Abstract
We designed a series of novel phenothiazine-1,2,3-triazole hybrids by the molecular hybridization strategy and evaluated their antiproliferative activity against three cancer cell lines (MDA-MB-231, MDA-MB-468 and MCF-7). For the structure-activity relationships, the importance of 1,2,3-triazole and substituents on phenyl ring was explored. Among these phenothiazine-1,2,3-triazole hybrids, compound 9f showed the most potent inhibitory effect against MCF-7 cells, with an IC50 value of 0.8 μM. Importantly, compound 9f could induce apoptosis against MCF-7 cells by regulating apoptosis-related proteins (Bcl-2, Bax, Bad, Parp, and DR5). These potent phenothiazine-1,2,3-triazole hybrids as novel apoptosis inducers might be used as antitumor agents in the future.
Highlights
According to the cancer epidemiology data collected in the cancer statistics 2017, breast cancer accounts for about 14.4% of cancer related death and 29.6% of new cases in female, and which is the top type of female new cancer cases and the second cause of female cancer related death worldwide after lung cancer [1]
When 4-CH3 substituent (9d) as an electron-donating group was replaced by the electron-withdrawing groups like F, Cl, Br (9a, 9b, 9c), the antiproliferative activity was decreased against all cancer cell lines
9f was among phenothiazine-1,2,3-triazole hybrids, the antiproliferative antiproliferative mechanism explored
Summary
According to the cancer epidemiology data collected in the cancer statistics 2017, breast cancer accounts for about 14.4% of cancer related death and 29.6% of new cases in female, and which is the top type of female new cancer cases and the second cause of female cancer related death worldwide after lung cancer [1]. It is necessary to develop the potent antitumor agents to treat breast cancer. Phenothiazine is a useful scaffold in antitumor drug design [3,4,5]. Many phenothiazine derivatives were designed as novel anticancer agents. Phenothiazine derivative 1 (Figure 1) proved to be a microtubule-interacting agent with great cell growth inhibition profile (GI50 in the nanomolar range on human melanoma-adenocarcinoma MDA-MB-435 cells) [6]. Phenothiazine derivative 2 could arrest tumor cell cycle in the G2/M phase [7]. The 3-hydroxy-4-methoxyphenylethyl derivative 3 was a potent in vitro tubulin polymerization inhibitor but with weak cytotoxicity toward the human colon adenocarcinoma HT29 cell line, in the micromolar range [8].
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