Silicon switch: Carbon-silicon Bioisosteric replacement as a strategy to modulate the selectivity, physicochemical, and drug-like properties in anticancer pharmacophores

Abstract

Bioisosterism is one of the leading strategies in medicinal chemistry for the design and modification of drugs, consisting in replacing an atom or a substituent with a different atom or a group with similar chemical properties and an inherent biocompatibility. The objective of such an exercise is to produce a diversity of molecules with similar behavior while enhancing the desire biological and pharmacological properties, without inducing significant changes to the chemical framework. In drug discovery and development, the optimization of the absorption, distribution, metabolism, elimination, and toxicity (ADMETox) profile is of paramount importance. Silicon appears to be the right choice as a carbon isostere because they possess very similar intrinsic properties. However, the replacement of a carbon by a silicon atom in pharmaceuticals has proven to result in improved efficacy and selectivity, while enhancing physicochemical properties and bioavailability. The current review discusses how silicon has been strategically introduced to modulate drug-like properties of anticancer agents, from a molecular design strategy, biological activity, computational modeling, and structure-activity relationships perspectives.

Keywords: ADMET profile refining; Bioisosteric silicon switch; anticancer agents; in silico modeling; selectivity modulation.