title: Theoretical study of the protonation and tautomerization of adenosine, formycin, and their 2-NH2 and 2-F derivatives: functional implications in the mechanism of reaction of adenosine deaminase.
abstract: A quantum chemical study of adenosine, formycin, and their 2-NH2 and 2-F derivatives is performed. The tautomerism of neutral and protonated species as well as the protonation of adenosine, formycin, and their derivatives are theoretically studied using semiempirical MNDO and AM1, as well as ab initio STO-3G methods. Calculations have been performed on a reduced model, in which the ribose moiety has been substituted by a hydroxy-methyl group. Results indicate that adenosine is mainly protonated at the N1 atom, whereas formycin can be protonated on N1 or N3, depending on the tautomeric form (N8-H or N7-H). The quantum chemical study of the N1-protonated molecules shows that a second protonation of adenosine is mainly on the N3 atom, whereas formycin can be protonated on N8 or N3, depending on the tautomeric form. On the other hand, results indicate that the protonation of formycin and its derivatives at the N1 atom leads to a change in their tautomeric preference from N7-H to N8-H. The importance of both tautomerism and protonation reactions in the mechanism of action of adenosine deaminase is studied by means of a quantitative structure activity relationships strategy. Significant correlations were found between several electronic parameters and the logarithm of the maximum rate of deamination (log Vm) of the studied compounds. For formycin and its derivatives, it was necessary to consider their N8-H tautomeric forms. The electronic parameters giving good correlations were as follows: energy of the minimum of the ab initio molecular electrostatic potential on N1, net charge over purine (pyrazolo-pyrimidine) and pyrimidine rings, and the N1 protonation energy. It must be noted that all these parameters are informative in relation to a proton attack. Adenosine and purine ribosides have been studied largely because of their high biological relevance. They are constituents of nucleic acids, intermediates in secondary metabolism, neuromodulators, and neurohormones. Their analogues have been extensively used because of their wide range of pharmacological effects (1). Formycin A (Fig. 1) is one of the most studied analogues of adenosine. It is a natural product extracted from Nocardia interforma (2) with proven antiviral (3-5), antibiotic (2), immunodepressant (6), antitumor (6), and antimetabolic (5) activities.
authors.affiliation: Departament de Bioquímica i Fisiologia, Universitat de Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Orozco
authors.forename: E I
authors.initials: EI
authors.lastname: Canela
authors.forename: R
authors.initials: R
authors.lastname: Franco
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives; D000243:Adenosine Deaminase / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000031:analogs & derivatives; D003641:Deamination; D005573:Formycins / Q000031:analogs & derivatives; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D009700:Nucleoside Deaminases / Q000494:pharmacology*; D011522:Protons; D013329:Structure-Activity Relationship
chemical_list: D000903:Antibiotics, Antineoplastic; D005573:Formycins; D011522:Protons; C034550:formycin; D009700:Nucleoside Deaminases; D000243:Adenosine Deaminase; D000241:Adenosine