Design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives to reduce SREBPs expression for the treatment of hyperlipidemia

Haixia Ge; Weitao Zhang; Kai Yuan; Hanyue Xue; Hao Cheng; Weijiao Chen; Yishi Xie; Jian Zhang; Xiaojun Xu; Peng Yang

doi:10.1016/j.ejmech.2021.113522

Design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives to reduce SREBPs expression for the treatment of hyperlipidemia

Eur J Med Chem. 2021 Oct 5:221:113522. doi: 10.1016/j.ejmech.2021.113522. Epub 2021 May 5.

Authors

Haixia Ge¹, Weitao Zhang², Kai Yuan², Hanyue Xue², Hao Cheng², Weijiao Chen², Yishi Xie², Jian Zhang³, Xiaojun Xu⁴, Peng Yang⁵

Affiliations

¹ School of Life Sciences, Huzhou University, Huzhou, 313000, China.
² State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
³ State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
⁴ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
⁵ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].

PMID: 33984804
DOI: 10.1016/j.ejmech.2021.113522

Abstract

Statins play an important role in the treatment of hyperlipidemia, but drug resistance and adverse effects greatly limits their application. To discover new lipid-lowering drugs, three different series of tetrahydroprotoberberine derivatives (THPBs) were designed and synthesized. These compounds were first tested for their effects on viability of HepG2 cells and 21 compounds with the percent of cell viability over 90% were further screened to evaluate their ability to reduce total cholesterol (TC) and triglyceride (TG) levels. Among these derivatives, two compounds displayed significant down-regulation both intracellular of TC and TG content, especially compound 49 exhibited the greatest efficacy. Mechanistically, compound 49 promoted proteasomal degradation of SREBPs. Importantly, compound 49 displayed superior bioavailability (F = 65.1%) and obvious efficacy in the treatment of high fat diet induced obesity in vivo. Therefore, compound 49 is a promising candidate to develop new treatment of hyperlipidemia.

Keywords: Hyperlipidemia; SREBPs; Tetrahydroprotoberberine derivatives.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Berberine Alkaloids / chemical synthesis
Berberine Alkaloids / chemistry
Berberine Alkaloids / pharmacology*
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Hep G2 Cells
Humans
Hyperlipidemias / drug therapy*
Hyperlipidemias / metabolism
Hyperlipidemias / pathology
Molecular Structure
Sterol Regulatory Element Binding Protein 1 / antagonists & inhibitors*
Sterol Regulatory Element Binding Protein 1 / genetics
Sterol Regulatory Element Binding Protein 1 / metabolism
Sterol Regulatory Element Binding Protein 2 / antagonists & inhibitors*
Sterol Regulatory Element Binding Protein 2 / genetics
Sterol Regulatory Element Binding Protein 2 / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Berberine Alkaloids
SREBF1 protein, human
SREBF2 protein, human
Sterol Regulatory Element Binding Protein 1
Sterol Regulatory Element Binding Protein 2
berbine