Synthesis of α,β-Unsaturated Carbonyl-Based Compounds, Oxime and Oxime Ether Analogs as Potential Anticancer Agents for Overcoming Cancer Multidrug Resistance by Modulation of Efflux Pumps in Tumor Cells

Abstract

Sixty-nine novel α,β-unsaturated carbonyl based compounds, including cyclohexanone, tetralone, oxime, and oxime ether analogs, were synthesized. The antiproliferative activity determined by using seven different human cancer cell lines provided a structure-activity relationship. Compound 8ag exhibited high antiproliferative activity against Panc-1, PaCa-2, A-549, and PC-3 cell lines, with IC50 value of 0.02 μM, comparable to the positive control Erlotinib. The ten most active antiproliferative compounds were assessed for mechanistic effects on BRAF(V600E), EGFR TK kinases, and tubulin polymerization, and were investigated in vitro to reverse efflux-mediated resistance developed by cancer cells. Compound 8af exhibited the most potent BRAF(V600E) inhibitory activity with an IC50 value of 0.9 μM. Oxime analog 7o displayed the most potent EGFR TK inhibitory activity with an IC50 of 0.07 μM, which was analogous to the positive control. Some analogs including 7f, 8af, and 8ag showed a dual role as anticancer and MDR reversal agents.

Synthesis and biological evaluation of new tetramethylpyrazine‐based chalcone derivatives as potential anti‐Alzheimer agents

“…Our recent report described the synthesis of α, β‐unsaturated carbonyl‐based chalcone derivatives using direct coupling method (Scheme , Table ) . For the synthesis of 17 new compounds, base‐catalyzed Claisen–Schmidt condensation was used to react various ketones with ligustrazine‐based aromatic aldehyde ( 10 ) at feed ratio 1:1.…”

Synthesis and mechanistic studies of curcumin analog‐based oximes as potential anticancer agents

“…The previously reported method by our group was used to synthesize new oxime analogs using most potent α, β‐unsaturated carbonyl‐based compounds ( 1–8 ) as precursors. Each selected compound (1 mmol) was reacted to hydroxylamine hydrochloride (2 mmol) in 10 ml of ethanol to produce the corresponding oxime ( 1a–8a ).…”

“…3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide (MTT) assay was conducted to determine the effect of new oxime compounds on mammary epithelial cells (MCF‐10A) . Different types of cell lines including HT‐29 (colon cancer), PC‐3 (prostate cancer), A‐549 (epithelial), Panc‐1 (pancreas cancer), MCF‐7 (breast cancer), H‐460 (lung cancer), and PaCa‐2 (pancreatic carcinoma) were used to perform PI fluorescence assay to study the antiproliferative efficacy of compounds. Tubulin Polymerization Assay Kit (Cytoskeleton Inc., Denver, CO, USA), which works on the principle of fluorescent reporter enhancement, was used to investigate the effect of compounds on tubulin polymerization.…”

“…Some compounds were found to be strong anticancer agents exhibiting 81%–82% cytotoxicity. In another study, we found that the oxime analogs showed strong antiproliferative activity against cancer cell lines as compared to curcumin‐like oxime ether, cyclohexanone, and tetralone analogs …”

Synthesis and Characterization of Chalcone‐Pyridinium Hybrids as Potential Anti‐Cancer and Anti‐Microbial Agents

“…were reported earlier as anticancer agents . In addition, substituted 1‐tetralones were also reported as potential anticancer agents . Also, pyridine has attained a great attention from the medicinal chemists because of its antiproliferative potency .…”