Drug Design Based on the Carbon/Silicon Switch Strategy

Abstract

Silicon chemistry has been demonstrated to be a novel source of chemical diversity in drug design. The carbon/silicon switch strategy, i.e., the strategic replacement of a carbon atom with a silicon atom (sila-substitution) within a well-known drug, with the rest of the molecule being identical, is one of the methods that are currently used for the design and development of new silicon-based drugs. Some of the fundamental differences between carbon and silicon (e.g., differences in the covalent radii and electronegativities) can lead to marked alterations in the physicochemical and biological properties of the sila-drugs. In general, the sila-analogues share the same mode of action as the parent carbon compounds but may have altered biological properties. Incorporation of silicon into a drug can affect and, ideally, improve the pharmacological potency and selectivity, the pharmacodynamics, and the pharmacokinetics. Examples resulting from the carbon/silicon switch strategy are sila-venlafaxine, sila-haloperidol, and disila-bexarotene, the silicon analogues of the serotonin/noradrenaline reuptake inhibitor venlafaxine, the dopamine antagonist haloperidol, and the retinoid agonist bexarotene, respectively. Using these particular examples, the basic principles of the carbon/silicon strategy in drug design are illustrated in this review.