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.

Betulinic Acid-Nitrogen Heterocyclic Derivatives: Design, Synthesis, and Antitumor Evaluation in Vitro

“…The IC 50 of derivatives compound 7e were 2.05 ± 0.66 µM, 2.79 ± 0.53 µM, 3.52 ± 0.37 µM and 3.13 ± 0.84 µM against Hela, HepG-2, BGC-823 and SK-SY5Y, respectively. It was further verified that the small molecule nitrogen heterocycle could enhance BA's bioactivity, which was in line with our previous report [20].…”

Design, synthesis and cytotoxic evaluation of novel betulonic acid-diazine derivatives as potential antitumor agents

“…The antitumor activity was assessed by MTT assay, as previously reported ( Fang et al, 2018 ). Each tested compound and positive control drugs were dissolved in DMSO and diluted with the medium to the test concentrations, and the final concentration of DMSO in the culture medium was controlled at less than 0.5% (v/v).…”

“…Furthermore (3R,4S)-3-(4-bromophenyl)-4-(4-fluorobenzoyl)-2-(2-oxo-2-phenylethyl)-3,4-dihydropyrrolo [1,2-a] pyrazin-2-ium bromide, synthesized based on pyrrolo [1,2-a] pyrazine, was suggested as a novel potential anticancer agent via caspase-3 activation and PARP cleavage ( Seo et al, 2020 ). Previously, we had reported the preparation of a series of novel natural product derivatives with ligustrazine (2,3,5,6-tetramethylpyrazine, TMP) which was a major effective component of Ligusticum chuanxiong Hort and observed that these derivatives possessed potent selective cytotoxicity ( Xu et al, 2015 ; Bi et al, 2016 ; Xu et al, 2017 ; Wang H. et al, 2018 ; Wang P. et al, 2018 ; Fang et al, 2018 ). Meanwhile, we synthesized hederagenin derivatives containing pyrazines with different methyl numbers and positions, and most of these derivatives showed much stronger cytotoxicity than the parent compound ( Fang et al, 2018 ).…”

Design, Synthesis and Biological Evaluation of Diosgenin-Amino Acid Derivatives with Dual Functions of Neuroprotection and Angiogenesis

“…Besides, amino acids successfully gained our attention because of its neuroprotection. For instance, L-type lysine could improve the function of central nervous tissue [32], glycine can reduce the damage of toxic substances generated during the ischemic processes and generate neuroprotective effects [33] and the neuroprotective effect of sarcosine is associated with changes in glycine transport and reduction of NR2B-containing NMDAR expression [34,35]. Therefore, they have inspired our interest in using diosgenin as the template parent to synthesize novel neuroprotective agents by combination with amino acids.…”