Department of Biology, Faculty of Science, Golestan University, Gorgan, Iran.
Pharm Biol. 2012 Dec;50(12):1551-60. doi: 10.3109/13880209.2012.695799. Epub 2012 Sep 18.
As microtubules are highly involved in cellular growth, it appears to be a preferential target for cancer treatment. Therefore, many efforts have been performed to discover drugs that affect on microtubule function. Several microtubule inhibitors are in various stages of laboratory evaluations and clinical trials.
A series of chromene-based chalcones with chlorine, methoxy, fluorine, tetrahydropyranyloxy and cyanide substituents were prepared and evaluated for cytotoxic effects against K562 and SK-N-MC cell lines, and the inhibitory effect on tubulin polymerization was studied as well.
MTT, tubulin polymerization assays and binding measurements were evaluated by using related spectroscopy. Immunocytochemical study, morphological observations and apoptosis assay were examined using a fluorescence microscope and a flow cytometer.
(E)-3-(6-Chloro-2H-chromen-3-yl)-1-(3,4,5-trimethoxyphenyl) prop-2-en-1-one (compound 14) proved to be the most active in this series as an inhibitor of tubulin assembly [IC₅₀, 19.6 µM] and cytotoxic agent on K562 cells [IC₅₀, 38.7 µM]. Furthermore, these compounds exhibited a strong inhibitory effect on tubulin polymerization and reduced the in vitro assembly and bundling of proto-filaments. Also, compound 14 bound to the tubulin with a dissociation constant of 9.4 ± 0.7 µM and induced conformational changes in this protein.
This study suggests that the compound 14 could be a good antitumor agent because of its biological functions. Compound 14 appears to bind directly to tubulin and thereby perturbs microtubule stability and the function of the spindle apparatus, which causes cancer cells to arrest and undergo apoptosis.
由于微管在细胞生长中高度参与，因此它似乎是癌症治疗的首选靶标。因此，已经进行了许多努力来发现影响微管功能的药物。几种微管抑制剂处于实验室评估和临床试验的各个阶段。
合成了一系列带有氯、甲氧基、氟、四氢吡喃氧基和氰基取代基的色烯基查耳酮，并对其进行了细胞毒性评价，以确定其对 K562 和 SK-N-MC 细胞系的作用，同时研究了其对微管聚合的抑制作用。
采用相关光谱法评估 MTT、微管聚合试验和结合测量。免疫细胞化学研究、形态学观察和凋亡试验采用荧光显微镜和流式细胞仪进行检测。
（E）-3-（6-氯-2H-色烯-3-基）-1-（3,4,5-三甲氧基苯基）丙-2-烯-1-酮（化合物 14）是该系列中最有效的微管组装抑制剂[IC₅₀，19.6 µM]和 K562 细胞的细胞毒性剂[IC₅₀，38.7 µM]。此外，这些化合物对微管聚合有很强的抑制作用，并减少了原纤维的体外组装和束状。此外，化合物 14与微管的解离常数为 9.4 ± 0.7 µM，并诱导该蛋白构象发生变化。
本研究表明，化合物 14 可能是一种良好的抗肿瘤药物，因为它具有生物功能。化合物 14 似乎直接与微管结合，从而扰乱微管的稳定性和纺锤体装置的功能，导致癌细胞停滞并发生凋亡。
