New modification strategy of matrine as Hsp90 inhibitors based on its specific L conformation for cancer treatment. Issue 4 (15th February 2020)

• Record Type: Journal Article
• Authors: Xu, Yiming; Jing, Dewang; Zhao, Dong; Wu, Yongji; Xing, Lu; ur Rashid, Haroon; Wang, Haodong; Wang, Lisheng; Cao, Huiling
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 4(2020)
• Publication Date: 2020-02-15
• Subjects: L-shaped matrine derivatives -- Radicicol -- Thermal shift assay -- Anticancer activity -- Mechanism of action; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115305
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 Hsp90 N inhibitors as anticancer agents. TSA (Thermal Shift Assay) results indicated that 21e, 22a-c and 22e-g exhibited strong binding force against Hsp90 N 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.