A synthesis of 9-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)adenine and -hypoxanthine. An effect of C3'-endo to C2'-endo conformational shift on the reaction course of 2'-hydroxyl group with DAST

Pankiewicz, Krzysztof W.; Krzeminski, Jacek; Ciszewski, Lech; Ren, Wu Yon; Watanabe, Kyoichi A.

doi:10.1021/jo00028a030

Cited by 71 publications

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“…Fluorination of 15 with diethylaminosulfur trifluoride (DAST) afforded 16 . 29 After selective removal of the 5′-OTBS employing TFA in 2:1 H 2 O–THF, intermediate 17 was converted to sulfamate 18 . The 1 H NMR data of 17 and 18 agreed with reported analytical data, 30 indicating that the C-2′ configuration of 16 was R .…”

Section: Resultsmentioning

confidence: 99%

Reaction intermediate analogues as bisubstrate inhibitors of pantothenate synthetase

Wei

Martinelli

et al. 2014

Bioorganic & Medicinal Chemistry

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The biosynthesis of pantothenate, the core of coenzyme A (CoA), has been considered an attractive target for the development of antimicrobial agents since this pathway is essential in prokaryotes, but absent in mammals. Pantothenate synthetase, encoded by the gene panC, catalyzes the final condensation of pantoic acid with β–alanine to afford pantothenate via an intermediate pantoyl adenylate. We describe the synthesis and biochemical characterization of five PanC inhibitors that mimic the intermediate pantoyl adenylate. These inhibitors are competitive inhibitors with respect to pantoic acid and possess submicromolar to micromolar inhibition constants. The observed SAR is rationalized through molecular docking studies based on the reported co-crystal structure of 1a with PanC. Finally, whole cell activity is assessed against wild-type Mtb as well as a PanC knockdown strain where PanC is depleted to less than 5% of wild-type levels.

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Section: Resultsmentioning

confidence: 99%

Reaction intermediate analogues as bisubstrate inhibitors of pantothenate synthetase

Wei

Martinelli

et al. 2014

Bioorganic & Medicinal Chemistry

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“…2. Our strategy was based on the direct stereospecific introduction of fluorine in the 2′-A position by fluorination of a suitably protected derivative of MeSAdo with (Et 2 NSF 3 ) according to the method developed by Pankiewicz et al [24]. Since the conformation (C3′-endo/C2′-endo) of the sugar moiety of a nucleoside influences the facility of nucleophilic displacement of a 2′-β leaving group or the competitive 1′,2′-elimination process, as indicated by these authors, we used an O-benzyl protecting group in the arabino analogue 11, to favour a C3′-endo conformation and limit the formation of elimination product during the fluorination step.…”

Section: Methodsmentioning

confidence: 99%

The catalytic mechanism of adenosylhomocysteine/methylthioadenosine nucleosidase from Escherichia coli

Allart

Gâtel

Guillerm

et al. 1998

European Journal of Biochemistry

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The substrate and inhibitory specificity of Escherichia coli adenosylhomocysteine (AdoHcy)/methylthioadenosine (MeSAdo) nucleosidase has been explored with several MeSAdo analogues modified on the sugar moiety at the 2′, 3′ and 5′ positions. Alteration at C3′ or at C2′ and C3′ positions in MeSAdo abolished substrate activity. However, the 2′-deoxy analogue of MeSAdo is effective as a substrate; this result provides evidence against a possible general-base catalysis involving the anchimeric assistance of the 2′-A-hydroxy group and the formation of a 1,2-epoxide as an intermediate in the catalytic process. The results of a study of the interaction of an 8,5′-cyclo analogue of MeSAdo with the enzyme indicate the importance of the glycosidic conformation of the substrate for binding to the active site. The enzyme discriminates against methanol attack from the solvent during catalysis. This implies the participation of an enzyme-directed water nucleophile. A poor solvent kinetic deuterium-isotope effect was measured (0.93) on the V max . Plots of log V max and log (V max /K m ) for MeSAdo as a function of pH values from 5.0 to 8.5 are similar, with two presumably essential ionisable groups for catalysis with apparent pK a values of 5.6 and 8.2, whereas K m is independent of pH. When the 2′-A-hydroxy group of MeSAdo is substituted by fluorine, a significant decrease (28 500-fold) in the V max for enzyme-catalysed hydrolysis of the modified substrate is observed. This result indicates a transition state with a substantial oxocarbenium character. From these data, the reaction mechanism for AdoHcy/MeSAdo nucleosidase is discussed.Keywords : adenosylhomocysteine nucleosidase ; substrate; inhibitor ; catalytic mechanism.S-Adenosylhomocysteine (AdoHcy) is the product of biological transmethylation reactions that utilise S-adenosylmethionine (AdoMet) as a methyl donor [1,2]. In various microorganisms (bacteria and protozoa), this compound and 5′-methylthioadenosine (MeSAdo), formed from adenosylmethionine by several independent pathways [3], are substrates of AdoHcy/ MeSAdo nucleosidase. This enzyme catalyses the cleavage of the metabolites into S-ribosylhomocysteine and methylthioribose, respectively, adenine also being generated by both reactions [4,5].AdoHcy/MeSAdo nucleosidase is involved in a variety of biological processes. In particular it is required for the regeneration of free Hcy from AdoHcy in various prokaryotes [5,6], and plays a significant role in the metabolism of these microorganisms via the regulation of the MeSAdo concentration (a potent inhibitor of spermidine and spermine synthases) [7Ϫ9]. In microorganisms in which MeSAdo phosphorylase is missing, AdoHcy/MeSAdo nucleosidase is essential for methionine salvage [10Ϫ12].Correspondence to G. Guillerm, Laboratoire de Chimie Bioorganique, U.M.R. 6519, U.F.R. Sciences de Reims, Moulin de la Housse, B.P. 1039, F-51687 Reims cedex 2, France Fax: ϩ33 3 26 05 31 66. E-mail: georges.guillerm@univ-reims.fr Abbreviations. AdoHcy, S-adenosylhomocysteine; MeSAdo, 5′-d...

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“…Previously we fluorinated the sugar ring of adenosine in the 2'-ribo and -arabino configuration using bulky trityl groups to force a similar conformational shift and using DAST (diethylaminosulfur trifluoride) as a nucleophilic reagent [33]. We then prepared the corresponding NAD analogues as potential inhibitors of NAD kinase [34], Fig.…”

Section: Selectivity and Conformations Of Nucleosides Bound At The N mentioning

confidence: 99%

Rehab of NAD(P)-Dependent Enzymes with NAD(P)-Based Inhibitors

Felczak

Pankiewicz

2011

CMC

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A large number of enzymes that use nicotinamide adenine dinucleotide NAD or its phosphorylated form NADP as a cofactor or substrate were found to play an important role in the growth and reproduction of living organisms. NAD(P)-dependent and NAD(P)-utilizing enzymes [NAD(P)-addicted?] have been extensively investigated and implicated in a wide variety of diseases. NAD, generally considered a key component involved in redox reactions, has been found to participate in a broad spectrum of cellular processes, including signal transduction, DNA repair, and post-translational protein modifications. The reduced form of NADP, i.e. NADPH, guards the cell against oxidative stress and it has been suggested that suppression of NADPH oxidase activity could result in anti-angiogenesis and anticancer effects. Consequently, small molecule NAD(P)-based inhibitors that selectively bind at the NAD(P)-binding domain of the targeted enzyme have been designed for novel treatment of medical disorders. The NAD(P)-binding domain is modular in nature; it can be divided into three sub-sites, the nicotinamide monophosphate (NMN) binding sub-site (N sub-site), the adenosine monophosphate (AMP) binding sub-site (A sub-site), and the pyrophosphate binding sub-site (P sub-site or P-groove). Each sub-site plays an important role in securing proper and tight binding; however, each has its own requirements. In this review we discuss a number of conformational and structural factors that might affect (improve) the affinity of various inhibitors to these sub-sites, as well as to the whole binding domain. We have focused on potential selectivity of NAD(P)-like molecules toward targeted enzymes and their potential application in biology and medicine.

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A synthesis of 9-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)adenine and -hypoxanthine. An effect of C3'-endo to C2'-endo conformational shift on the reaction course of 2'-hydroxyl group with DAST

Cited by 71 publications

References 0 publications

Reaction intermediate analogues as bisubstrate inhibitors of pantothenate synthetase

Reaction intermediate analogues as bisubstrate inhibitors of pantothenate synthetase

The catalytic mechanism of adenosylhomocysteine/methylthioadenosine nucleosidase from Escherichia coli

Rehab of NAD(P)-Dependent Enzymes with NAD(P)-Based Inhibitors

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