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

Hederagenin () is a novel triterpene template for the development of new antitumor compounds. In this study, 26 new ⁻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 . Remarkably, the most potent was compound (half maximal inhibitory concentration (IC) was 3.45 ± 0.59 μM), which exhibited similar antitumor activities against A549 (human non-small-cell lung cancer) as the positive drug cisplatin (; IC was 3.85 ± 0.63 μM), while it showed lower cytotoxicity on H9c2 (murine heart myoblast; IC was 16.69 ± 0.12 μM) cell lines. Compound 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 . The present studies highlight the importance of pyrazine derivatives of in the discovery and development of novel antitumor agents.