Studies on the Spin-Lattice Relaxation Times of the Carbons of the Investigational Antileukemic Drug and Enzyme Inhibitor Methylglyoxal Bis(Amidino-Hydrazone) ['Methylglyoxal BIS(Guanylhydrazone)'] and Its Dialkylglyoxal Analogs

Abstract

The first study on the ¹³C relaxation times of bis(amidinohydrazones) is reported. The spin-lattice relaxation times (T₁) of the carbons of the free bases of methylglyoxal bis(amidinohydrazone) (MGBG) and of four dialkylglyoxal analogs thereof were determined with the aid of the inversion recovery method and using dimethyl sulfoxide as the solvent. In the series of compounds studied, one of the side chains was always a methyl group, while the other one was altered (hydrogen, methyl, ethyl, propyl, butyl). Remarkable differences were found to exist between the T₁ values of the various carbons within each molecule. The T₁ values were in the range 1.5 - 2 s for methyl carbons, 0.16 - 1.9 s for carbons of longer alkyl groups, 4.3 - 7.0 s for unprotonated carbons of the glyoxal moiety, 0.57 s for the protonated glyoxal carbon of MGBG, and 2.6 - 3.1 s for guanidino carbons. The bulk of the differences are explainable by assuming that the major relaxation mechanism for the protonated carbons is dipolar relaxation. In alkyl side chains, the T₁ values increased in a very regular fashion down the chain. This effect made possible the assignment of two previously unassigned carbon resonances of the butyl group of BMGBG. T₁ studies thus offer a facile and reliable method for the assignment of side-chain carbon resonances of bis(amidinohydrazones). Further, T₁ measurements were found to offer a very good method for the individual assignment of the glyoxal carbons of unsymmetrical congeners, whose assignment has so far constituted a problem. The method, based on the finding that the one of the carbons bonded to the shorter alkyl chain has a longer relaxation time than does the other one, made possible the unambiguous assignment of several previously unassigned carbon resonances. The results obtained also offer a reliable method for unambiguously distinguishing between the resonances of glyoxal carbons and guanidino carbons that have been difficult to distinguish from each other because the separation of their chemical shifts is often extremely small. Correlations observed between T₁ values and the degree of alkyl substitution in the molecule are discussed, as are also possible relaxation mechanisms. Somewhat unexpectedly, the results obtained suggest that dipolar relaxation through the hydrogens of neighboring carbon atoms may to a significant extent contribute to the relaxation of some unprotonated carbons in bis(amidinohydrazones).

Key Words:

• Adenosylmethionine Decarboxylase Inhibitors
• Antitumor Agents
• Assignment of Carbon Resonances
• Carbon NMR Spectroscopy
• Enzyme Inhibitors
• Polyamine Antimetabolites