Silicon-carbon bioisosterism

Keywords C/Si bioisosterism, carbon/silicon switch, chirality, o ligands,... 

E. Isoserism criteria Present E. Groups with similar polar A. Carbon-silicon bioisosterism... 

Tacke et al45 synthesized the enantiomers of sila-linalool (61) as shown in Figure 11. The starting material 60 was converted into ( )-61, which was resolved by GC to give both (+)-61 and (—)-61. Both enantiomers were bioactive as tested by electroantennographic detection (EAD) on the males of the vernal solitary bee Colletes cunicularius. There was no major difference between the bioactivity of the sila-pheromone 61 and the natural linalool. The substitution of a carbon atom by silicon provides a good example of bioisosterism. 

In this section we describe some exotic applications of the bioisostery concept implying the utilization of unusual elements such as silicon, boron, selenium, arsenic, and antimony. The use of those elements as bioisosteres of carbon in existing drugs is a different approach enabling the introduction of a new drug-like chemical space into the drug discovery and development process. 

Compared to their carbon bioisosteres, silicon-containing molecules are more sensitive to hydrolysis and to nucleophilic attack in general, even when located in the center of a quaternary structure, the risk exists that the silicon atom will be attacked. Thus, l-chloro-l-sila-bicyclo-(2,2,l)-heptane can still be hydrolyzed by an attack on the vacant d orbital this attack is lateral and therefore possible even in the cases where the corresponding carbon derivative would have been inert toward a Sn2 reaction (Figure 15.69). 

Replacement of the central carbon atom by a silicon atom in the (R)-enantiomers of the hydroxymethyl analogue of HHD (3->4) and THP (8- 9) lowered affinity and stereoselectivity, whereas the receptor selectivity for compounds 3 and 4 was unchanged. In contrast, the corresponding (R)- and (S)-enantiomers of the Si/Ge analogues exhibited very similar affinities to the different muscarinic receptors indicating a strongly pronounced Si/Ge bioisosterism. 

A recent example of bioisosteric replacement of a carbon atom with silicon was reported by Warneck and colleagues at Paradigm Therapeutics, who synthesized the silicon derivative of the p38 MAP kinase inhibitor BIRB-796 (Figure 2.4), which is in clinical evaluation for several inflammatory diseases, such as rheumatoid arthritis, Crohn s disease, and psoriasis [14]. This silicon isostere, compound 1, was found to be unusually less lipophilic than BIRB-796, of comparable potency, and more metabolically stable in human hver microsomes. 

C/Si bioisosterism has been considered repeatedly due to some fundamental differences between carbon and silicon that are useful in drug design [50-52]. These include ... 

The properties of bioisosteric compounds prompted Tacke et al. to prepare sila-fexofenadine (49) and to study the bioisosterism of this and some related Hi-receptor antagonists [55, 56]. Replacement with a silicon atom of the tert-carbon atom bearing the OH group in fexofenadine was attempted, and the synthesis of sila-fexofenadine was achieved according to Schemes 10.11-10.13. 

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