3110-98-3Relevant academic research and scientific papers
Synthesis and characterization of 3',4'-anhydroadenosylcobalamin: A coenzyme B12 analogue with unusual properties
Magnusson,Frey
, p. 8807 - 8813 (2000)
The question of how coenzyme B12-Dependent enzymes facilitate the cleavage of the Co-C bond of the cofactor is of interest. We have synthesized an analogue of 5'-Deoxyadenosylcobalamin (AdoCbl1) designed to stabilize the 5'-Deoxyadenosyl radical (5'-Deoxyadenosine-5'-Yl) that is produced upon homolysis of the Co-C bond. By replacement of the upper axial ligand of AdoCbl by a 3',4'-Anhydro-5'-Deoxyadenosyl moiety, the radical formed on the nucleoside analogue is stabilized by allylic delocalization. The compound, 5'-Deoxy- 3',4'-Anhydroadenosylcobalamin (3',4'-AnAdoCbl) was synthesized by chemical and enzymatic methods. The final step was coupling of cob(I)alamin and 3',4'-AnhydroATP catalyzed by CobA, an ATP: corrinoid adenosyltransferase. 3',4'-AnAdoCbl displays interesting properties. The compound has not been purified to homogeneity due to its thermal and oxygen sensitivity. It was characterized by UV-Vis spectroscopy, ESI-MS, and NMR spectroscopy. The bond dissociation energy of the Co-C bond of the analogue was measured by radical trapping techniques. A significantly weaker bond (24 ± 2 kcal/mol) as compared to AdoCbl (30 kcal/mol) was observed, as was homolytic cleavage at ambient temperature. Photolysis experiments conducted under anaereobic conditions reveal no formation of cob(II)alamin, whereas the compound breaks down rapidly under aerobic conditions as measured by cob(III)alamin formation. We postulate that the weak Co-C bond is cleaved reversibly by photolysis, where recombination of the allylic radical and cob(II)alamin occurs efficiently in the absence of a radical scavanger. Activation of the coenzyme B12-Dependent enzymes dell dehydrase and ethanolamine ammonia-Lyase was observed with the cofactor analogue. The measured activity was low and no formation of cob(II)alamin could be detected in the steady-State of the reaction for either enzyme. Comparative interactions of AdoCbl and 3',4'-An AdoCbl with dell dehydrase and ethanolamine ammonia-Lyase suggest that cleavage of the Co-C bond is facilitated by enzyme-coenzyme binding contacts that are remote from the Co-C bond.
Anticancer and antiviral effects and inactivation of S-adenosyl-L- homocysteine hydrolase with 5'-carboxaldehydes and oximes synthesized from adenosine and sugar-modified analogues
Wnuk, Stanislaw F.,Yuan, Chong-Sheng,Borchardt, Ronald T.,Balzarini, Jan,De Clercq, Erik,Robins, Morris J.
, p. 1608 - 1618 (2007/10/03)
Selectively protected adenine nucleosides were converted into 5'- carboxaldehyde analogues by Moffatt oxidation (dimethyl sulfoxide/dicyclohexylcarbodiimide/dichloroacetic acid) or with the Dess- Martin periodinane reagent. Hydrolysis of a 5'-fluoro-5'-S-methyl-5'-thio (α-fluoro thioether) arabinosyl derivative also gave the 5'-carboxaldehyde. Treatment of 5'-carboxaldehydes with hydroxylamine [or O-(methyl, ethyl, and benzyl)hydroxylamine] hydrochloride gave E/Z oximes. Treatment of purified oximes with aqueous trifluoroacetic acid and acetone effected trans-oximation to provide clean samples of 5'-carboxaldehydes. Adenosine (Ado)-5'- carboxaldehyde and its 4'-epimer are potent inhibitors of S-adenosyl-L- homocysteine (AdoHcy) hydrolase. They bind efficiently to the enzyme and undergo oxidation at C3' to give 3'-keto analogues with concomitant reduction of the NAD+ cofactor to give an inactive, tightly bound NADH-enzyme complex (type I cofactor-depletion inhibition). Potent type I inhibition was observed with 5'-carboxaldehydes that contain a ribo cis-2',3'-glycol. Their oxime derivatives are 'proinhibitors' that undergo enzyme-catalyzed hydrolysis to release the inhibitors at the active site. The 2'-deoxy and 2'-epimeric (arabinosyl) analogues were much weaker inhibitors, and the 3'-deoxy compounds bind very weakly. Ado-5'-carboxaldehyde oxime had potent cytotoxicity in tumor cell lines and was toxic to normal human cells. Analogues had weaker cytotoxic and antiviral potencies, and the 3'-deoxy compounds were essentially devoid of cytotoxic and antiviral activity.
Adenosine-5'-carboxaldehyde: A potent inhibitor of S-adenosyl-L- homocysteine hydrolase
Liu,Wnuk,Yuan,Robins,Borchardt
, p. 883 - 887 (2007/10/02)
Adenosine-5'-carboxaldehyde (3) and its 4'-epimer (4) were synthesized and shown to be potent type I mechanism-based inhibitors of recombinant rat liver AdoHcy hydrolase with k2/K1 values of 16.7 x 10-3 and 5.5 x 10-3
