Design, Synthesis, and Cytotoxic Analysis of Novel Hederagenin⁻Pyrazine Derivatives Based on Partial Least Squares Discriminant Analysis.

Abstract

Hederagenin (He) is a novel triterpene template for the development of new antitumor compounds. In this study, 26 new He⁻pyrazine derivatives were synthetized in an attempt to develop potent antitumor agents; they were screened for in vitro cytotoxicity against tumor and non-tumor cell lines. The majority of these derivatives showed much stronger cytotoxic activity than He. Remarkably, the most potent was compound 9 (half maximal inhibitory concentration (IC50) was 3.45 ± 0.59 μM), which exhibited similar antitumor activities against A549 (human non-small-cell lung cancer) as the positive drug cisplatin (DDP; IC50 was 3.85 ± 0.63 μM), while it showed lower cytotoxicity on H9c2 (murine heart myoblast; IC50 was 16.69 ± 0.12 μM) cell lines. Compound 9 could induce the early apoptosis and evoke cell-cycle arrest at the synthesis (S) phase of A549 cells. Impressively, we innovatively introduced the method of cluster analysis modeled as partial least squares discriminant analysis (PLS-DA) into the structure⁻activity relationship (SAR) evaluation, and SAR confirmed that pyrazine had a profound effect on the antitumor activity of He. The present studies highlight the importance of pyrazine derivatives of He in the discovery and development of novel antitumor agents.

• Authors: Kang Fang, Xiao-Hua Zhang, Yao-Tian Han, Gao-Rong Wu, De-Sheng Cai, Nan-Nan Xue, Wen-Bo Guo, Yu-Qin Yang, Meng Chen, Xin-Yu Zhang, Hui Wang, Tao Ma, Peng-Long Wang, Hai-Min Lei
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 19 Issue 10 (Sep 30 2018) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 30274380 (Publication Type: Journal Article)

Chemical References

• Pyrazines
• Oleanolic Acid
• hederagenin

Topics

• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Death
• Cell Line, Tumor
• Cell Shape (drug effects)
• Cluster Analysis
• Discriminant Analysis
• Drug Design
• Humans
• Inhibitory Concentration 50
• Least-Squares Analysis
• Oleanolic Acid (analogs & derivatives, chemical synthesis, chemistry, toxicity)
• Principal Component Analysis
• Pyrazines (chemical synthesis, chemistry, toxicity)
• Staining and Labeling
• Structure-Activity Relationship