Nucleoside complexing. A 13C 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 13C 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 13C 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 2SO) 2Cl 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.