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

Abstract

Hederagenin (<b>He</b>) is a novel triterpene template for the development of new antitumor compounds. In this study, 26 new <b>He</b>⁻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<i>.</i> The majority of these derivatives showed much stronger cytotoxic activity than <b>He</b>. Remarkably, the most potent was compound <b>9</b> (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 (<b>DDP</b>; 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 <b>9</b> 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 <b>He</b>. The present studies highlight the importance of pyrazine derivatives of <b>He</b> in the discovery and development of novel antitumor agents.