中，化合物9对 MCF-7/ADR 的侧枝敏感性最强，效力是 MCF-7 的 499 倍。值得注意的是，与铅2相比，化合物9的溶解度增加了 70 倍。初步药理研究表明，化合物9明显增加了Rh123在MCF-7/ADR中的积累，并释放NO在溶酶体中产生ROS，从而破坏溶酶体膜并诱导细胞凋亡。这些结果合理地解释了化合物9的附带敏感性MCF-7/ADR 与 P-gp 介导的溶酶体损伤和细胞凋亡密切相关。此外，化合物9在 MCF-10A 和 hERG 钾通道中均显示出非常弱的细胞毒性，并且在离子回旋共振 (ICR) 小鼠中具有理想的安全性。因此，化合物9值得进一步研究，以通过 MDR 癌细胞系中的附带敏感性的潜在机制开发一种理想的抗 MDR MCF-7/ADR 候选物。

更新日期：2022-06-23

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