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

摘要

Noscapine, a phthalide isoquinoline alkaloid isolated from the opium poppy Papaver somniferum, 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 7a–o and 11a–o. Natural α-noscapine was N-demethylated to nornoscapine 4 and then reacted with 4-(chloromethyl) thiazole-2-amine. The resultant noscapinoid 5 was coupled with various bromomethyl ketones 10a–o to give N-imidazothiazolyl noscapinoids 7a–o in very good yields. Similarly, natural α-noscapine 1 was O-demethylated using sodium azide/sodium iodide, reacted with 4-(chloromethyl)thiazole-2-amine, and coupled with bromomethyl ketones 10a–o to result in O-imidazothiazolyl noscapinoids 11a–o. All the new analogues 7a–o and 11a–o were fully characterized by their NMR and mass spectral analysis. In vitro cytotoxicity assay was performed for compounds 5, 7a–o, 9, and 11a–o against four different cancer cell lines: HeLa (cervical), MIA PaCa-2 (pancreatic), SK-N-SH (neuroblastoma), and DU145 (prostate cancer). Among these conjugates, 5, 7a, 9, 11b, 11c, 11e, and 11o showed potent cytotoxicity with low IC50 values. Further, flow cytometry analysis revealed that MIA PaCa-2 cells treated with these compounds induced cell cycle G2/M-phase arrest. 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.