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

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.
Kun Li 1,  Tianyi Ma 1,  Jingjing Cai 1,  Min Huang 1,  Hongye Guo 1,  Di Zhou 1,  Shenglin Luan 1,  Jinyu Yang 1,  Dan Liu 2,  Yongkui Jing 3,  Linxiang Zhao 4
Affiliations

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.

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