Inhibition of Purine Nucleoside Phosphorylase by Phosphonoalkylpurines 1

Nakamura, Charles E.; Chu, Shih–Hsi; Stoeckler, Johanna D.; Parks, Robert E.

doi:10.1080/07328318908054271

Cited by 17 publications

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“…32 Interestingly, when the side chain is not tethered as with 9-pentylhypoxanthine (16) (Ki = 52 FM) and 9-(3,3-dimethylpentyl)hypoxanthine (17) (Ki = 110 pM), the methyl groups reduce binding. 31 Replacement of the hydrogens on the carbon adjacent to the phosphonate moiety by fluorine, which increases the acidity of the phosphonate, in 9-(5-phosphonopenty1)guanine resulted in a 10-fold increase in potency of the resultant 9-(5,5-difluoro-5-phosphonopentyl)guanine (18) (Ki = 0.018 Unfortunately, this change decreases the ability of the inhibitor to cross cell membranes, making it necessary to employ a concentration of 100 pM to The concept of drug design based on x-ray crystallographic and modeling methods has received much attention, yet few true examples of the application of this technique have appeared in the literature. Two exceptions are the design of inhibitors of HIV protease40 and the design of inhibitors of thymidylate synthase inhibit01-s.~~ Recently, we reported on the design of inhibitors of PNP using computer modeling of the three-dimensional structure of the active site of the enzyme and the active site containing the substrate guanine, as well as known inhibitors including 8-aminoguanine (l), 9-benzyl-%amino-guanine (3), 5'-iodo-9-deazainosine (9), and acyclovir diphosphate (13).…”

Section: Inhibitorsmentioning

confidence: 97%

Purine nucleoside phosphorylase: A target for drug design

Montgomery

1993

Medicinal Research Reviews

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Section: Inhibitorsmentioning

confidence: 97%

Purine nucleoside phosphorylase: A target for drug design

Montgomery

1993

Medicinal Research Reviews

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“…11). 105 These examples demonstrate the potential of a-halogenated phosphonates as immunosuppressive agents, and the corresponding a-bromo phosphonate compounds remain to be explored. This class of inhibitors for PNP are of interest as potential immunosuppressive agents.…”

Section: A-bromophosphonocarboxylates and Abromobisphosphonatesmentioning

confidence: 99%

“…12 The corresponding fully-saturated phosphonate of compound 63 was found to inhibit human erythrocyte PNP with a K I of 174 nM, while 63 had substantially increased activity. 105 These examples demonstrate the potential of a-halogenated phosphonates as immunosuppressive agents, and the corresponding a-bromo phosphonate compounds remain to be explored.…”

Section: A-bromophosphonates On a Carbohydrate Scaffoldmentioning

confidence: 99%

Synthesis of α-brominated phosphonates and their application as phosphate bioisosteres

Downey

Cairo

2014

Med. Chem. Commun.

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Substrate phosphorylation is a key modulator of signal transduction. Abnormal phosphorylation in vivo is implicated in many diseases including cancer, diabetes, and Alzheimer's disease. Inhibitors of phosphaterecognizing proteins have potential as medicinal agents as well as tools to study phosphorylation pathways. A well-known and common inhibition strategy is to synthetically replace the labile phosphate moiety with a non-hydrolyzable phosphonate. Fully saturated, a-fluoro and a,a-difluorophosphonates are often effective phosphate bioisosteres and have been well studied. More recently a-brominated phosphonates have begun to emerge as inhibitors of phosphate recognizing enzymes, some of which operate by irreversible mechanisms. Herein we discuss the synthetic approaches to aliphatic and benzylic a-bromophosphonates and their biological activities.Scheme 5 The synthesis of an aliphatic a-bromophosphonate derivative. 52 Scheme 6 An improved synthetic strategy to alkyl abromophosphonates. 53This journal is

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“…Hence, they are not promising candidates as in vivo inhibitors. This has stimulated the synthesis of some mimics with the terminal phosphate being replaced by a phosphonate [6] or a difluorometylene phosphonate [7], which confer metabolic stability. Moreover, some phosphonates appear to be capable of slowly traversing the cell membrane, conceivably via an endocytosis‐like process [8,9].…”

Section: Introductionmentioning

confidence: 99%

9‐Deazaguanine derivatives connected by a linker to difluoromethylene phosphonic acid are slow‐binding picomolar inhibitors of trimeric purine nucleoside phosphorylase

Breer¹,

Glavaš‐Obrovac

Suver

et al. 2010

The FEBS Journal

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Genetic deficiency of purine nucleoside phosphorylase (PNP; EC 2.4.2.1) activity leads to a severe selective disorder of T‐cell function. Therefore, potent inhibitors of mammalian PNP are expected to act as selective immunosuppressive agents against, for example, T‐cell cancers and some autoimmune diseases. 9‐(5′,5′‐difluoro‐5′‐phosphonopentyl)‐9‐deazaguanine (DFPP‐DG) was found to be a slow‐ and tight‐binding inhibitor of mammalian PNP. The inhibition constant at equilibrium (1 mm phosphate concentration) with calf spleen PNP was shown to be = 85 ± 13 pm (pH 7.0, 25 °C), whereas the apparent inhibition constant determined by classical methods was two orders of magnitude higher ( = 4.4 ± 0.6 nm). The rate constant for formation of the enzyme/inhibitor reversible complex is (8.4 ± 0.5) × 105 m−1·s−1, which is a value that is too low to be diffusion‐controlled. The picomolar binding of DFPP‐DG was confirmed by fluorimetric titration, which led to a dissociation constant of 254 pm (68% confidence interval is 147–389 pm). Stopped‐flow experiments, together with the above data, are most consistent with a two‐step binding mechanism: E + I ↔ (EI) ↔ (EI)*. The rate constants for reversible enzyme/inhibitor complex formation (EI), and for the conformational change (EI) ↔ (EI)*, are kon1 = (17.46 ± 0.05) × 105 m−1·s−1, koff1 = (0.021 ± 0.003) s−1, kon2 = (1.22 ± 0.08) s−1 and koff2 = (0.024 ± 0.005) s−1, respectively. This leads to inhibition constants for the first (EI) and second (EI)* complexes of Ki = 12.1 nM (68% confidence interval is 8.7–15.5 nm) and = 237 pm (68% confidence interval is 123–401 pm), respectively. At a concentration of 10−4 m, DFPP‐DG exhibits weak, but statistically significant, inhibition of the growth of cell lines sensible to inhibition of PNP activity, such as human adult T‐cell leukaemia and lymphoma (Jurkat, HuT78 and CCRF‐CEM). Similar inhibitory activities of the tested compound were noted on the growth of lymphocytes collected from patients with Hashimoto’s thyroiditis and Graves’ disease. The observed weak cytotoxicity may be a result of poor membrane permeability.

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Inhibition of Purine Nucleoside Phosphorylase by Phosphonoalkylpurines 1

Cited by 17 publications

References 0 publications

Purine nucleoside phosphorylase: A target for drug design

Purine nucleoside phosphorylase: A target for drug design

Synthesis of α-brominated phosphonates and their application as phosphate bioisosteres

9‐Deazaguanine derivatives connected by a linker to difluoromethylene phosphonic acid are slow‐binding picomolar inhibitors of trimeric purine nucleoside phosphorylase

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