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

• Published in: European journal of medicinal chemistry 2015-06, Vol.97, p.235-244
• Main Authors: Zhang, Hengyuan, Wang, Yiwei, Zhu, Peiqing, Liu, Jie, Xu, Shengtao, Yao, Hequan, Jiang, Jieyun, Ye, Wencai, Wu, Xiaoming, Xu, Jinyi
• Format: Article
• Language: English
• Subjects: 23-Hydroxybetulinic acid; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; 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; Pyrazine; Pyrazines - chemical synthesis; Pyrazines - chemistry; Pyrazines - pharmacology; Structure-Activity Relationship; Triterpenes - chemistry; Triterpenoid
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.04.057

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. Compound 12a caused cell arrest in G1 phase and significantly induced apoptosis of B16 cells in a dose-dependent manner. [Display omitted] •A series of pyrazine-fused 23-hydroxybetulinic acid derivatives was synthesized.•All of the synthesized compounds showed significant anti-proliferative activity.•Compound 12a caused G1 phase arrest and apoptosis on B16 cancer cells.•Compound 12a significantly inhibited the tumor growth in vivo.