A novel lumazine synthase inhibitor derived from oxidation of 1,3,6,8-tetrahydroxy-2,7-naphthyridine to a tetraazaperylenehexaone derivative.
Air oxidation of 1,3,6,8-tetrahydroxy-2,7-naphthyridine afforded 2,5,8,11-tetraaza-5,11-dihydro-4,10-dihydroxyperylene-1,3,6,7,9,12-hexaone. X-ray crystallography of the product revealed that it exists in the meso form in the solid state. The mechanism of product formation most likely involves oxidative phenolic coupling and oxidation. The product proved to be a competitive inhibitor of Schizosaccharomyces pombe lumazine synthase with a Ki of 66+/-13 microM in Tris buffer and 22+/-4 microM in phosphate buffer. This is significantly more potent than the reactant (Ki 350+/-76 microM, competitive inhibition), which had previously been identified as a lumazine synthase inhibitor by high-throughput screening. Ab initio calculations indicate that the meso form is slightly less stable than the enantiomeric form, and that the two forms interconvert rapidly at room temperature.
Zhang
Yanlei
Y
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, and The Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
Illarionov
Boris
B
Bacher
Adelbert
A
Fischer
Markus
M
Georg
Gunda I
GI
Ye
Qi-Zhuang
QZ
Vander Velde
David
D
Fanwick
Phillip E
PE
Song
Yunlong
Y
Cushman
Mark
M
D001372:Aza Compounds / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009287:Naphthyridines / Q000737:chemistry*; D010084:Oxidation-Reduction; D010569:Perylene / Q000737:chemistry; D019800:Phenol / Q000737:chemistry; D012568:Schizosaccharomyces / Q000201:enzymology*
D001372:Aza Compounds; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D009097:Multienzyme Complexes; D009287:Naphthyridines; D019800:Phenol; D010569:Perylene; C044822:6,7-dimethyl-8-ribityllumazine synthase