Abstract
A series of naphthalene-chalcone derivatives (3a–3t) were prepared and evaluated as tubulin polymerisation inhibitor for the treatment of breast cancer. All compounds were evaluated for their antiproliferative activity against MCF-7 cell line. The most of compounds displayed potent antiproliferative activity. Among them, compound 3a displayed the most potent antiproliferative activity with an IC50 value of 1.42 ± 0.15 µM, as compared to cisplatin (IC50 = 15.24 ± 1.27 µM). Additionally, the promising compound 3a demonstrated relatively lower cytotoxicity on normal cell line (HEK293) compared to tumour cell line. Furthermore, compound 3a was found to induce significant cell cycle arrest at the G2/M phase and cell apoptosis. Compound 3a displayed potent tubulin polymerisation inhibitory activity with an IC50 value of 8.4 µM, which was slightly more active than the reference compound colchicine (IC50 = 10.6 µM). Molecular docking analysis suggested that 3a interact and bind at the colchicine binding site of the tubulin.
Highlights
Microtubules are essential components of the cytoskeleton of eukaryotic cells, and they play important roles in a series of cellular processes such as determination and maintenance of cell shape, regulation of motility, organisation of intracellular architecture, secretion, cellular transport, and cell division[1,2]
Many previous studies have shown that the presence of a 20-hydroxyl group on the A-ring is important for the antitumor activity of chalcone derivatives[13–15]
Many researchers think that chalcones possessed significant anticancer activity due to their have a similar mode of action to the structurally related natural combretastatin A-417, and the methoxy substituent in A ring is a crucial pharmacophoric group for the anticancer potency by inhibition of tubulin polymerisation (Figure 1(III–V))[18–23]
Summary
Microtubules (composed of a-tubulin and b-tubulin heterodimers) are essential components of the cytoskeleton of eukaryotic cells, and they play important roles in a series of cellular processes such as determination and maintenance of cell shape, regulation of motility, organisation of intracellular architecture, secretion, cellular transport, and cell division[1,2]. A number of synthetic and natural chalcones exhibited potent anticancer activity against many cancer cell lines via inhibition of tubulin polymerization[10–12]. Lee et al reported the synthesis of 20-hydroxy50,60-naphthochalcone derivatives and the most active compound (HMNC-74) was found to be strongly inhibited the clonogenicity of SW620 colon cancer cells (Figure 1(II)). Many researchers think that chalcones possessed significant anticancer activity due to their have a similar mode of action to the structurally related natural combretastatin A-417, and the methoxy substituent in A ring is a crucial pharmacophoric group for the anticancer potency by inhibition of tubulin polymerisation (Figure 1(III–V))[18–23].
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