No abstract

Thalidomides were initially thought to be broad-range drugs specifically for curing insomnia and relieving morning sickness in pregnant women. However, its use was discontinued because of a major drawback of causing teratogenicity. In this study, we found that a thalidomide derivative, 5-hydroxy-2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione (5HPP-33), inhibited the proliferation of MCF-7 with a half-maximal inhibitory concentration of 4.5 ± 0.4 μM. 5HPP-33 depolymerized microtubules and inhibited the reassembly of cold-depolymerized microtubules in MCF-7 cells. Using time-lapse imaging, the effect of 5HPP-33 on the dynamics of individual microtubules in live MCF-7 cells was analyzed. 5HPP-33 (5 μM) decreased the rates of growth and shortening excursions by 34 and 33%, respectively, and increased the time microtubules spent in the pause state by 92% as compared to that of the vehicle-treated MCF-7 cells. 5HPP-33 (5 μM) reduced the dynamicity of microtubules by 62% compared to the control. 5HPP-33 treatment reduced the distance between the two poles of a bipolar spindle, induced multipolarity in some of the treated cells, and blocked cells at mitosis. In vitro, 5HPP-33 bound to tubulin with a weak affinity. Vinblastine inhibited the binding of 5HPP-33 to tubulin, and 5HPP-33 inhibited the binding of BODIPY FL-vinblastine to tubulin. Further, a molecular docking analysis suggested that 5HPP-33 shares its binding site on tubulin with vinblastine. The results provided significant insight into the antimitotic mechanism of action of 5HPP-33 and also suggest a possible mechanism for the teratogenicity of thalidomides.

This article describes the preparation of 2-heteroaryl and 600 dpi in TIF format)??>2,3-diheteroaryl-1,4-naphthoquinones by an environmentally benign short synthetic route with the goal of finding 1,4-naphthoquinone derivatives that induce apoptosis in cancer cells.

The copper(i) complexes containing phosphorus donor ligands such as diazadiphosphetidine, cis-{(o-OCH2C5H4N)P(μ-N(t)Bu)}2 (1) and aminobis(phosphonite), C6H5N{P(OC6H3(OMe-o)(C3H5-p))2}2 (2, PNP), have been synthesized. Treatment of 1 with copper iodide afforded the 1D coordination polymer [{Cu(μ-I)}2{(o-OCH2C5H4N)P(μ-N(t)Bu)}2]n (3). Treatment of 3 with 2,2'-bipyridine (bpy) and 1,10-phenanthroline (phen) produced mixed-ligand complexes [(L)2Cu2{(o-OCH2C5H4N)P(μ-N(t)Bu)}2][I]2 (4 L = bpy; 5 L = phen) in good yields. The reaction of 2 with copper iodide yielded a rare tetranuclear copper complex [(CuI)2C6H5N(PR2)2]2 (6), which on subsequent treatment with various pyridyl ligands produced binuclear complexes [{Cu(μ-I)(py)}2(μ-PNP)] (7), [Cu2(μ-I)(bpy)2(μ-PNP)]I (8), [Cu2(μ-I)I(bpy)(μ-PNP)] (9), [Cu2(phen)(bpy)(μ-PNP)](OTf)2 (10), [Cu2(μ-I)I(phen)(μ-PNP)] (11) and [Cu2(μ-I)(phen)2(μ-PNP)]I (12), in an almost quantitative yield. The new copper(i) complexes (4, 5 and 7-12) were tested for anti-cancer activity against three human tumor cell lines. Compounds 5, 10 and 12 showed in vitro antitumor activity 5-7 fold higher than cisplatin, the most used anticancer drug. These three most potent compounds (5, 10 and 12) were chosen for detailed study to understand their mechanism of action. The copper(i) compounds studied in the present investigation were found to inhibit tumor cell growth by arresting cells at the S-phase of the cell cycle. The characteristic nuclear morphology of treated cells showed signs of DNA damage. The experimental evidence clearly indicated that these compounds initiated apoptosis, which is mediated through the p53 pathway.