Nucleoside complexing. A13C NMR spectroscopic investigation of the metal binding sites in 7-methylguanosine, 7-methylinosine and some related new synthetic betains

Abstract Once deprotonated, both the N1 and O6 positions of 6-oxopurine nucleosides become important metal binding sites. In a continuation of our studies of metal binding to 6-oxopurines alkylated at N7 and deprotonated at N1, we have carried out a 13 C NMR spectroscopic study of the binding of various metal species including hard metal species (Sr, Ba, La, Pr), intermediate metal species (Zn, Cd, Pb), and soft metal species (Pt, Hg). A detailed study was not possible with HgCl 2 since mercuration occurred readily at C8. The 13 C NMR shift patterns for the O6 resonance of 7-methylguanosine, 7-methylinosine, 2-dimethylamino-7,9-dimethylhypoxanthinium betain, 2-diethylamino-7-methyl-9-propylhypoxanthinium and betain and ethylamino and 6 thio analogs of the latter betain suggest that metal species of intermediate ‘softness’ prefer endocyclic N1 binding over exocyclic O6 a larger extent than they prefer endocyclic N3 binding over exocyclic O2 binding in cytosine derivatives. Most dramatically, the presence of a dialkylamino group ortho to the endocyclic binding site does not appear to prevent N binding in the betains whereas such binding is greatly, if not completely, prevented to cytosine derivatives. In particular, the complex cis -[Pt(Me 2 SO) 2 Cl 2 ] forms a complex with 2-dimethylamino-7,9-dimethyl-hypoxanthinium betain with an upfield shift characteristic of endocyclic N binding. The hard metal salts, Ba(NO 3 ) 2 and Pr(NO 3 ) 3 interacted weakly, if at all, with 2-diethylamino-7-methyl-9-propyl-6-thiopurinium betain whereas the nitrate salts of Zn, Cd and Pb gave pronounced upfield shifts of C6. This result is consistent with coordination at the exocyclic S. The compound, 2-dimethylamino-9-methylhypoxanthine, was prepared starting from 5-amino-4,6-dihydroxy-2-dimethylaminopyrimidine. This 5-aminopyrimidine derivative and methyl isothiocyanate were converted to N-(4,6-dihydroxy-2-dimethylamino-5-pyrimidinyl)-N′-methylthiourea which was then converted to 2-dimethylamino-6-hydroxy-9-methyl-8-purinethiol with hot hydrochloric acid. Raney nickel desulfurization in a basic solution gave 2-dimethylamino-9-methylhypoxanthine. The related compounds, 2-ethylamino-9-propyl- and 2-diethylamino-9-propylhypoxanthine, were prepared from 4,6-diamino-2-methylmercapto-5-nitrosopyrimidine. Treatment of this pyrimidine with dimethyl-, ethyl- and diethyl-amine led to the initial intermediate 2-alkyl-amino-4,6-diamino-5-nitrosopyrimidines. Treatment of these pyrimidines with sodium hydrosulfite, formic acid and formamide in one flask gave the mixture of corresponding 2-alkyl-aminoadenines and 2-alkylamino-6-formamido-purines. The latter compounds were successfully converted to the desired 2-alkylaminoadenines by alkali treatment. Alkylation with alkyl halides at the 9-positions of these adenine derivatives and subsequent deamination with nitrous acid gave 2-dimethylamino-9-methyl-, 2-ethylamino-9-propyl- and 2-ethylamino-9-propylhypoxanthines. These hypoxanthines were further methylated at their 7-position to give the corresponding hypoxanthinium betains. 2-Diethylamino-7-methyl-9-propyl-6-thiopurinium betain was prepared by the methylation at the 7-position of 2-diethylamino-9-propylhypoxanthine followed by 6-chlorination and, then, by treatment with thiourea.