<p>Synthesis and Biological Evaluations of Monocarbonyl Curcumin Inspired Pyrazole Analogues as Potential Anti-Colon Cancer Agent</p>

Abstract

The monocarbonyl analogs of curcumin (MCACs) have been widely studied for their promising antitumor activity. Pyrazole is a five-membered aromatic heterocyclic system with various bioactivities incorporated frequently in drugs. However, few of MCACs inspired pyrazole analogues were investigated. To search for more potent cytotoxic agents based on MCACs, a series of new 1,5-diaryl/heteroaryl-1,4-pentadien-3-ones inspired pyrazole moiety was synthesized and evaluated on their anti-colon cancer activities. Methods: Fifteen new compounds were synthesized and characterized by spectral datum, and then they were tested preliminarily by MTT assay for their cytotoxic activities against a panel of four human cancer cell lines, namely, gastric (SGC-7901), liver (HepG2), lung (A549), and colon (SW620) cancer cells. Compound 7h exhibited excellent selectivity and outstanding anti-proliferation activity against SW620 cells among these 15 compounds. Further, the mechanisms were investigated by transwell migration and invasion assay, clonogenic assay, cell apoptosis analysis, cell cycle analysis, Western blot analysis. Results: The IC 50 value of 7h against SW620 cells was 12 nM, being more potent than curcumin (IC 50 = 9.36 μM), adriamysin (IC 50 = 3.28 μM) and oxaliplatin (IC 50 = 13.33 μM). Further assays showed that 7h inhibited SW620 cell migration, invasion and colony formation obviously, which was due to its ability to induce cell cycle arrest in the G2/M and S phases and apoptosis. Western blot assay revealed that 7h decreased the protein expression of ATM gene, which may primarily contribute to its anticancer activity against SW620 cells. Conclusion: A new MCACs 7h was synthesized and found to exhibit excellent antiproliferation activity against SW620 cells. Further studies indicated that 7h exerted its anticancer activity against SW620 cells probably via decreasing the ATM protein expression. The present study suggested that 7h was a promising candidate as an anti-colon cancer drug for future development.

Diarylpentanoid (1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one) (MS13) Exhibits Anti-proliferative, Apoptosis Induction and Anti-migration Properties on Androgen-independent Human Prostate Cancer by Targeting Cell Cycle–Apoptosis and PI3K Signalling Pathways

“…Similar results were reported when a diarylpentanoid, DM-1 treated in melanoma cells and EF24 in hepatocellular carcinoma cells (Liu et al, 2012;Faião-Flores et al, 2013). Besides, studies on multiple human colon cancer cell lines indicated that DAPs induced apoptosis by activating caspase-3 activity (Subramaniam et al, 2008;Selvendiran et al, 2010;Liang et al, 2017;Min et al, 2020) and reducing Bcl-2 protein (Lin et al, 2011;He et al, 2016). These findings suggest that activation of caspase-3 and downregulation of Bcl-2 in treated cells demonstrated the apoptosis-inducing ability of MS13.…”

The Curcumin Analogue, MS13 (1,5-Bis(4-hydroxy-3- methoxyphenyl)-1,4-pentadiene-3-one), Inhibits Cell Proliferation and Induces Apoptosis in Primary and Metastatic Human Colon Cancer Cells

“…FLLL-11 which is identical to MS13 was believed to inhibit cell viability, proliferation and induce apoptosis via caspase 3 in human colorectal cancer cell lines [ 45 ]. It was reported that DAPs demonstrated anti-cancer effect through induction of apoptosis in various human colon cancer cell lines involving activation of caspase-3 [ 28 , 39 , 114 , 115 ] and down-regulation of anti-apoptotic Bcl-2 protein [ 116 , 117 ] even at a very low concentration between the range of 2.5–6.0 µM [ 45 , 117 ]. Another DAP, 1,5-bis (2-metoxyphenyl)-1,4-pentadiene-3-one (B63) was shown to induce apoptosis in human colon cancer cells via the mitochondrial apoptotic pathway which includes down-regulation of mitochondrial complexes, up-regulation of pro-apoptotic proteins-Bad and Bim, activation of caspase-3, PARP cleavage and cytochrome c release [ 119 ].…”

Synthesis, Biological Evaluation, and Molecular Modeling Studies of 1-Aryl-1H-pyrazole-Fused Curcumin Analogues as Anticancer Agents

“…Among asymmetric MACs synthesized, 7a , 7c , 7g, 10a , and 10g were described before in the literature. 55 , 56 …”

“…Among asymmetric MACs synthesized, 7a, 7c, 7g, 10a, and 10g were described before in the literature. 55,56 Figure 9. Physicochemical properties of compounds 7d, 7h, and 10c, in comparison with those of curcumin, colchicine, and paclitaxel.…”

“….1.1. (1E,4E)-1-(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-5-(3,4-dimethoxyphenyl)penta-1,4-dien-3-one (7a) 56. Yellow solid (171.7 mg, 42%); mp 137−140 °C; TLC (R f , dichloromethane−methanol 95:5) 0.67; IR (ATR, ν cm −1 ): 2938 (ArH), 2839 (Me), 1655 (C�O), 1589 (C� C), 772 (C−Cl); HPLC purity 99.410% (r.t. 11.589 min); 1 H-NMR (500 MHz, DMSO-d 6 , δ ppm): 7.67 (1H, d, J = 16.0 Hz, −CH�), 7.61−7.50 (5H, m, ArH), 7.55 (1H, d, J = 16.0 Hz, −CH�), 7.42 (1H, d, J = 1.0 Hz, ArH), 7.34 (1H, dd, J = 1.5, 8.5 Hz, ArH), 7.23 (1H, d, J = 16.0 Hz, −CH�), 7.14 (1H, d, J = 16.0 Hz, −CH�), 7.02 (1H, d, J = 8.5 Hz, ArH), 3.84 (3H, s, OMe), 3.81 (3H, s, OMe), 2.49 (3H, s, Me); 13 C-NMR (125 MHz, DMSO-d 6 , δ ppm): 187.6, 151.2, 149.4, 149.0, 142.9, 137.2, 130.4, 129.3, 128.8, 128.0, 127.4, 125.0, 124.8, 124.1, 123.4, 113.6, 111.6, 110.7, 55.6, 55.6, 14.0; HR-MS (ESI, m/z): C 23 H 21 ClN 2 O 3 [M + H] + calcd 409.1320, found 409.1297.…”