Designing a Pronucleotide Stratagem: Lessons from Amino Acid Phosphoramidates of Anticancer and Antiviral Pyrimidines

Drontle, Dan P.; Wagner, Carston R.

doi:10.2174/1389557043403945

Cited by 64 publications

(56 citation statements)

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“…The first inhibitor examined was based on the replacement of the carbamate backbone in 3 with a bioisosteric acyl-sulfamate backbone. The synthesis of compound 4 (Scheme 1) began with 5′-OH sulfamoylation of 2′,3′-O-isopropylidene guanosine (8) to provide intermediate 9. Coupling of 9 with the Nhydroxysuccinic acid ester of 3-indole propionic acid in the presence of DBU (1,8-diazabicyclo[5.4.0] undec-7-ene) afforded 10.…”

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confidence: 99%

Design, Synthesis, and Characterization of Sulfamide and Sulfamate Nucleotidomimetic Inhibitors of hHint1

Shah

Strom

Zhou

et al. 2016

ACS Med. Chem. Lett.

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Hint1 has recently emerged to be an important target of interest due to its involvement in the regulation of a broad range of CNS functions including opioid signaling, tolerance, neuropathic pain, and nicotine dependence. A series of inhibitors were rationally designed, synthesized, and tested for their inhibitory activity against hHint1 using isothermal titration calorimetry (ITC). The studies resulted in the development of the first small-molecule inhibitors of hHint1 with submicromolar binding affinities. A combination of thermodynamic and high-resolution X-ray crystallographic studies provides an insight into the biomolecular recognition of ligands by hHint1. These novel inhibitors have potential utility as molecular probes to better understand the role and function of hHint1 in the CNS.

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confidence: 99%

Design, Synthesis, and Characterization of Sulfamide and Sulfamate Nucleotidomimetic Inhibitors of hHint1

Shah

Strom

Zhou

et al. 2016

ACS Med. Chem. Lett.

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“…Nevertheless, many nucleosides are poor substrates for endogenous nucleoside kinases. To overcome this hurdle, several pronucleotide approaches have been investigated, including the use of nucleoside monophosphoramidates (24,26).…”

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confidence: 99%

31P NMR and Genetic Analysis Establish hinT as the Only Escherchia coli Purine Nucleoside Phosphoramidase and as Essential for Growth under High Salt Conditions

Chou

Bieganowski

Shilinski

et al. 2005

Journal of Biological Chemistry

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Eukaryotic cells encode AMP-lysine (AMP-N-⑀-(N-␣acetyl lysine methyl ester) 5-phosphoramidate) hydrolases related to the rabbit histidine triad nucleotidebinding protein 1 (Hint1) sequence. Bacterial and archaeal cells have Hint homologs annotated in a variety of ways, but the enzymes have not been characterized, nor have phenotypes been described due to loss of enzymatic activity. We developed a quantitative 31 P NMR assay to determine whether Escherichia coli possesses an adenosine phosphoramidase activity. Indeed, soluble lysates prepared from wild-type laboratory E. coli exhibited activity on the model substrate adenosine 5-monophosphoramidate (AMP-NH 2 ). The E. coli Hint homolog, which had been comprehensively designated ycfF and is here named hinT, was cloned, overexpressed, purified, and characterized with respect to purine nucleoside phosphoramidate substrates. Bacterial hinT was several times more active than human or rabbit Hint1 on five model substrates. In addition, bacterial and mammalian enzymes preferred guanosine versus adenosine phosphoramidates as substrates. Analysis of the lysates from a constructed hinT knock-out strain of E. coli demonstrated that all of the cellular purine nucleoside phosphoramidase activity is due to hinT. Physiological analysis of this mutant revealed that the loss of hinT results in failure to grow in media containing 0.75 M KCl, 0.9 M NaCl, 0.5 M NaOAc, or 10 mM MnCl 2 . Thus, cation-resistant bacterial cell growth may be dependent on the hydrolysis of adenylylated and/or guanylylated phosphoramidate substrates by hinT.

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“…In the past decades, several strategies have been developed to improve the therapeutic potential of nucleoside analogs using pronucleotides (Cahard et al, 2004;Drontle and Wagner, 2004;Jessen et al, 2008;Meier et al, 2004;Parang et al, 2000;Peyrottes et al, 2004;Schultz, 2003). These investigations have been associated with the development of different approaches in order to demonstrate the selectivity of processes involved in the intracellular delivery of 5′-mononucleotide from its phosphorylated precursor.…”

Section: Resultsmentioning

confidence: 99%

“…In order to circumvent this limitation, the use of 5′-mononucleotides could not be envisaged due to their polar nature under physiological conditions (limiting their ability to cross cell membranes) and their rapid dephosphorylation in extracellular fluids and on cell surfaces (Ho, 1971;Jessen et al, 2008;LePage et al, 1975;Schrecker and Goldin, 1968). Consequently, several approaches have been developed to improve the therapeutic potential of nucleoside analogs using mononucleotide prodrugs (pronucleotides) (Cahard et al, 2004;Drontle and Wagner, 2004;Meier et al, 2004;Peyrottes et al, 2004). The difficulty of a pronucleotide approach lies in the fact that transformations involved in the 5′-mononucleotide delivery from its corresponding prodrug selectively occur inside the cells.…”

Section: Introductionmentioning

confidence: 99%

Decomposition of 3′‐azido‐2′,3′‐dideoxythymidine 5′‐monophosphate (AZTMP) prodrugs in biological media studied by on‐line solid‐phase extraction coupled to liquid chromatography mass spectrometry

Lefèbvre

Beltran

Peyrottes

et al. 2009

Biomedical Chromatography

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Using a column-switching HPLC method previously described, we studied the behavior of some mononucleotide prodrugs (pronucleotides) of 3'-azido-2',3'-dideoxythymidine in various biological media. From UV data, this method allowed quantification of transient metabolites resulting from prodrug bioconversion. The kinetic data related to the successive steps were calculated according to pseudo-first-order kinetic models and optimized using mono- or poly-exponential regressions. Various metabolites were identified by co-injection with authentic samples and/or ESI-MS coupling. The results led us to propose, for each considered pronucleotide, a global decomposition pathway ending in the selective delivery of the corresponding mononucleotide. Associated to the determination of other parameters (lipophilicity, aqueous solubility), the present study contributes to the search of suitable pharmacological properties for further in vivo evaluations.

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Designing a Pronucleotide Stratagem: Lessons from Amino Acid Phosphoramidates of Anticancer and Antiviral Pyrimidines

Cited by 64 publications

References 0 publications

Design, Synthesis, and Characterization of Sulfamide and Sulfamate Nucleotidomimetic Inhibitors of hHint1

Design, Synthesis, and Characterization of Sulfamide and Sulfamate Nucleotidomimetic Inhibitors of hHint1

31P NMR and Genetic Analysis Establish hinT as the Only Escherchia coli Purine Nucleoside Phosphoramidase and as Essential for Growth under High Salt Conditions

Decomposition of 3′‐azido‐2′,3′‐dideoxythymidine 5′‐monophosphate (AZTMP) prodrugs in biological media studied by on‐line solid‐phase extraction coupled to liquid chromatography mass spectrometry

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