ABSTRACT
The blending of key structural features from the purine and pyrimidine nucleobase scaffolds gives rise to a new class of hybrid nucleosides. The purine-pyrimidine hybrid nucleosides can be viewed as either N-3 ribosylated purines or 5,6-disubstituted pyrimidines, thus recognition by both purine- and pyrimidine-metabolizing enzymes is possible. Given the increasing reports of the development of resistance in many enzymatic systems, a drug that could be recognized by more than one enzyme could prove highly advantageous in overcoming resistance mechanisms related to binding site mutations. In that regard, the design, synthesis and results of preliminary biological activity for a series of carbocyclic uracil derivatives with either a fused imidazole or thiazole ring are presented herein.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Purine Nucleosides/chemistry , Purine Nucleosides/pharmacology , Pyrimidine Nucleosides/chemistry , Pyrimidine Nucleosides/pharmacology , Adenosylhomocysteinase/antagonists & inhibitors , Adenosylhomocysteinase/metabolism , Enzyme Inhibitors/chemical synthesis , Imidazoles/chemistry , Molecular Structure , Purine Nucleosides/chemical synthesis , Pyrimidine Nucleosides/chemical synthesis , Thiazoles/chemistry , Uracil/chemical synthesis , Uracil/chemistry , Uracil/pharmacologyABSTRACT
The design, synthesis, and unexpected inhibitory activity against S-adenosyl-homocysteine (SAH) hydrolase (SAHase, EC 3.3.1.1) for a series of truncated carbocyclic pyrimidine nucleoside analogues is presented. Of the four nucleosides obtained, 10 was found to be active with a Ki value of 5.0 microM against SAHase.
Subject(s)
Adenosylhomocysteinase/antagonists & inhibitors , Pyrimidine Nucleosides/chemical synthesis , Pyrimidine Nucleosides/pharmacology , Drug Design , Kinetics , Structure-Activity RelationshipABSTRACT
[structure: see text] Isoadenosine (IsoA), a structural isomer of adenosine, was shown to possess interesting biological activity but was inherently unstable. In an effort to overcome this, we have designed a series of carbocyclic IsoA analogues, combining the unique connectivity of IsoA with the structural features of some biologically significant Neplanocin A analogues. Their design, synthesis, and structural elucidation is reported.
