Incorporation of Organosilicon Motifs in Natural and Synthetic Small Molecules for Anticancer Therapeutics: Current Perspectives and Future Opportunities in Drug Design

Silicon is among the most abundant elements on Earth, yet its incorporation into organic molecules is atypical in most biological contexts. However, the strategic introduction of silicon, in line with the demonstrated success of the incorporation of other bio-orthogonal elements, has emerged as a powerful approach in medicinal chemistry, enabling access to small molecules with unique chemical, physical, and biological properties that offer improved potency, stability, tolerability, or bioavailability profiles for the discovery and development of anticancer therapeutics. In this review, we describe the direct connection between reactivity and physiochemical paradigms of different classes of organosilicon-containing functional groups and their strategic deployment in small molecule design, including silanes, silyl ethers, siloxanes, and organosilicates. Specifically, we aimed to demonstrate how these strategies can be informed by first principles of reactivity in organosilicon containing functional groups, in both synthetic small molecules and bioactive natural products. Particular emphasis is placed on how silicon replacement and addition can be leveraged beyond simple isosteric carbon replacement, and how consequent structure–activity relationships arising from installation of diverse organosilicon motifs can also serve a unique role in unveiling new aspects of biological mechanism and function. Ultimately, the growing body of literature in applications of organosilicon-containing anticancer small molecules and the increasing sophistication and selectivity of synthetic methods used to construct these motifs will undoubtedly continue to expand the appreciation of organosilicon-based functional groups in the medicinal chemist’s toolbox.