Synthesis, Molecular Modeling, Cytotoxicity, and Apoptosis-Inducing Activity of Some Novel 4,6-Dihydroisothiochromeno[4,3-B]Pyran Derivatives as Potent Anticancer and Tubulin-Inhibiting Agents

Thiochromene analogs are known for a broad spectrum of remarkable biological and pharmacological activities such as anticancer. In this study, a series of new 4,6-dihydroisothiochromeno[4,3-b]pyran compounds have been synthesized, and their cytotoxicity of these compounds was evaluated on two cancer cell lines by MTT assay. Compounds 4b, 4d, 4e, 4g, 4j, 4m, and 4n showed the most potent cytotoxic activity (IC50 values less than 110 µM) on the MCF-7 cell line. These compounds' ability to induce apoptosis in MCF-7 cells was analyzed by flow cytometry, and all the compounds could lead the cell's fate to apoptosis. During the computational study of these compounds, several potential targets were identified, and subsequent molecular docking experiments revealed that tubulin inhibition could provide a plausible mechanism for their effectiveness. Tubulin, a key structural protein involved in the formation of microtubules, plays a crucial role in processes such as cell division, motility, and intracellular transport. The interaction of these compounds with key tubulin residues, such as Thr 351 and Lys 350, suggests that they could interfere with microtubule dynamics, potentially disrupting cell division and inhibiting the proliferation of cancer cells. This finding highlights tubulin as a promising target for further investigation, offering valuable insight into the compounds' mechanisms of action and their potential as anticancer agents.