Imidazo[2,1-]thiazole-Coupled Natural Noscapine Derivatives as Anticancer Agents.

Noscapine, a phthalide isoquinoline alkaloid isolated from the opium poppy is traditionally being used as an anticough drug. With a safe in vitro toxicological profile, noscapine and its analogues have been explored to show microtubule-regulating properties and anticancer activity against various mammalian cancer cell lines. Since then, our group and other research groups worldwide are working on developing new noscapinoids to tap its potential as the leading drug molecule. With our continuing efforts, we herein present synthesis and anticancer evaluation of a series of imidazothiazole-coupled noscapinoids and . Natural α-noscapine was -demethylated to nornoscapine and then reacted with 4-(chloromethyl) thiazole-2-amine. The resultant noscapinoid was coupled with various bromomethyl ketones to give -imidazothiazolyl noscapinoids in very good yields. Similarly, natural α-noscapine was -demethylated using sodium azide/sodium iodide, reacted with 4-(chloromethyl)thiazole-2-amine, and coupled with bromomethyl ketones to result in -imidazothiazolyl noscapinoids . All the new analogues and were fully characterized by their NMR and mass spectral analysis. In vitro cytotoxicity assay was performed for compounds , , and against four different cancer cell lines: HeLa (cervical), MIA PaCa-2 (pancreatic), SK-N-SH (neuroblastoma), and DU145 (prostate cancer). Among these conjugates, , , , , , , and showed potent cytotoxicity with low IC values. Further, flow cytometry analysis revealed that MIA PaCa-2 cells treated with these compounds induced . In addition, Western blot analysis revealed that the cells treated with these conjugates accumulate tubulin in the soluble fraction and also elevate cyclin-B1 protein expression levels. Moreover, the conjugates also increased the expression of caspase-3 and PARP levels which is indicative of apoptotic cell death. In silico molecular docking studies showed several noncovalent interactions like van der Waals and hydrogen-bonding with tubulin protein and with good binding energy. The results indicated that these noscapine analogues may serve as novel compounds that can possibly inhibit tubulin protein and can be considered for further optimization as a clinical candidate for treating pancreatic cancer.