Synthesis and biological evaluation of 2-substituted-4-(3′,4′,5′-trimethoxyphenyl)-5-aryl thiazoles as anticancer agents

Abstract

Antitumor agents that bind to tubulin and disrupt microtubule dynamics have attracted considerable attention in the last few years. To extend our knowledge of the thiazole ring as a suitable mimic for the cis-olefin present in combretastatin A-4, we fixed the 3,4,5-trimethoxyphenyl at the C4-position of the thiazole core. We found that the substituents at the C2- and C5-positions had a profound effect on antiproliferative activity. Comparing compounds with the same substituents at the C5-position of the thiazole ring, the moiety at the C2-position influenced antiproliferative activities, with the order of potency being NHCH3> Me ≫ N(CH3)2. The N-methylamino substituent significantly improved antiproliferative activity on MCF-7 cells with respect to C2-amino counterparts. Increasing steric bulk at the C2-position from N-methylamino to N,N-dimethylamino caused a 1–2 log decrease in activity. The 2-N-methylamino thiazole derivatives 3b, 3d and 3e were the most active compounds as antiproliferative agents, with IC50 values from low micromolar to single digit nanomolar, and, in addition, they are also active on multidrug-resistant cell lines over-expressing P-glycoprotein. Antiproliferative activity was probably caused by the compounds binding to the colchicines site of tubulin polymerization and disrupting microtubule dynamics. Moreover, the most active compound 3e induced apoptosis through the activation of caspase-2, -3 and -8, but 3e did not cause mitochondrial depolarization.

Synthesis and Biological Evaluation of 2-Methyl-4,5-Disubstituted Oxazoles as a Novel Class of Highly Potent Antitubulin Agents

“…The binding mode in the colchicine site of tubulin of the newly prepared 2-methyloxazole derivatives was elucidated performing a series of molecular docking simulations, following a previous reported procedure21. The binding observed for all the derivatives is closely related to the one found for the co-crystallized DAMA-colchicine, and it is consistent with those previously reported for different tubulin polymerization inhibitors2123.…”

“…These compounds were one to three orders of magnitude less active than CA-4, in terms of molar IC 50 values21. These compounds also caused accumulation of HeLa and Jurkat cells in the G2/M phase of the cell cycle, as is typical for antimicrotubule agents.…”

Tubulin-interactive stilbene derivatives as anticancer agents

“…The rationale of the design of active compounds was to retain the appropriate geometry of the two adjacent aryl groups required for potent bioactivity of chemically stable cis-restricted derivatives of CA-4. These were obtained by incorporating the olefinic double bond into vicinally diaryl-substituted fivemember aromatic heterocyclic rings (Table 1), such as pyrazole [67], imidazole [67][68][69], thiazole [70][71][72], furazan (1,2,5-oxadiazole) [73], furan [74,75], thiophene [76,77], isoxazole [78,79], oxazole [67,68,80,81], 1,2,3-thiadiazole [39], triazole [82,83,84,85], 1,2,3,4-tetrazole [70,86] and dioxolane [87]. Replacement of the olefinic bond with a five-member heterocyclic ring allowed the retention of the correct geometric orientation of the two phenyl rings of CA-4, placing them at an appropriate distance for efficient interaction with the colchicine-binding domain on tubulin [35].…”

One-pot multicomponent synthesis of novel 1-thiazolyl-5-coumarin-3-yl-pyrazole derivatives and evaluation of their cytotoxic activity

“…Pyrazole scaffolds are not only independent, along with other heterocycles like thiazole and coumarins, but also possess marked biological activities [13][14][15][16][17][18]. Thiazoles and coumarins also portray an important role in medicinal and pharmaceutical chemistry due to their versatile biological applications, such as antimicrobial [19,20], anticancer [21,22], antitumor [23,24], antiulcer [25,26], antiviral [27,28], antioxidant [29,30], anticonvulsant [31,32] and antihypertensive [33,34] activities.…”