New modification strategy of matrine as Hsp90 inhibitors based on its specific L conformation for cancer treatment

Yiming Xu; Dewang Jing; Dong Zhao; Yongji Wu; Lu Xing; Haroon Ur Rashid; Haodong Wang; Lisheng Wang; Huiling Cao

doi:10.1016/j.bmc.2020.115305

New modification strategy of matrine as Hsp90 inhibitors based on its specific L conformation for cancer treatment

Bioorg Med Chem. 2020 Feb 15;28(4):115305. doi: 10.1016/j.bmc.2020.115305. Epub 2020 Jan 7.

Authors

Yiming Xu¹, Dewang Jing², Dong Zhao³, Yongji Wu⁴, Lu Xing³, Haroon Ur Rashid⁵, Haodong Wang², Lisheng Wang⁶, Huiling Cao⁷

Affiliations

¹ Medicinal College, Guangxi University, Nanning 530004, China; School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, China.
² School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, China.
³ Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic Translational Medicine, Xi'an Medical University, Xi'an 710021, China.
⁴ College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China.
⁵ School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, China; Department of Chemistry, Sarhad University of Science & Information Technology, Peshawar, Khyber Pakhtunkhwa 25120, Pakistan.
⁶ Medicinal College, Guangxi University, Nanning 530004, China. Electronic address: [email protected].
⁷ Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic Translational Medicine, Xi'an Medical University, Xi'an 710021, China. Electronic address: [email protected].

PMID: 31928863
DOI: 10.1016/j.bmc.2020.115305

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.

Keywords: Anticancer activity; L-shaped matrine derivatives; Mechanism of action; Radicicol; Thermal shift assay.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alkaloids / chemical synthesis
Alkaloids / chemistry
Alkaloids / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
HSP90 Heat-Shock Proteins / metabolism
Humans
Matrines
Molecular Conformation
Molecular Docking Simulation
Quinolizines / chemical synthesis
Quinolizines / chemistry
Quinolizines / pharmacology*
Structure-Activity Relationship

Substances

Alkaloids
Antineoplastic Agents
HSP90 Heat-Shock Proteins
Quinolizines
Matrines