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Objective: Several anti-tubulin agents were introduced for the cancer treatment so far. Despite successes in the treatment of cancer, these agents cause toxic side effects, including peripheral neuropathy. Comparing anti-tubulin agents, indibulin seemed to cause minimal peripheral neuropathy, but its poor aqueous solubility and other potential clinical problems have led to its remaining in a preclinical stage. Methods: Herein, indibulin analogues were synthesized and evaluated for their in vitro anti-cancer activity using MTT assay (on the MCF-7, T47-D, MDA-MB231 and NIH-3T3 cell lines), annexin V/PI staining assay, cell cycle analysis, anti-tubulin assay and caspase 3/7 activation assay. Results: One of the compounds, 4a, showed good anti-proliferative activity against MCF-7 cells (IC50: 7.5 μM) and low toxicity on a normal cell line (IC50 > 100 μM). All of the tested compounds showed lower cytotoxicity on normal cell line in comparison to reference compound, indibulin. In the annexin V/PI staining assay, induction of apoptosis in the MCF-7 cell line was observed. Cell cycle analysis illustrated an increasing proportion of cells in the sub-G-1 phase, consistent with an increasing proportion of apoptotic cells. No increase in G2/M cells was observed, consistent with the absence of anti-tubulin activity. A caspase 3/7 assay protocol showed that apoptosis induction by more potent compounds was due to activation of caspase 3. Conclusion: Newly synthesized compounds exerted acceptable anticancer activity and further investigation of current scaffold would be beneficial.

Background: The role of microtubules in cell division and signaling, intercellular transport, and mitosis has been well known. Hence, they have been targeted for several anti-cancer drugs. Methods: A series of 3-(alkylthio)-5,6-diphenyl-1,2,4-triazines were prepared and evaluated for their cytotoxic activities in vitro against three human cancer cell lines; human colon carcinoma cells HT-29, human breast adenocarcinoma cell line MCF-7, human Caucasian gastric adenocarcinoma cell line AGS as well as fibroblast cell line NIH-3T3 by MTT assay. Docking simulation was performed to insert these compounds into the crystal structure of tubulin at the colchicine binding site to determine a probable binding model. Compound 5d as the most active compound was selected for studying of microtubule disruption. Results: Compound 5d showed potent cytotoxic activity against all cell lines. The molecular modeling study revealed that some derivatives of triazine strongly bind to colchicine binding site. The tubulin polymerization assay kit showed that the cytotoxic activity of 5d may be related to inhibition of tubulin polymerization. Conclusion: The cytotoxicity and molecular modeling study of the synthesized compounds with their inhibition activity in tubulin polymerization demonstrate the potential of triazine derivatives for development of new anti-cancer agents.

Background: Cancer is an important cause of human death worldwide. During the last decades, many anticancer agents with anti-tubulin mechanism have been synthesized or extracted from nature and some of them also entered clinical use. Indibulin is one of the most potent tubulin polymerization inhibitors with minimal peripheral neuropathy, which is a big problem by some of the antimitotic agents such as taxanes and vinka alkaloids. With respect to this giant benefit, herein we decided to design and synthesize novel indibulin related compounds and investigate their anticancer activity against HT-29, Caco-2 and T47-D cancerous cell lines as well as NIH-T3T as normal cell line. Objective: The aim of this study was to synthesize new anti-cancer agents and evaluates their cytotoxic activity on diverse cancerous and normal cell lines. Method: Target compounds were synthesized in multistep reaction and cytotoxic activity was investigated by MTT cell viability assay. Results: Herein, nine novel target compounds were synthesized in moderate to good yield. Some of the compounds exerted good cytotoxic activity against cancerous cell lines. Annexin V/PI staining showed that compound 4g could induce apoptosis and necrosis in HT-29 cell line. Conclusion: It is valuable to do further investigation on compound 4g which showed the highest activity against HT-29 and Caco-2 (IC50 values are 6.9 and 7 &µM respectively). Also, synthesis of new derivatives of current synthesized compounds is suggested.

Indibulin is one of the most potent tubulin polymerization inhibitors with minimal peripheral neuropathy. The design and synthesis of new indibulin analogs were carried out in order to investigate their anti-cancer activity. The target compounds 4a–i were synthesized in multistep reactions starting with the related indole derivatives. Compound 4f shows the highest cytotoxic activity on HT-29 and Caco-2 cell lines with the respective half maximal inhibitory concentration (IC50) values of 5.1 μm and 7.3 μm. In the case of the T47-D cell line, compound 4c exerts the best cytotoxic activity with an IC50 value of 11.5 μm. In the cell cycle analysis on HT-29 cells, compound 4f at 5.1 μm showed an increase in the percentage of cells in the sub-G1 phase. Altogether, nine target compounds were synthesized and characterized by infrared spectroscopy (IR), proton nuclear magnetic resonance (1H NMR), carbon-13 nuclear magnetic resonance (13C NMR), mass spectrometry (MS) and elemental analysis. Some of the compounds show good cytotoxic activity against cancerous cell lines.

A facile and general procedure is presented for the one-pot synthesis of 2-aminotetrahydrothiopyrano[4,3-b]pyran-3-carbonitrile derivatives. It is based on the three-component condensation of aliphatic, aromatic, or heterocyclic aldehydes, malononitrile, and thiopyran in the presence of mesoporous amino-functionalized MCM-41 silica in ethanol. This efficient technique has the advantage of giving 2-aminotetrahydrothiopyrano[4,3-b]pyran-3-carbonitrile derivatives using a heterogeneous mesoporous reagent in high yields, in short reaction times, and offers a simple product isolation procedure.

A facile and general procedure is presented for the one-pot synthesis of 2-aminotetrahydrothiopyrano[4,3-b]pyran-3-carbonitrile derivatives. It is based on the three-component condensation of aliphatic, aromatic, or heterocyclic aldehydes, malononitrile, and thiopyran in the presence of mesoporous amino-functionalized MCM-41 silica in ethanol. This efficient technique has the advantage of giving 2-aminotetrahydrothiopyrano[4,3-b]pyran-3-carbonitrile derivatives using a heterogeneous mesoporous reagent in high yields, in short reaction times, and offers a simple product isolation procedure.