Abstract
A series of novel 3-alkyl-1,5-diaryl-1H-pyrazoles were synthesized as combretastatin A-4 (CA-4) analogues and evaluated for antiproliferative activity against three human cancer cell lines (SGC-7901, A549 and HT-1080). Most of the target compounds displayed moderate to potent antiproliferative activity, and 7k was found to be the most potent compound. Structure-activity relationships indicated that compounds with a trimethoxyphenyl A-ring at the N-1 position of the pyrazole skeleton were more potent than those with the A-ring at the C-5 position. Tubulin polymerization and immunostaining experiments revealed that 7k potently inhibited tubulin polymerization and disrupted tubulin microtubule dynamics in a manner similar to CA-4. Computational modelling demonstrated that the binding of 7k to the colchicine binding site on microtubules may involve a similar mode as CA-4.
Highlights
Microtubules are an essential component of the cytoskeleton and have many cellular functions, including regulation of motility, cell division, organelle transport, maintenance of cell morphology and signal transduction [1]
The synthesis of target pyrazole derivatives 7a-s were performed according to Fig 3. 3,4,5-Trimethoxy-benzoic acid (9) was treated with concentrated nitric acid in acetic acid at 40°C to yield 1,2,3-trimethoxy-5-nitrobenzene (10), which was reduced to amine 11 with hydrazine, ferric chloride hexahydrate and activated carbon in methanol at 65°C [22,23]. 3,4,5-Trimethoxyphenylhydrazine hydrochloride (12) was prepared from 11 via diazotization with sodium nitrite, followed by reduction with stannous chloride dihydrate [24]
Compounds 14a-g were prepared via a Claisen condensation between 13a-g and ethyl acetate, ethyl propionate or ethyl butanoate in the presence of sodium [25]
Summary
Microtubules are an essential component of the cytoskeleton and have many cellular functions, including regulation of motility, cell division, organelle transport, maintenance of cell morphology and signal transduction [1]. Compound 7k exhibited the most potent antiproliferative activity, with IC50 values between 0.076 and 0.12 μM against the three cancer cell lines. Introduction of a formyl (7l), hydroxymethyl (7m) or bromo (7o) group at the C-4 position of the pyrazole skeleton resulted in reduced activity compared to the corresponding compounds (7i and 7k).
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