53640-85-0Relevant academic research and scientific papers
New ways to derivatize at position 6 of 7,7-dimethyl-7,8-dihydropterin
Shi, Genbin,Ji, Xinhua
, p. 6174 - 6176 (2011)
Reported are the synthesis of two intermediates for derivatization at position 6 of 7,7-dimethyl-7,8-dihydropterin: 6-carboxylic acid ethyl ester-7,7-dimethyl-7,8-dihydropterin, which is a novel compound, and 6-aldehyde-7,7-dimethyl-7,8-dihydropterin, which is synthesized by a new method with a yield of 90%.
HPPK INHIBITORS USEFUL AS ANTIBACTERIAL AGENTS
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, (2018/04/27)
The disclosure provides linked purine pterin compounds of Formula I that are novel inhibitors of HPPK, a kinase responsible for an essential step in the biosynthesis of folic acid. (Formula I) The variables, e.g., A1-A3, R1-R4, B1-B2, and L1 are defined in the disclosure. These linked purine pterin inhibitors bind to HPPK with high affinity and specificity. Pharmaceutical compositions containing the HPPK inhibitors and methods of treating a bacterial infection in a patient with one or more of the HPPK inhibitors of the disclosure are also provided.
Bisubstrate analogue inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: New design with improved properties
Shi, Genbin,Shaw, Gary,Liang, Yu-He,Subburaman, Priadarsini,Li, Yue,Wu, Yan,Yan, Honggao,Ji, Xinhua
scheme or table, p. 47 - 57 (2012/02/05)
6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), a key enzyme in the folate biosynthetic pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin. The enzyme is essential for microorganisms, is absent from humans, and is not the target for any existing antibiotics. Therefore, HPPK is an attractive target for developing novel antimicrobial agents. Previously, we characterized the reaction trajectory of HPPK-catalyzed pyrophosphoryl transfer and synthesized a series of bisubstrate analog inhibitors of the enzyme by linking 6-hydroxymethylpterin to adenosine through 2, 3, or 4 phosphate groups. Here, we report a new generation of bisubstrate analog inhibitors. To improve protein binding and linker properties of such inhibitors, we have replaced the pterin moiety with 7,7-dimethyl-7,8- dihydropterin and the phosphate bridge with a piperidine linked thioether. We have synthesized the new inhibitors, measured their Kd and IC 50 values, determined their crystal structures in complex with HPPK, and established their structure-activity relationship. 6-Carboxylic acid ethyl ester-7,7-dimethyl-7,8-dihydropterin, a novel intermediate that we developed recently for easy derivatization at position 6 of 7,7-dimethyl-7,8- dihydropterin, offers a much high yield for the synthesis of bisubstrate analogs than that of previously established procedure.
Specific Inhibitors in Vitamin Biosynthesis. Part 7. Syntheses of Blocked 7,8-Dihydropteridines via &α-Amino Ketones
Al-Hassan, Saiba S.,Cameron, Robert J.,Curran, Adrian W. C.,Lyall, William J. S.,Nicholson, Sydney H.,et al.
, p. 1645 - 1660 (2007/10/02)
The synthesis of 15 blocked 7,8-dihydropteridines is described in which the pyrazine ring is built from a derivative of an α-amino ketone.Three routes to the amino ketones based upon amino acids, nitrosyl chloride addition to alkenes, and nitro alcohols are discussed.The compounds synthesised are inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase , an enzyme in the pathway leading to dihydrofolate, and the inhibitory potencies of the compounds are discussed in the light of a hypothetical active site model for the enzyme.
Specific Inhibitors in Vitamin Biosynthesis. Part 8. Syntheses of some Functionalised 7,7-Dialkyl-7,8-dihydropterins
Cameron, Robert,Nicholson, Sydney H.,Robinson, David H.,Suckling, Colin J.,Wood, Hamish C. S.
, p. 2133 - 2144 (2007/10/02)
The synthesis of variety of functionalised blocked 7,8-dihydropteridines is described.The functional groups were chosen to provide compounds with potential for investigating the protein chemistry of enzymes in the pathway leading to dihydrofolate and, in particular, of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase.The potential of 7-substituents to provide sites of attachment of inhibitors to columns for affinity chromatography was explored but the extent of the study was curtailed by the restricted applicability of nitrosyl chloride addition to alkenes, a reaction used in the synthesis of pteridine precursors.The syntheses of two compounds, a 6-trichlorophenoxymethyldihydropteridine and of a thiadiazolopteridine, designed to have enchanced transport properties, are also described.
Specific Inhibitors in Vitamin Biosynthesis. Part 9. Reactions of 7,7-Dialkyl-7,8-dihydropteridines of Use in the Synthesis of Potential Inhibitors of Tetrahydrofolate Biosynthesis.
Al-Hassan, Saiba S.,Cameron, Robert,Nicholson, Sydney H.,Robinson, David H.,Suckling, Colin J.,Wood, Hamish C. S.
, p. 2145 - 2150 (2007/10/02)
Reactions of 7,7-dialkyl-7,8-dihydropteridines which are of potential use in modifying substituents on the pyrazine ring to yield compounds with inhibitory activity against 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase and dihydrofolate reductase are described.These enzymes lie along the pathway leading to the coenzyme tetrahydrofolate. 6-Methyl substituents showed typical reactivity of alkyl groups α- to a pyrazine nitrogen atom and underwent exchange of protium for deuterium under acidic and basic conditions: however, they failed to undergo clean bromination or aldol condensation.Autoxidation of alkyl groups at this position provided ready access to pteridines substituted with carbonyl groups at C-6. 6-Formyl derivatives underwent Wittig-type reactions to yield 6-aralkylidene compounds that are potential inhibitors of dihydrofolate reductase.Alkylation of the anion of 2,4-diamino-7,8-dihydro-6,7,7-trimethylpteridine occured at N-8 in low yield.The reduction of the blocked dihydropteridine system was readily accomplished using catalytic hydrogenation in a manner analogous to that used for normal pteridines.
