Conjugates of 18β-glycyrrhetinic acid derivatives with 3-(1H-benzo[d]imidazol-2-yl)propanoic acid as Pin1 inhibitors displaying anti-prostate cancer ability

Kun Li; Tianyi Ma; Jingjing Cai; Min Huang; Hongye Guo; Di Zhou; Shenglin Luan; Jinyu Yang; Dan Liu; Yongkui Jing; Linxiang Zhao

doi:10.1016/j.bmc.2017.08.002

Conjugates of 18β-glycyrrhetinic acid derivatives with 3-(1H-benzo[d]imidazol-2-yl)propanoic acid as Pin1 inhibitors displaying anti-prostate cancer ability

Bioorg Med Chem. 2017 Oct 15;25(20):5441-5451. doi: 10.1016/j.bmc.2017.08.002. Epub 2017 Aug 4.

Authors

Kun Li¹, Tianyi Ma¹, Jingjing Cai¹, Min Huang¹, Hongye Guo¹, Di Zhou¹, Shenglin Luan¹, Jinyu Yang¹, Dan Liu², Yongkui Jing³, Linxiang Zhao⁴

Affiliations

¹ Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
² Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: sammyld@163.com.
³ School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: yongkjing@yahoo.com.
⁴ Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: linxiang.zhao@vip.sina.com.

PMID: 28838831
DOI: 10.1016/j.bmc.2017.08.002

Abstract

Twenty-six conjugates of 18β-glycyrrhetinic acid derivatives with 3-(1H-benzo[d]imidazol-2-yl)propanoic acid were designed and synthesized as Pin1 inhibitors. Most of these semi-synthetic compounds showed improved Pin1 inhibitory activity and anti-proliferative effects against prostate cancer cells as compared to 3-(1H-benzo[d]imidazol-2-yl)propanoic acid and GA. Compounds 10a and 12i were the most potent to inhibit growth of prostate cancer PC-3 with GI₅₀ values of 7.80μM and 3.52μM, respectively. The enzyme inhibition ratio of nine compounds at 10μM was over 90%. Structure-activity relationships indicated that both appropriate structure at ring C of GA and suitable length of linker between GA skeleton and benzimidazole moiety had significant impact on improving activity. Western blot assay revealed that 10a decreased the level of cell cycle regulating protein cyclin D1. Thus, these compounds might represent a novel anti-proliferative agent working through Pin1 inhibition.

Keywords: 18β-Glycyrrhetinic acid derivatives; Anti-proliferative activity; Cyclin D1; Pin1 inhibitors.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Glycyrrhetinic Acid / analogs & derivatives*
Glycyrrhetinic Acid / chemistry
Glycyrrhetinic Acid / pharmacology
Humans
Imidazoles / chemistry
Imidazoles / pharmacology*
Male
Molecular Conformation
NIMA-Interacting Peptidylprolyl Isomerase / antagonists & inhibitors*
NIMA-Interacting Peptidylprolyl Isomerase / metabolism
Propionates / chemistry
Propionates / pharmacology*
Prostatic Neoplasms / drug therapy*
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
Structure-Activity Relationship

Substances

3-(1H-benzo(d)imidazol-2-yl)propanoic acid
Antineoplastic Agents
Enzyme Inhibitors
Imidazoles
NIMA-Interacting Peptidylprolyl Isomerase
Propionates
18alpha-glycyrrhetinic acid
PIN1 protein, human
Glycyrrhetinic Acid