Inhibitor binding chemical modifications

These studies demonstrated that (1) even a relatively minor chemical modification e.g., introduction of a 5-mercapto group into the cytosine base of 1 out of 100 nucleotide units) can convert a functional DNA or RNA template into a potent, competitive inhibitory analogue (antitemplate) which will bind to the template site of a polymerase either reversibly or irreversibly, and (2) even such antitemplates that are not made to be specific structural analogues of a natural template e.g., MPC) can differentiate between various polymerases. However, there are already some indications that antitemplates more closely related to the natural template of a given polymerase are more effective inhibitors of the latter, and it is expected that modified nucleic acids of viruses and tumors will show even much greater selectivities toward the corresponding reverse transcriptases in the presence of their endogenous templates. 

Starting from spirooxindoles, Hoffmann-La Roche has obtained several classes of potent MDM2 inhibitors through extensive chemical modifications. One class of compounds is structurally closely related to the spirooxindoles reported by the University of Michigan but these compounds differ in their stereochemistry [55, 56]. The most potent compounds disclosed in patents from Hoffmann-La Roche bind to MDM2 with IC50 values in the low nanomolar range. 

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