- Synthesis and Characterization of Water-Soluble and Photolabile 10-Arylisoalloxazines: Tools for Studying the Mechanism of Action of Flavin-Type Antimalarials
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Isoalloxazine derivatives such as 1a-d are promising antimalarial agents which act as inhibitors of the antioxidant enzyme glutathione reductase and possibly of other proteins.The molecular mechanism of the pharmacological effects has not been studied in detail because compounds 1a-d are poorly soluble in aqueous solutions of physiological pH.In the present study we introduce two new types of isoalloxazine derivatives with improved solubility properties.The 10-aryl-3-carboxymethylisoalloxazines 2a-d, and the isomeric 3-methyl-10-(N-methylpyridiniumyl)isoalloxazine salts 3 and 4.In addition, for the purpose of photoaffinity labeling experiments, the 10-aryl-8-azido-3-methylisoalloxazine 5 was designed.The syntheses and characterizations of these new flavins as well as an alternative synthetic approach to the known antimalarials 1a-d are described. - Keywords: Flavins/Isoalloxazines/Arylisoalloxazines/Malaria/Antimalarials/Glutathione reductase inhibitors/Photoaffinity labels
- Kirsch, Peer,Schoenleben-Janas, Annette,Schirmer, R. Heiner
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p. 1275 - 1282
(2007/10/02)
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- Fluorescence Studies with Tryptophan Analogues: Excited State Interactions Involving the Side Chain Amino Group
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The fluorescence of a large set of tryptophan analogues, including several that are conformationally constrained, was studied.The constrained analogues include tetrahydrocarboline-3-carboxylic acid and 3-amino-3-carboxytetrahydrocarbazole.Steady state and time-resolved fluorescence measurements were made as a function of pH.The fluorescence quantum yields of the constrained analogues are higher than those for the unconstrained counterparts.The emission intensity of the constrained analogues, as well as 4-methyltryptophan, decreases with deprotonation of the side chain α-ammonium groups; this is in contrast to the increase in fluorescence of tryptophan with deprotonation of this group.These results are consistent with the existence of excited state proton transfer to carbon 4 of the indole ring as a quenching mechanism, which is sterically prohibited in the constrained analogues and 4-methyltryptophan.From quantum yield and lifetime data (most decays are nonexponential), the effective rate constant for nonradiative depopulation of the excited state was calculated.For tryptophan analogues having two side chain functional groups, there is a synergistic effect; the presence of two side chain groups causes more quenching than expected from the sum of the individual contributions.For analogues having an α-ammonium group, this synergism appears to be correlated with an induced change in the pKa of this group.Deprotonation of this α-ammonium group also caused a red shift in the emission of these compounds; this appears to be due to electrostatic repulsion between the α-NH3+ group and the excited indole dipole.
- Eftink, Maurice R.,Jia, Yiwei,Hu, Dana,Ghiron, Camillo, A.
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p. 5713 - 5723
(2007/10/02)
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