NAD analogs. 1. Synthesis of isosteric analogs of nicotinamide adenine dinucleotide containing C-nucleotide of nicotinamide or picolinamide

Pankiewicz, Krzysztof W.; Zeidler, Joanna; Ciszewski, Lech; Bell, John; Goldstein, Barry; Jayaram, Hiremagalur N.; Watanabe, Kyoichi A.

doi:10.1021/jm00065a008

Cited by 23 publications

(18 citation statements)

References 19 publications

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“…Indeed, NAD(P)-binding domains usually show a relatively high degree of conservation among different enzymes. Contrary to this observation, potent and selective in vitro and in vivo inhibitors of different NAD(P)-dependent oxidoreductases have been found [112][113][114][115]. This finding can be rationalized by the concept that even subtle differences among the properties of the active sites of different dehydrogenases greatly affect their sensitivity toward different inhibitors.…”

Section: Future Directions: Defining Specific Ptfnr Inhibitorsmentioning

confidence: 89%

“…Another example is 5-β-Dribofuranosylnicotinamide adenine dinucleotide (a Cnucleoside isoester of NAD; Fig. (2), 4), a highly specific inhibitor of alcohol dehydrogenase, with a K i of 1-2 nM [114,118]. Protein contacts to the ribose moieties of NAD(P) play an important role in coenzyme binding by Hbonding [119].…”

Section: Future Directions: Defining Specific Ptfnr Inhibitorsmentioning

confidence: 99%

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The Plant-Type Ferredoxin-NADP+ Reductase/Ferredoxin Redox System as a Possible Drug Target Against Apicomplexan Human Parasites

Seeber¹,

Aliverti²,

Zanetti

2005

CPD

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Apicomplexa are unicellular, obligate intracellular parasites of great medical importance. They include human pathogens like Plasmodium spp., the causative agent of malaria, and Toxoplasma gondii, an opportunistic parasite of immunosuppressed individuals and a common cause of congenital disease (toxoplasmosis). They alone affect several hundred million people worldwide so that new drugs, especially for plasmodial infections, are urgently needed. This review will focus on a recently emerged, potential drug target, a plant-type redox system consisting of ferredoxin-NADP(+) reductase (FNR) and its redox partner, ferredoxin (Fd). Both reside in an unique organelle of these parasites, named apicoplast, which is of algal origin. The apicoplast has been shown to be required for pathogen survival. In addition to other pathways already identified in this compartment, the FNR/Fd redox system represents a promising drug target because homologous proteins are not present in host organisms. Furthermore, a wealth of structural information exists on the closely related plant proteins, which can be exploited for structure-function studies of the apicomplexan protein pair. T. gondii and P. falciparum FNRs have been cloned, and the T. gondii enzyme was shown to be a flavoprotein active as a NADPH-dependent oxidoreductase. Both phylogenetic and biochemical analyses indicate that T. gondii FNR is similar in function to the isoform present in non-photosynthetic plastids whereby electron flow is from NADPH to oxidized Fd. The resulting reduced Fd is then presumably used as a reductant for various target enzymes whose nature is just starting to emerge. Among the likely candidates is the iron-sulfur cluster biosynthesis pathway, which is also located in the apicoplast and dependent on reducing power. Furthermore, lipoic acid synthase and enzymes of the isoprenoid biosynthetic pathway may be other conceivable targets. Since all these metabolic steps are vital for the parasite, blocking electron flow from FNR to Fd by inhibition of either FNR activity or its molecular interaction with Fd should also interfere with these pathways, ultimately killing the parasite. Although the three-dimensional structure of FNR from T. gondii is not yet known, experimental and computational evidence shows that apicomplexan and plant enzymes are very similar in structure. Furthermore, single amino acid changes can have profound effects on the enzyme activity and affinity for Fd. This knowledge may be exploited for the design of inhibitors of protein-protein interaction. On the other hand, specifically tailored NAD(P) analogues or mimetics based on previously described substances might be useful lead compounds for apicomplexan FNR inhibitors.

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Section: Future Directions: Defining Specific Ptfnr Inhibitorsmentioning

confidence: 89%

Section: Future Directions: Defining Specific Ptfnr Inhibitorsmentioning

confidence: 99%

The Plant-Type Ferredoxin-NADP+ Reductase/Ferredoxin Redox System as a Possible Drug Target Against Apicomplexan Human Parasites

Seeber¹,

Aliverti²,

Zanetti

2005

CPD

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“…Direct incorporation during solid-phase synthesis shows little promise due to the lability of nicotinamide riboside . However, there is a large body of literature on the synthesis of NAD analogs. − The challenge was finding a method that ideally allows site-specific functionalization of unprotected RNA with its multitude of functional groups.…”

mentioning

confidence: 99%

“…We decided to focus on approach 1, namely, on the reaction of a 5′-monophosphate-RNA with activated nicotinamide mononucleotide (NMN). On the nucleotide level, the utilization of carbonyldiimidazole (CDI) for 5′-phosphate activation and subsequent pyrophosphate formation has been reported to be mild, robust, and high-yielding. , Such phosphorimidazolides are known to react with numerous nucleophiles, such as pyrophosphates or nucleoside mono-, di-, or triphosphates. − Numerous NAD analogs have been prepared by phosphorimidazolide chemistry. ,,, On the oligonucleotide level, imidazolide activation has been used extensively for conjugation, , nonenzymatic ligation, and polymerization reactions, as well as for the preparation of adenylylated and capped RNAs. , These reports indicate that side reactions of the phosphorimidazolide with undesired nucleophiles (e.g., exocyclic amines of nucleobases) are not a major problem.…”

mentioning

confidence: 99%

“…30−34 Numerous NAD analogs have been prepared by phosphorimidazolide chemistry. 18,19,26,27 On the oligonucleotide level, imidazolide activation has been used extensively for conjugation, 35,36 nonenzymatic ligation, 37 and polymerization reactions, 38 as well as for the preparation of adenylylated and capped RNAs. 39,40 These reports indicate that side reactions of the phosphorimidazolide with undesired nucleophiles (e.g., exocyclic amines of nucleobases) are not a major problem.…”

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confidence: 99%

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Synthesis of 5′-NAD-Capped RNA

et al. 2016

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In prokaryotic organisms, certain regulatory RNAs have recently been found to be linked to the ubiquitous redox cofactor nicotinamide adenine dinucleotide (NAD) at their 5'-ends. Biochemical and structural investigations of this new caplike RNA modification require synthetic access to pure NAD-RNA. Here we report a chemoenzymatic approach to generate 5'-NAD-capped RNA in high yields and purity under mild conditions. This approach uses unprotected 5'-monophosphate RNA synthesized either chemically or enzymatically, 5',5'-pyrophosphate bond formation by phosphorimidazolide chemistry, and an enzymatic cleanup step. Thus, 5'-NAD-modified RNA can be synthesized independent of length, structure, and nucleotide sequence.

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Synthese des ersten 1,2,4‐Triazin‐C‐Nukleosids und dessen Umwandlung in neue Pyridin‐C‐Nukleoside durch “inverse” [4 + 2]‐Cycloaddition

Richter

Seitz

1995

Archiv der Pharmazie

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Die anomeren, zur C-Nukleosid-Synthese geeigneten C-Glycosyl-Precursoren 6 und 7 -ausgestattet rnit einer Imidoester-Gruppe -wurden hergestellt. Sie werden als Heterodienophile in der Diels-Alder-Reaktion mit inversem Elektronenbedarf eingesetzt zur Gewinnung der O-benzylgeschutzten 543-und 5-(a-~-Ribofuranosyl)-1,2,4-triazine 9 und 10, Derivate einer neuen Klasse von C-Nukleosiden. Nach hydrogenolytischer Entfemung der Schutzgruppen mit Hfld/C erhalt man das bisher unbekannte C-Nukleosid 11. Das Aglykon von 9 enthalt ein durch elektronenziehende Substituenten aktiviertes Diazadiensystem, das rnit einer Reihe elektronenreicher Dienophile wie Ketenacetalen, Enolethem oder Enaminen "inver- Wir berichten hier uber die Synthese des ersten 5 4 -DRibofuranosy1)-1,2,4-triazins und dessen Reaktivitat in der Diels-Alder-Reaktion mit inversem Elektronenbedd).Als Edukte dienten die 0-benzylgeschutzten Nitrile 4 und 5, die nach einer modifizierten Vorschrift von de las Heras aus 0-benzylgeschutzter Ribose 1 uber den p-Nitrobenzoesaureester 3 mit TrimethylsilylcyanidF3 als glatt trennbares Diastereomerengemisch gut zugi-inglich sind7). Nach sc Trennung an Kieselgel kann man die Nitrile 4 bzw. 5 unter Anwendung des Reaktionsprinzips von Riley und Mitarb.8) rnit etwa 70% Ausb. in die Imidoester 6 bzw. 7 uberfuhren. Imidoester besitzen eine donorsubstituierte C=N-Doppelbindung rnit ausgepragten dienophilen Eigens~haften~.'~). Mit dem hochreaktiven 1,2,4,5-Tetrazin 8l') als Diazadien konnen 6 und 7 mit jeweils etwa 6Oproz. Ausb. in die 0-benzylgeschutzten Triazin-C-Nukleoside 9 und 10 umgewandelt werden. tion ReactionsThe anomeric C-glycosyl precursors 6 and 7, appropriate for C-nucleoside synthesis and functionalized by an imidate group, were prepared. They were utilized as heterodienophiles in a Diels-Alder reaction with inverse electron demand to yield the 0-benzyl protected 5-(P-and 5-(a-~-ribofuranosyl)-1,2,4-triazines 9 and 10, derivatives of a new class of C-nucleosides. 9 could be deprotected by hydrogenolysis with Pd/C as catalyst to furnish the hitherto unknown C-nucleoside 11. The aglycon of 9 contains a diazadiene system, activated by electron withdrawing substituents, which reacts with various electron rich dienophiles like ketene acetals, enol ethers or enamines in an inverse [4 + 21-cycloaddition reaction. After N,-elimination the 0-benzyl protected 2-(P-D-nbofuranosyl)-pynd~es 13, 15, 17, 19, and 21 are formed. Removal of the protecting benzyl groups from the glycon moiety of 13, 15, and 17 leads to the novel 2-(P-~-ribofuranosy1)-pyridines 22-24. Using the 0-benzoyl protected thioimidate 25 as dienophile the reaction with the tetrazine 8 yields the 5-(furane-2-~1)-1,2,4-triazine 28 as sole product besides benzoic acid.Hydrogenolytische Entfemung der Benzylschutzgruppen von 9 rnit Palladiumkohle als Katalysator liefert mit etwa 52% Ausb. das erste C-Nukleosid rnit einem 1,2,4-Triazin als Aglykon. Bisher sind u.W. nur Triazin-C-Nukleoside beschrieben, die 1,3,5-Triazine8) oder 1 ,2,4-Triazindione12) als Basenanalo...

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NAD analogs. 1. Synthesis of isosteric analogs of nicotinamide adenine dinucleotide containing C-nucleotide of nicotinamide or picolinamide

Cited by 23 publications

References 19 publications

The Plant-Type Ferredoxin-NADP+ Reductase/Ferredoxin Redox System as a Possible Drug Target Against Apicomplexan Human Parasites

The Plant-Type Ferredoxin-NADP+ Reductase/Ferredoxin Redox System as a Possible Drug Target Against Apicomplexan Human Parasites

Synthesis of 5′-NAD-Capped RNA

Synthese des ersten 1,2,4‐Triazin‐C‐Nukleosids und dessen Umwandlung in neue Pyridin‐C‐Nukleoside durch “inverse” [4 + 2]‐Cycloaddition

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