Evaluation of anticancer activity of ferrocene based benzothiazole and β-ketooxothioacetal

Abstract

Ferrocene-based compounds have recently gained widespread importance in cancer treatment becuase of their lower toxicity and cost-effective synthesis. However, ferrocene-based compounds do not exist in nature. Moreover, the synthesis of thianes containing ferrocene is quite rare. In the recent past, our group has reported iodine catalyzed synthesis of ferrocenated benzothiazole and β-ketooxothioacetal by the thermal reaction of ferrocenated β-chlorocinnamaldehyde with 2-aminothiophenol and 2-mercaptoethanol respectively.The molecular structure of both the compounds is quite interesting due to the presence of ferrocene which makes them highly important from an anticancer point of view. In this script, the synergistic effect of ferrocene and thiol has been observed in ferrocene functionalized thiols (Fenton reagents) for tumour growth suppression. The anticancer properties of both the compounds separately as well as in combination show a significant anticancer effect on cancer cell lines HCT116 (Colon), A549 (lung cancer), and MCF7 (Breast cancer). Both compounds and their combinations reflect cell death by generating ROS and depolarization of mitochondrial membrane potential. Gene expression profiling and protein expression studies of apoptosis-related genes (cleaved caspase 9, cleaved caspase 3, cleaved PARP and Bcl-2) were also evaluated. Results indicated that ferrocenated benzothiozole and β-ketooxothioacetal induced apoptosis through oxidative stress-mediated activation of intrinsic apoptosis pathway by generating intracellular ROS, loss of MMP, and alteration of expression of genes related to apoptosis. In addition, the anti-metastatic activity of benzothiozole and β-ketooxothioacetal was seen by wound healing assay showing anti-migratory properties. The properties like anti metastatic activity, cytotoxicity and showing synergistic effect when used in combination make benzothiozole and β-ketooxothioacetal potent platforms for the development of new anticancer agents. Benzothiazole and β-ketooxothioacetal can replace existing organometallic compounds with rare metals like platinum, due to their higher stability, lower cost, and lower toxicity.