Reaction mechanism in the photochemistry of the antileukaemic agents 2-chloro- and 2-bromo-2'-deoxyadenosine, studied by nanosecond laser flash photolysis.

The reaction mechanism in the UV photochemistry of 2-chloro-2'-deoxyadenosine (Cladibrine) and 2-bromo-2'-deoxyadenosine in aqueous solution has been studied by laser photolysis at nanosecond time resolution. It is found that excitation at 266 nm wavelength produces heterolytic cleavage of the halogen-carbon bond by one-photon absorption and formation of the unstable 2-hydroxy tautomer of 2'-deoxyisoguanosine as predominant 'primary' product. The 2-hydroxy tautomer then transforms in 10(-6)-10(-5) s into the stable 2-oxo tautomer in an acid-base-catalysed reaction. A reaction mechanism is proposed and discussed in relation to previous UV low-intensity studies of these halogenodeoxyadenosines.

Intermediates in the oxidation of a dihydropyridine derivative of AZT related to AIDS dementia, studied by nanosecond laser photolysis.

Radicals of the AZT derivative 5'-(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)-3'-azido-2',3'-dideo xythymidine) were obtained on exposure of this compound in alkaline aqueous solution to pulsed laser emission of lambda = 355 nm and pulsewidth 2 ns FWHM. The radical formation was shown to be due to photoelectron ejection from the pyridine group following two-step excitation of the compound. The radicals were found to deprotonate rapidly. Electrochemical analysis showed that the photoionization does not affect the azido group.

Electrochemical reduction products of azido nucleosides, including zidovudine (AZT): mechanisms and relevance to their intracellular metabolism.

Previous studies on electrochemical reduction of the HIV reverse transcriptase inhibitor, 3'-azido-3'-deoxythymidine (Zidovudine, AZT) and several of its analogues, have been extended to 2'-AZdT and two of the intracellular metabolites of AZT, the 5'-O-glucuronide (GAZT) and the 5'-phosphate (AZTMP). Also investigated were azido nucleosides with aglycons susceptible to electrochemical reduction, cytosine and adenine. The surface activities of these compounds at the mercury electrode were examined. In all instances, reduction of the azido group was a two-electron process, with conversion to an amino group. For an azido adenine nucleoside, it proved possible to reduce the azido group without affecting the aglycon. Electrochemical reduction is shown to provide a simple one-step synthesis of amino nucleosides from the available azido nucleosides. The reduced compounds, several hitherto unknown, are useful reference standards for following intracellular metabolism of azido nucleosides, and may also prove of interest as new potential antimetabolites.

Photochemical and enzymatic redox transformations of reduced forms of coenzyme NADP+.

The two reduced forms of NADP+, NADPH and its dimer (NADP)2, on irradiation in aqueous medium at 365 nm, are converted to enzymatically active NADP+, with accompanying formation of H2O2. The rate photooxidation of NADPH is strongly dependent on the presence of oxygen, but that of (NADP)2 is similar under aerobic and anaerobic conditions. In the presence of oxygen, but not in its absence, O2-. is an intermediate in the reaction. Generation of H2O2 under anaerobic conditions, confirmed by the fact that presence of peroxidase in irradiated solutions of (NADP)2 enhances photooxidation of the latter, is ascribed to attack on water of the excited dimer. Under anaerobic conditions at pH 9.5, Fe(EDTA)2+ and Fe(CN)4-(6) increase the rate of photooxidation of NADP dimer two-fold. gamma-Irradiation of (NADP)2 at pH 9.5 in the presence of N2O results in 80% conversion to enzymatically active NADP+. A mechanism for photooxidation of (NADP)2 under anaerobic conditions is suggested, and some relevant biological implications are presented.

Preparative electrochemical reduction of 2-amino-6-chloropurine and synthesis of 6-deoxyacyclovir, a fluorescent substrate of xanthine oxidase and a prodrug of acyclovir.

D.c. polarography of 2-amino-6-chloropurine in aqueous medium over a broad pH range revealed two diffusion waves, the first of which corresponds to reduction of the C(6)-Cl bond, leading to formation of 2-aminopurine in high yield. Condensation of the sodium salt of 2-aminopurine with (2-acetoxyethoxy)methyl chloride led to the two isomeric 9- and 7-(2-hydroxyethoxymethyl)-2-aminopurines. The 9- isomer, 6-deoxyacyclovir, a prodrug of acyclovir previously synthesized by another route, was readily converted to the latter by xanthine oxidase; the 7-isomer was not a substrate. The intense fluorescence of 6-deoxyacyclovir makes it a convenient fluorescent substrate for xanthine oxidase, although less sensitive than xanthine; it is shown that 2-aminopurine would be a very sensitive fluorescent substrate. The polarographic behaviour of the riboside of 2-amino-6-chloropurine was virtually identical with that of the parent purine, leading to a simple procedure for conversion of 2-amino-6-chloropurine nucleosides and acyclonucleosides to the corresponding 2-aminopurine congeners.

Electrochemical study of the reduction of toyocamycin and sangivamycin in aqueous media.

The redox behaviour of two antibiotics, toyocamycin and sangivamycin, structurally related pyrrolopyrimidine nucleosides, and their reduction products in buffered aqueous media, have been examined by direct current polarography and cyclic voltammetry. Both compounds exhibit one 3-electron polarographic wave in the pH range 1-6. Macroscale electrolysis at the crest of the polarographic wave was followed electrochemically and by UV spectroscopy. The photochemical transformation of the reduction products on UV irradiation has been examined. It was found that the reduction of both compounds occurs in the pyrimidine ring, leading to two reduction products. One of these (lambda max = 306 nm) is photochemically reversible to the parent compound.