The n.m.r. chemical shifts of the 8-protons in xanthines with an unsubstituted imidazole ring (class a) and in 7-methylxanthines (class b ) are very similar; however the 8-H signals for 9-methyl derivatives (class c ) occur at higher field. Thus, in aqueous solution, members of class a must be essentially present as the N(7) H tautomers.Methyl substituents in various positions may be distinguished by their n.m.r. signals; their 6 values can be arranged in the following order: 7-> 9-=-3-> l-methyl. The signals of individual N-methyl groups are influenced only slightly by introduction of additional alkyl substituents, with the exception of 3.9-dimethylxanthines, in the spectra of which both methyl signals are shifted to lower field because of steric interference. U.V. spectra establish the order of anion formation in 7and 9-methylxanthineas3-1 and in 3-methylxanthine as 7 -w 1. However, the displacement of the 8-H signals in the n.m.r. spectra of xanthine and its 1 -methyl derivative suggests that their monoanions are tautomeric mixtures in which both the N(3)H and N(7)H groups participate in ionisation. Cation formation is accompanied by a much larger displacement of the 8-H n.m.r. signal in class c than in class a or b.IN aqueous solution purines can exist in a variety of tautomeric and ionic forms. Information about the species present under particular conditions is of great importance in the interpretation of biochemical processes. We show here that a study of U.V. and n.m.r. spectra sheds light on the structures of xanthines in their neutral and ionic forms in aqueous solution.
EXPERIMENTALMaterials.-The following compounds were commercial samples : xanthine, theophylline, theobromine, and caffeine. 3,9-Dimethylxanthine was a gift from Professor W.
Ultraviolet spectra show that hypoxanthine and 6‐thiopurine are present in aqueous solution predominantly as 1H, 9H‐tautomers. However, a 3‐methyl group causes the imidazole ring to assume the 7‐NH form. The sequence of anion formation in hypoxanthine is 9(7) → 1 and in 6‐thiopurine 1 → 9(7). The NMR spectra suggest that the mono‐anion of hypoxanthine is a mixture of tautomers. Protonation always takes place in the imidazole ring, with the exception of 3‐methyl derivatives. In the latter, formation of mono‐cations involves the pyrimidine moiety.
The electric dipole moments and the U.V. absorption spectra of some adenine derivatives were measured, In agreement with theoretical predictions, the moments of the N ( 7 ) H tautomer derivatives were found to be by several debyes higher than those of the derivatives of the N ( 9 ) H and N ( 3 ) H tautomers. The N ( 3 ) H tautomer of adenine is possibly a mixture of the amine and the imine forms, while the N (7) H and N (9) H tautomers exist wholly in the amine form.
Reaction of a 6-methylmercaptopurine with methyl iodide in an aprotic solvent gives only a single methylation product. Both the 7-and the 9-methyl derivatives are alkylated at N-3. 3-Methyl-6-methylmercaptopurine is attacked at N-7, while the I-methyl isomer is substituted at position 9. The course of the latter reaction depends markedly on the reaction conditions, as in the presence of an alkali carbonate alkylation takes place at N-7. The mechanism of these methylations is discussed.
A method for extracting LD50 values from antitumor test data is described. A quantitative structure--activity relationship (QSAR) for 7- and 10-substituted colchicines is presented. This correlation equation closely parallels that which had been derived earlier for potency. This result indicates that attempts to modify 7- and 10-substituted colchicines in order to decrease toxicity will likely produce a simultaneous decrease in potency. Ring A modified colchicines do not obey the potency and toxicity correlations. 4-Substituted colchicines appear promising in terms of decreased toxicity, greater ILS, and a broader therapeutic range.
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