Abstract
The pharmacological effects of carbon to silicon bioisosteric replacements have been widely explored in drug design and medicinal chemistry. Here, we present a systematic investigation of the impact of different silyl groups on the anticancer activity of mucobromic acid (MBA) bearing furan-2(5H)-one core. We describe a comprehensive characterization of obtained compounds with respect to their anticancer potency and selectivity towards cancer cells. All four novel compounds exert stronger antiproliferative activity than MBA. Moreover, 3b induce apoptosis in colon cancer cell lines. A detailed investigation of the mechanism of action revealed that 3b activity stems from the down-regulation of survivin and the activation of caspase-3. Furthermore, compound 3b attenuates the clonogenic potential of HCT-116 cells. Interestingly, we also found that depending on the type of the silyl group, compound selectivity towards cancer cells could be precisely controlled. Collectively, we demonstrated the utility of silyl groups for adjusting both the potency and selectivity of silicon-containing compounds. These data reveal a link between the types of silyl group and compound potency, which could have bearings for the design of novel silicon-based anticancer drugs.
Highlights
IntroductionWith over 19 million new cases and 9.9 million deaths in 2020, cancer remains a worldwide cause of premature mortality [1]
Not all cancers respond to such treatment and further evaluation of predictive markers and combination therapies is required before cancer immunotherapy becomes a gold standard in clinical oncology [3]
Silylation of 5-hydroxyl group in the mucobromic acids (MBA) ring leads to set of novel compounds with increased cytotoxic potency against cancer cells in comparison to lead molecule 1
Summary
With over 19 million new cases and 9.9 million deaths in 2020, cancer remains a worldwide cause of premature mortality [1]. Despite the continuous progress in the development of novel anticancer drugs, current treatments, including targeted therapies, have their limitations and they still cause severe side effects [2]. Cancer immunotherapies have recently emerged to provide improved clinical outcomes. Not all cancers respond to such treatment and further evaluation of predictive markers and combination therapies is required before cancer immunotherapy becomes a gold standard in clinical oncology [3]. There is still a great need for the discovery and development of new lead small-molecule compounds with increased activity and reduced toxicity to non-malignant cells
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