Convergent Synthesis and Biological Evaluation of 2-Amino-4-(3′,4′,5′-trimethoxyphenyl)-5-aryl Thiazoles as Microtubule Targeting Agents

Abstract

Combretastatin A-4, a potent tubulin polymerization inhibitor, caused us to synthesize a novel series of 2-amino-4-(3′,4′,5′-trimethoxyphenyl)-5-aryl thiazoles with the goal of evaluating the effects of substituents on the phenyl at the 5-position of the thiazole skeleton on biological activities. An ethoxy group at the para-position produced the most active compound in the series, with IC50 values of 0.03–0.9 nM against five of seven cancer cell lines. The most active compounds retained full activity in multidrug resistant cancer cells and acted through the colchicine site of tubulin. Treated cells were arrested in the G2/M phase of the cell cycle, with cell death proceeding through an apoptotic pathway that was only partially caspase-dependent. Preliminary results suggest that, in addition to cell death by apoptosis, cells were also killed via mitotic catastrophe as an alternative cell death mechanism.

TR-644 a novel potent tubulin binding agent induces impairment of endothelial cells function and inhibits angiogenesis

“…11 (panel C), cell proliferation in the whole tumor significantly decreased after TR-644, while CA4-P did not. These results are in well agreement with the higher antiproliferative activity of TR-644 in many tumor cell lines relative to the lead compound CA-4 [15].…”

“…We previously demonstrated that TR-644 displayed effective antiproliferative activity in numerous cell lines derived from human solid tumors and leukemias, including multidrug resistant cell lines [15]. We also showed that TR-644 induced depolymerization of tubulin and inhibited normal spindle formation in HeLa cells, resulting in mitotic arrest and cell death.…”

“…Drugs and cell culture TR-644 was synthesized as previously described [15]. Combretastatin A4 (CA4) and CA4-P were synthesized as described [16][17][18].…”

“…Thus, to retain the appropriate geometry of the two adjacent aryl groups required for a potent bioactivity, chemically stable cis-restricted derivatives of CA-4 were obtained by incorporating the olefinic double bond with vicinal diarylsubstituted five-member aromatic heterocyclic rings, such as pyrazole [8], imidazole [9], thiazole [10], furazan (1,2,5-oxadiazole) [11], isoxazole [12], oxazole [8], 1,2,3-thiadiazole [13], triazole [14] and 1,2,3,4-tetrazole [10]. We recently synthesized [15] a new series of 2-amino-4-(3 0 ,4 0 ,5 0 -trimethoxyphenyl)-5-aryl thiazoles in which we identified compound TR-644 as the most active compound (Fig. 1).…”

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].…”