Sila-drugs

In vitro studies on the isolated guinea-pig ileum have shown that the replacement of the central carbon atom in the antihistaminic diphenhydramine (118a) for a silicon atom leads to a total loss of histaminolytic activity190. Under the test conditions employed (Tyrode s solution 37 °C, pH 7.4), hydrolysis of siladiphenhydramine (118b) (cleavage of the Si-OC and Si-H bond) was so fast that no histaminolytic effect of the intact sila-drug could be detected. 

Few of the compounds described in Section 9.18.2.1 have any significant applications but one area of recent growth is that of the preparation of sila-drugs , compounds that are silicon analogues of known heterocyclic organic dmgs. For... 

R. Tacke, Recent Results in Bioorganosilicon Chemistry Novel Sila-Drugs and Microbial Transformations of Organosilicon Compounds , in Organosilicon and Bioorganosilicon Chemistry Structure, Bonding, Reactivity and Synthetic Application (Ed. H. Sakurai), Ellis Horwood, Chichester, 1985, pp. 251-262. 

Silas Mainville Burroughs, American pharmacist who founded the highly successful drug company Burroughs Wellcome with Henry Wellcome. The company, established in London in 1880, produced medicine in a compressed form called a Tabloid and eventually a tablet. The invention... 

Sila-pharmaca with a potential site of fracture in their framework could be useful in cases, in which the dmg shall act only for a short time (e.g. spasmolytic or analgesic compounds). After effecting in the desired manner the drug will be destroyed by the water of the biological surrounding without help of complex enzymatic systems. 

In nearly all cases carbon atoms of organic drugs have at least one C-H bond. So it seems not to be very useful to substitute such carbon atoms for silicon atoms, because of the high hydrolytic sensitivity of Si—H bonds (Chap. 2). This fact reduces the possibilities of expanding the field of sila-pharmaca. 

Initially, the purpose was to synthesize sila-analogs of known drugs for comparison of their efficiency and to get information on the mechanism of their action.475 As investigations continued, an increasing number of biologically active molecules appeared. Perhaps the best known of these molecules are the silatranes, compounds that have no analogous carbon counterpart.476... 

In a recently published review, silicon chemistry has been demonstrated to be a novel powerful source of chemical diversity in drug design [1]. Sila-substitution of drugs (carbon/silicon switch) is one of the concepts that have been successhilly used for the development of new silicon-based drugs (for recent examples, see Ref. [2]). 

In context with our systematic studies on sila-substituted drugs [1,2], we have been interested in the pharmacological properties of novel potential a ligands of the l,4 -silaspiro[tetralin-l,4 -piperidine] tj, compoimds lb - 4b (cf Ref. [2e] for structurally related o ligands of the... 

As can be seen from Fig. 2, sila-substitution of rac-Sa (-> rac-Sh) substantially affects the pharmacological profile with respect to serotonin reuptake inhibition. The other (major) structural changes in the molecular shape of rac-5b (-> rac-6, rac-7) also influenced the pharmacological profile with respect to monoamine selectivity rac-1) and/or absolute potency rac-6). These results clearly demonstrate that the carbon/silicon switch strategy is a powerful tool for drug design. 

Tacke, R., Zilch, H. Sila-substitution-a useful strategy for drug design . Endeavour, New Series 1986, 10, 191-197. 

From these simple considerations it becomes clear that organic drugs and their sila-analogues may differ in their chemical (reactivity) and in their physicochemical properties (e.g. lipophilicity) as well as in their structure (shape and size, bonding geometries, conformational behavior). It can be expected that these chemical, physicochemical and structural sila-substitution effects may, in principle, result in biological sila-substitution effects—by influencing the pharmacodynamics and/or the pharmacokinetics. 

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