Nonclassical Antimetabolites XX: Simulation of 5′-phosphoribosyl binding IV. Attempted simulation with nucleoside-5′-carbamates

• Published in: Journal of pharmaceutical sciences 1965-07, Vol.54 (7), p.987-994
• Main Authors: Baker, B.R., Tanna, Prafullchandra M., Jackson, Graham D.F.
• Format: Article
• Language: English
• Subjects: Antimetabolites; Carbamates; Chemical Phenomena; Chemistry; Nucleosides; Phosphates
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.2600540708

Twenty-two different ways can be envisioned for the mode of binding of the phosphate moiety of a nucleotide to an enzyme depending upon whether one, two, or three phosphate oxygens are involved and the specific groups involved on the enzyme are disregarded. A nucleoside-5′-carbamate should be able to simulate 13 of these possibilities, that is, all the modes of binding involving hydrogen bonds, but not anionic–cationic interactions. 5′-O-Carbamoylthioinosine (XIIa) was synthesized, but failed to simulate the binding of thioinosinic acid (IV) to succinoadenylate kinosynthetase. Similarly, 5′-O-carbamoyl-2′-deoxy-5-fluorouridine (XXIV) was synthesized and failed to simulate the binding of 2′-deoxy-5-fluoro-5′-uridylic acid (VII) to thymidylate synthetase. In conjunction with some previous data, it has been concluded that the most likely mode of binding of nucleotides to these two enzymes involves one hydrogen bond and one anionic–cationic interaction of which there are four possible combinations.