| Nucleoside analogues have been investigated as therapeutic agents against cancers, viruses, parasites and bacteria. Unfortunately, there are growing reports of resistance to currently used therapeutics. One main cause of resistance is attributed to the development of point mutations to key amino acid residues in the active site of the target enzyme. As a result, it is imperative to develop new drugs that may overcome this resistance mechanism. In that regard, use of flexible inhibitors that have the potential to interact with other amino acids not previously involved in the mechanism of action in an enzyme binding site could prove strategic. By endowing the inhibitor with the ability to change conformation and bypass point mutations, the drug could retain biological activity whereas a rigid analogue may not. Moreover, the flexible analogue could potentially sample more favorable binding interactions thereby increasing binding affinity. These advantages have been proven fruitful with several flexible nucleoside inhibitors known as "fleximers" developed in the Seley-Radtke laboratory. As an extension of our preliminary findings, we have designed a series of carbocyclic flexible nucleosides for the inhibition of S-adenosylhomocysteine hydrolase, adenosine deaminase, as well as viral polymerases. These compounds focus on combining the truncated carbocyclic sugar moiety with the flexible purine nucleobase. Synthesis was optimized using various coupling techniques such as those developed by Mitsunobu, Trost, Suzuki, Stille and Negishi. Compound design, synthesis and preliminary biological data will be discussed herein. |
