Use of adenine nucleotide derivatives to assess the potential of exo-active-site-directed reagents as species- or isozyme-specific enzyme inactivators. 3. Synthesis of adenosine 5'-triphosphate derivatives with N6- or 8-substituents bearing iodoacetyl groups

Publisher Website
Google Scholar
Abstract
Several series of N6- or 8-substituted derivatives of ATP were synthesized. N6-(.omega.-aminoalkyl) derivatives of AMP were converted into their .omega.-N-carbobenzyloxy derivatives, and these were converted, via the 2'',3''-O-carbonyl derivatives of their 5''-phosphorimidazolidates, into the corresponding ATP derivatives. Hydrogenolytic removal of the carbobenzyloxy groups, followed by iodoacetylation of the .omega.-amino groups with N-(iodoacetoxy)succinimide, gave N6-R-ATP, where R = (CH2)nNHCOCH2I (n = 2-8) or (CH2)nCON(CH3)(CH2)mN(CH3)CO(CH2)nNHCOCH2I (n = m = 3; n = 3, m = 4; n = 4, m = 3; n = m = 4). Condensation of N6-(.omega.-aminoalkyl) derivatives of AMP with N-hydroxysuccinimide esters of .omega.-[N-(carbobenzyloxy)amino] carboxylic acids gave N6-(CH2)nNHCO(CH2)mNH-Cbz derivatives of AMP which, upon conversion to the corresponding derivatives of ATP, followed by removal of the carbobenzyloxy group and iodoacetylation, as described above, gave N6-(CH2)nNHCO(CH2)mNHCOCH2I-ATP derivatives (n = 3, m = 5 or 6; n = 4, m = 5; n = 6, m = 1-6). The same sequence of reactions starting with N6-[.omega.-(methylamino)alkyl] derivatives of N6-CH3-AMP gave N6-CH3, N6-(CH2)nN(CH3)CO(CH2)mNHCOCH2I derivatives of ATP ( n = 4, m = 3, 5 or 6; n = 6, m = 5 or 6). Reaction of .alpha.,.omega.-diaminoalkanes with 8-Br-ATP gave 8-NH(CH2)nNH2 derivatives of ATP, which upon iodoacetylation gave 8-NH(CH2)nNHCOCH2I derivatives of ATP (n = 2, 4, 6, or 8). Substrate and inhibitor properties indicated that the ATP derivatives are potential exo-ATP-site-directed inactivators of [rat, yeast] hexokinases, adenylate kinases [rat], and [rat] pyruvate kinases.