A 18β-glycyrrhetinic acid conjugate with Vorinostat degrades HDAC3 and HDAC6 with improved antitumor effects

  • Eur J Med Chem. 2020 Feb 15;188:111991. doi: 10.1016/j.ejmech.2019.111991.
Min Huang  1 ,  Xiaorui Xie  2 ,  Ping Gong  2 ,  Yunfei Wei  1 ,  Heliang Du  1 ,  Yuanbo Xu  1 ,  Qihao Xu  1 ,  Yongkui Jing  3 ,  Linxiang Zhao  4
Affiliations
  • 1. Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 2. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 3. Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: [email protected].
  • 4. Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: [email protected].
PMID: 31883490 DOI: 10.1016/j.ejmech.2019.111991
Abstract

Semisynthetic 18β-glycyrrhetinic acid (GA) analogues bearing 1-en-2-cyano-3-oxo substitution on ring A have enhanced antitumor effects with reduced levels of HDAC3 and HDAC6 proteins. Aiming to inhibit both HDAC protein and activity, we developed a hybrid molecule by tethering active GA analogue methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate (CDODA-Me) and Vorinostat (SAHA). We tested the proper hybrid approaches of GA with hydroxamic acid and turned out that GA conjugated with SAHA by a piperazine linker was the best. The conjugate (15) of CDODA-Me and SAHA linked through a piperazine group was a potent cytotoxic agent against Cancer cells with Apoptosis induction. Compound 15 was more effective than the simple combination of CDODA-Me and SAHA to induce Apoptosis. Mechanistic studies revealed that 15 was less effective than SAHA to inhibit HDAC activity, but was more effective than CDODA-Me to decrease the levels of HDAC3 and HDAC6 proteins with upregulated levels of acetylated H3 and acetylated α-tubulin. Compound 15 represents a new HDAC3 and HDAC6 Inhibitor by reducing protein levels.

Keywords
18β-glycyrrhetinic acid; Anticancer; Conjugate; HDAC.
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