Discovery and Optimization of a Series of 2-Aryl-4-Amino-5-(3′,4′,5′-trimethoxybenzoyl)Thiazoles as Novel Anticancer Agents

Abstract

A new series of tubulin polymerization inhibitors based on the 2-aryl/heteroaryl-4-amino-5-(3′,4′,5′-trimethoxybenzoyl)thiazole scaffold was synthesized and evaluated for growth inhibition activity on a panel of cancer cell lines, cell cycle effects, and in vivo potency. Structure–activity relationships were elucidated with various substitutions at the 2-position of the thiazole skeleton. Hydrophobic moieties, such as phenyl and 3-thienyl, were well tolerated at this position, and variation of the phenyl substituents had remarkable effects on potency. The most active compound (3b) induced apoptosis through the mitochondrial pathway with activation of caspase-3. We also showed that it has potential antivascular activity since it reduced in vitro endothelial cell migration and disrupted capillary-like tube formation at noncytotoxic concentrations. Furthermore, compound 3b significantly reduced the growth of the HT-29 xenograft in a nude mouse model, suggesting that 3b is a promising new antimitotic agent with clinical potential.

Design, Synthesis, and Biological Evaluation of Novel Pyridine-Bridged Analogues of Combretastatin-A4 as Anticancer Agents

“…24,25 It is based on the principal that light is scattered by microtubules to an extent that is proportional to the concentration of the microtubule polymer. Compounds that interact with tubulin will alter the polymerization of tubulin, and this can be detected using a spectrophotometer.…”

Combined Molecular Docking, 3D‐QSAR, and Pharmacophore Model: Design of Novel Tubulin Polymerization Inhibitors by Binding to Colchicine‐binding Site

“…website and curated sixteen important medicinal chemistry papers carefully for analysis of the structure–activity relationship (SAR) and the binding pose of these ligands (Chart S1). From the year 2004–2012, Silvestri group reported a series of colchicine‐site inhibitors with arylthioindole skeleton, and recently their attentions were shifted to the replacement of the indole ring with thiazole . Kremmidiotis group depicted a class of tubulin polymerization inhibitors derived from the benzofuran scaffold, in which compound 95 ( BNC105 , Figure ) had been investigated under the clinical trial.…”

“…Besides, the alternation of the parent nucleus could circumvent tumor resistance . The compounds with mono‐aromatic ring system (thiazole or thiophene) might possess much of variation on alternative binding pose ; thus, this needed to be discussed carefully in the design process of novel CSIs. Thirdly, the SAR studies on the linker of a series of arylthioindole compounds revealed that A region tended toward the rigid moiety, such as ketone or amide, while the methylene can be tolerated .…”

“…This stimulated us to consider the design of compounds 132 ~ 143 , mainly due to that it was not sure at which position of these indole–pyrazole analogs the trimethoxybenzoyl group should be placed. The aromatic substituents ( m ‐OCH 3 ‐C 6 H 4 , p ‐F‐ C 6 H 4 , and so on) were selected from the corresponding reference . After checking carefully, the total of D‐series compounds amounted to 105.…”

“…All the compounds used in this study were extracted from a series of recently published literature . The compounds displayed in Chart S1 were picked up manually, and each molecule exhibited most potent activity in the corresponding paper.…”