Design, synthesis and antitumor activity of triterpenoid pyrazine derivatives from 23-hydroxybetulinic acid

Hengyuan Zhang; Yiwei Wang; Peiqing Zhu; Jie Liu; Shengtao Xu; Hequan Yao; Jieyun Jiang; Wencai Ye; Xiaoming Wu; Jinyi Xu

doi:10.1016/j.ejmech.2015.04.057

Design, synthesis and antitumor activity of triterpenoid pyrazine derivatives from 23-hydroxybetulinic acid

Eur J Med Chem. 2015 Jun 5:97:235-44. doi: 10.1016/j.ejmech.2015.04.057. Epub 2015 Apr 29.

Authors

Hengyuan Zhang¹, Yiwei Wang¹, Peiqing Zhu¹, Jie Liu², Shengtao Xu¹, Hequan Yao³, Jieyun Jiang⁴, Wencai Ye⁵, Xiaoming Wu¹, Jinyi Xu⁶

Affiliations

¹ State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
² State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Organic Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
³ State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China. Electronic address: [email protected].
⁴ Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536, USA.
⁵ College of Pharmacy and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, PR China.
⁶ State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China. Electronic address: [email protected].

PMID: 25984840
DOI: 10.1016/j.ejmech.2015.04.057

Abstract

Pyrazine-fused 23-hydroxybetulinic acid was synthesized by introducing a pyrazine ring between C-2 and C-3 position and further modifications were carried out by substitution of C-28 carboxyl group by ester and amide linkage to enhance the antitumor activity. The biological screening results showed that all of the derivatives exhibited more significant antiproliferative activity than the parent compound. In particular compound 12a exhibited the most potent activity with IC50 values of 3.53 μM, 4.42 μM and 5.13 μM against cell lines SF-763, B16 and Hela, respectively. In the preliminary mechanism study, 12a caused cell arrest in G1 phase and significantly induced apoptosis of B16 cells in a dose-dependent manner. Furthermore, the in vivo antitumor activity of 12a was validated (tumor inhibitory ratio of 55.6% and 62.7%, respectively) in mice with H22 liver cancer and B16 melanoma.

Keywords: 23-Hydroxybetulinic acid; Antitumor activity; Apoptosis; Pyrazine; Triterpenoid.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Proliferation / drug effects
Drug Design*
Drug Screening Assays, Antitumor
G1 Phase / drug effects
HeLa Cells
Humans
Liver Neoplasms / drug therapy*
Liver Neoplasms / pathology
Melanoma, Experimental / drug therapy*
Melanoma, Experimental / pathology
Mice
Molecular Structure
Morpholines / chemical synthesis*
Morpholines / pharmacology*
Pyrazines / chemical synthesis
Pyrazines / chemistry*
Pyrazines / pharmacology
Structure-Activity Relationship
Triterpenes / chemistry*

Substances

23-hydroxybetulinic acid
Antineoplastic Agents
Morpholines
N-(23-acetoxy-lup(3,2-b)pyrazine-20(29)-en-28-oyl)-morpholine
Pyrazines
Triterpenes