Photochemistry of 4'-benzophenone-substituted nucleoside derivatives as models for ribonucleotide reductases: competing generation of 3'-radicals and photoenols.
Ribonucleotide reductases (RNRs) catalyze the 2'-reduction of ribonucleotides, thus providing 2'-deoxyribonucleotides, the monomers for DNA-biosynthesis. The current mechanistic hypothesis for the catalysis effected by this class of enzymes involves a sequence of radical reactions. A 3'-hydrogen abstraction, effected by a radical at the enzyme's active site, is believed to initiate the catalytic cycle. As models for this substrate-enzyme interaction, the photochemically induced intramolecular hydrogen abstraction in a series of 4'-benzophenone-substituted nucleoside analogues was studied. Model compounds with hydroxy-, methoxy-, mesyloxy-groups or a cyclic carbonate in 2'- and 3'-positions were investigated. Depending on the substitution pattern, two different types of photoproducts were observed: Those which result from photoenol formation (gamma-H-abstraction) and those which result from abstraction of the 3'-H-atom (delta-H-abstraction). Photoenol formation was further supported by H/D-exchange experiments. Thus, the 3'-H-abstraction postulated as the initial step in RNR action was successfully modeled by photolysis of 4'-benzophenone-substituted nucleoside analogues. The regioselectivity of the photochemical H-abstraction and thus of the product distribution as a function of the 2'- and 3'-substituents was rationalized on the basis of a conformational analysis of the four model systems, utilizing molecular mechanics simulations.
Lehmann
T E
TE
Institut für Organische Chemie, Universität zu Köln, Germany.
Müller
G
G
Berkessel
A
A
D001577:Benzophenones / Q000138:chemical synthesis* / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D005609:Free Radicals / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D010777:Photochemistry; D010782:Photolysis; D012264:Ribonucleotide Reductases / Q000378:metabolism*
D001577:Benzophenones; D005609:Free Radicals; D009705:Nucleosides; D012264:Ribonucleotide Reductases