New modification strategy of matrine as Hsp90 inhibitors based on its specific L conformation for cancer treatment.,Bioorganic & Medicinal Chemistry

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New modification strategy of matrine as Hsp90 inhibitors based on its specific L conformation for cancer treatment.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2020-01-07 , DOI: 10.1016/j.bmc.2020.115305
Yiming Xu ₁ , Dewang Jing ₂ , Dong Zhao ₃ , Yongji Wu ₄ , Lu Xing ₃ , Haroon Ur Rashid ₅ , Haodong Wang ₂ , Lisheng Wang ₆ , Huiling Cao ₃

Affiliation

The similarity of spatial structure between radicicol and matrine urged us to perform conformation modification of matrine, followed by L-shaped matrine derivatives, 6, 12, 21a-h and 22a-h were originally designed, synthesized and evaluated for Hsp90N inhibitors as anticancer agents. TSA (Thermal Shift Assay) results indicated that 21e, 22a-c and 22e-g exhibited strong binding force against Hsp90N with∣ΔTm∣ > 3, meanwhile, MTT assay also revealed these compounds displayed potent anticancer activity with IC50 values below 25 μM against HepG2, HeLa and MDA-MB-231 cells lines. Then, compound 22g with a high ΔTm = 10.92 was chosen as a representative to perform further mechanism study. It can induce cell apoptosis, arrest the cell cycle at the S phase and decrease the expression level of Hsp90 in Hela cell. These results originally provided targeted modification strategy for matrine derivatives to serve as Hsp90 inhibitors for cancer therapy.

中文翻译：

苦参碱作为Hsp90抑制剂的新修饰策略基于其特定的L构象用于癌症治疗。

紫杉醇和苦参碱在空间结构上的相似性促使我们进行苦参碱的构象修饰，然后最初设计，合成和评估了L型苦参碱衍生物6，12，21a-h和22a-h作为抗癌剂的Hsp90N抑制剂。。TSA（热位移分析）结果表明21e，22a-c和22e-g对Hsp90N表现出强大的结合力，bindingΔTm∣> 3，同时，MTT分析还显示这些化合物显示出有效的抗癌活性，其IC50值低于25μM HepG2，HeLa和MDA-MB-231细胞系。然后，选择ΔTm= 10.92高的化合物22g作为代表进行进一步的机理研究。它可以诱导细胞凋亡，将细胞周期停在S期，并降低Hela细胞中Hsp90的表达水平。

更新日期：2020-01-07

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