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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 ?M), 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 ?M), while it showed lower cytotoxicity on H9c2 (murine heart myoblast; IC50 was 16.69 ± 0.12 ?M) 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.

SUBMITTER: Fang K

PROVIDER: S-EPMC6213900 | biostudies-other | 2018 Sep

REPOSITORIES: biostudies-other

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

Fang Kang K Zhang Xiao-Hua XH Han Yao-Tian YT Wu Gao-Rong GR Cai De-Sheng DS Xue Nan-Nan NN Guo Wen-Bo WB Yang Yu-Qin YQ Chen Meng M Zhang Xin-Yu XY Wang Hui H Ma Tao T Wang Peng-Long PL Lei Hai-Min HM

International journal of molecular sciences 20180930 10

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 (IC<su ...[more]

PMID: 30274380

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Project description:BackgroundChrysin (5,7-dihydroxyflavone) is a widely distributed natural flavonoid found in many plant extracts, honey and propolis. Several studies revealed that chrysin possesses multiple biological activities including anti-cancer effects. It has been established that activation of apoptosis is the key molecular mechanism responsible for the cytotoxic potential of chrysin. The objective of this study was to design and synthesize potent chrysin analogues as potential cytotoxic agents.MethodsA series of chrysin derivatives (3a-m) bearing N'-alkylidene/arylideneacetohydrazide moiety were designed, synthesized, and evaluated for their antiproliferative activity against two human breast cancer cell lines, MDA-MB-231 and MCF-7 by applying the MTT colorimetric assay. Selected compounds were tested for their ability to induce apoptosis through caspase 3/7 activation in MDA-MB-231 cells only since MCF-7 cells lack procaspase 3.ResultsCompounds (3a-m) were obtained as geometrical isomers (E/Z isomers) in good yields upon treatment of hydrazide 5 with different aliphatic and aromatic aldehydes. Most of the synthesized compounds demonstrated moderate-to-good activity against both cell lines. The cytotoxicity results revealed the importance of lipophilic moieties at C-4 position of ring D in imparting the cytotoxic activities to the compounds. Compound 3e with 4-benzyloxy substituent was found to be the most active among the synthesized compounds with IC50 3.3 µM against MDA-MB-231 and 4.2 µM against MCF-7 cell lines. The cytotoxic potential of compound 3e is comparable to that of the well-known anti-cancer agent doxorubicin. In addition, compounds substituted with fluoro (3b), nitro (3h), and dimethylamino (3j) exhibited good cytotoxicity with IC50 <6.5 µM against MDA-MB-231 and <12 µM against MCF-7. Selected compounds were able to induce apoptosis in MDA-MB-231 cells as indicated by caspase-3 and/or -7 activation.ConclusionOur results show that the newly designed chrysin derivatives exert anticancer activity in human breast cancer cell lines, MDA-MB-231 and MCF-7. Therefore, they can be considered as leads for further development of more potent and selective cytotoxic agents.

Dataset Information

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

Publications

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

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