Design and synthesis of formononetin-dithiocarbamate hybrids that inhibit growth and migration of PC-3 cells via MAPK/Wnt signaling pathways

Abstract

A series of novel formononetin-dithiocarbamate derivatives were designed, synthesized and evaluated for antiproliferative activity against three selected cancer cell line (MGC-803, EC-109, PC-3). The first structure-activity relationship (SAR) for this formononetin-dithiocarbamate scaffold is explored in this report with evaluation of 14 variants of the structural class. Among these analogues, tert-butyl 4-(((3-((3-(4-methoxyphenyl)-4-oxo-4H–chromen-7-yl)oxy)propyl)thio)carbonothioyl)piperazine-1-carboxylate (8i) showed the best inhibitory activity against PC-3 cells (IC50 = 1. 97 µM). Cellular mechanism studies elucidated 8i arrests cell cycle at G1 phase and regulates the expression of G1 checkpoint-related proteins in concentration-dependent manners. Furthermore, 8i could inhibit cell growth via MAPK signaling pathway and inhibit migration via Wnt pathway in PC-3 cells.

Discovery of 5,6-diaryl-1,2,4-triazines hybrids as potential apoptosis inducers

“…The Western blot analysis was performed according to the methods previously published [37]. Statistical analysis was performed according to the our reported methods [22]. Therefore, no details are given here.…”

“…Recently, our group have reported four series of 1,2,3-triazole derivatives as potential antitumor agents (Fig. 2): 1,2,3-triazole-chalcone hybrid 4 inhibited the proliferation of SK-N-SH cancer cells by inducing apoptosis and arresting the cell cycle at the G1 phase [15]; the novel 1,2,3-triazole-chalcone 5 bearing a 4,5-dihydrothiazole showed the potent activity with an IC 50 value of 8.16 µM against neuroendocrine cancer cells [16]; 1,2,3-triazole-dithiocarbamate based selective lysine specific demethylase 1 inactivator 6 inhibited gastric cancer cell apoptosis, invasion, and migration [17]; the steroidal hybrid 7 arrested cell cycle at G2/M phase, induced apoptosis accompanied with decrease of mitochondrial membrane potential [18]. …”

Molecular diversity of phenothiazines: design and synthesis of phenothiazine–dithiocarbamate hybrids as potential cell cycle blockers

“…The MTT assay, analysis of cell cycle distribution, detection of apoptosis, western blot analysis, and statistical analysis were carried out as previously reported [16]. …”

“…Four series of dithiocarbamates derivatives have been reported as potential antitumor agents by our group: The butenolide-containing dithiocarbamate 4 displayed a potent inhibitory activity with an IC 50 value of 0.77 μM against HeLa cells [13]; the novel dithiocarbamate–chalcone analogue 5 could induce apoptosis through apoptosis-related proteins and arrest the cell cycle at G0/G1 phase against SK-N-SH cells [14]; triazole–dithiocarbamate hybrid 6 inhibited cell growth, invasion, and migration on MGC-803 cell line [15]; formononetin–dithiocarbamate derivative 7 inhibited migration and growth of PC-3 cells and regulated MAPK/Wnt signaling pathways [16] (Fig. 2).…”

Efficient click reaction towards novel sulfonamide hybrids by molecular hybridization strategy as antiproliferative agents

“…10 Molecular hybridization strategy is a new concept in drug design and development based on the combination of pharmacophoric moieties of different bioactive substances to produce a new hybrid compound with improved affinity and efficacy, when compared to the parent drugs. 11 Based on the above interesting findings and our continuous quest to synthesize antitumor agents, [12][13][14][15][16] led us to carry out the molecular hybridization of biologically active sulfonamide and 1, 2, 3-triazole to integrate them in one molecular platform to generate new hybrid architecture with the aim of exploring the impact of such modification on the anticancer agents. As shown in Figure 3, a molecular hybridization strategy based on the structures of a bioactive sulfonamide derivative 1 and a bioactive 1, 2, 3-triazole compound5 yielded a scaffold which has three parts: (i) a 1, 2, 3-triazole as a central core, (ii) a substituted phenylsulfonamide (iii) another phenyl sulfonamide attached throughcarbon 4 ( Figure 3).…”