ABSTRACT
A series of shape-modified flexible nucleosides ('fleximers', 1, 2, and 3) was modeled, synthesized and subsequently assayed against S-adenosyl-L-homocysteine hydrolase (SAHase). No inhibitory activity was observed for the adenosine fleximer, which served as a substrate, but moderate inhibitory activity was exhibited by the guanosine fleximers. This is the first known report of a guanosine nucleoside analogue possessing activity against SAHase.
Subject(s)
Adenosylhomocysteinase/antagonists & inhibitors , Guanosine/analogs & derivatives , Guanosine/pharmacology , Adenosine/analogs & derivatives , Adenosine/metabolism , Adenosine/pharmacology , Calorimetry/methods , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Guanosine/chemical synthesis , Hydrogen Bonding , Hydrolysis , Inosine/analogs & derivatives , Inosine/chemical synthesis , Inosine/pharmacology , Kinetics , Models, Molecular , ThermodynamicsABSTRACT
A new class of shape-modified nucleosides is introduced. These novel "fleximers" feature the purine ring systems of adenosine, inosine, and guanosine split into their individual imidazole and pyrimidine components (as in 1-3). This structural modification serves to introduce flexibility into the nucleoside while still retaining the elements essential for recognition. As a consequence, these novel fleximers should find use as bioprobes for investigating enzyme-coenzyme binding sites as well as nucleic acid and protein interactions. Their design and synthesis are described.