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.

journal_name

Int J Mol Sci

authors

Fang K,Zhang XH,Han YT,Wu GR,Cai DS,Xue NN,Guo WB,Yang YQ,Chen M,Zhang XY,Wang H,Ma T,Wang PL,Lei HM

doi

10.3390/ijms19102994

subject

Has Abstract

pub_date

2018-09-30 00:00:00

issue

10

issn

1422-0067

pii

ijms19102994

journal_volume

19

pub_type

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