Third-Generation Immucillins: Syntheses and Bioactivities of Acyclic Immucillin Inhibitors of Human Purine Nucleoside Phosphorylase

Clinch, Keith; Evans, Gary B.; Fröhlich, Richard; Furneaux, Richard H.; Kelly, P. M.; Legentil, Laurent; Murkin, Andrew S.; Li, Lei; Schramm, Vern L.; Tyler, Peter C.; Woolhouse, Anthony D.

doi:10.1021/jm801421q

Cited by 68 publications

(70 citation statements)

References 51 publications

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“…Different geometry is poorly tolerated. Thus, in a family of eight diols related to DADMe-ImmH but with the open ring flexibility of DATMe-ImmH, all bound more weakly by factors of 50 to 35,000 (9). The 2′-hydroxyl of analogues is not critical for tight binding.…”

Section: Discussionmentioning

confidence: 93%

“…The transition states of human and bovine PNPs are distinct based on isotope effects and inhibitor specificity (5)(6)(7)(8)(9). Human PNP has a fully-dissociated purine leaving group with a fullydeveloped ribocation (5).…”

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confidence: 99%

“…1), was discovered by exploring acyclic cationic di-and trihydroxy groups linked to 9-deazahypoxanthine via the 9-methylene bridge (9). DATMe-ImmH is similar to ImmH except for the open ring structure between C1′ and C2′ and the altered stereochemistry of the 3′-hydroxyl group.…”

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confidence: 99%

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Four generations of transition-state analogues for human purine nucleoside phosphorylase

Shi

Rinaldo-Matthis

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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103

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Inhibition of human purine nucleoside phosphorylase (PNP) stops growth of activated T-cells and the formation of 6-oxypurine bases, making it a target for leukemia, autoimmune disorders, and gout. Four generations of ribocation transition-state mimics bound to PNP are structurally characterized. Immucillin-H (K Ã i ¼ 58 pM, firstgeneration) contains an iminoribitol cation with four asymmetric carbons. DADMe-Immucillin-H (K Ã i ¼ 9 pM, second-generation), uses a methylene-bridged dihydroxypyrrolidine cation with two asymmetric centers. DATMe-Immucillin-H (K Ã i ¼ 9 pM, third-generation) contains an open-chain amino alcohol cation with two asymmetric carbons. SerMe-ImmH (K Ã i ¼ 5 pM, fourth-generation) uses achiral dihydroxyaminoalcohol seramide as the ribocation mimic. Crystal structures of PNPs establish features of tight binding to be; 1) ion-pair formation between bound phosphate (or its mimic) and inhibitor cation, 2) leaving-group interactions to N1, O6, and N7 of 9-deazahypoxanthine, 3) interaction between phosphate and inhibitor hydroxyl groups, and 4) His257 interacting with the 5′-hydroxyl group. The first generation analogue is an imperfect fit to the catalytic site with a long ion pair distance between the iminoribitol and bound phosphate and weaker interactions to the leaving group. Increasing the ribocation to leaving-group distance in the second-to fourth-generation analogues provides powerful binding interactions and a facile synthetic route to powerful inhibitors. Despite chemical diversity in the four generations of transitionstate analogues, the catalytic site geometry is almost the same for all analogues. Multiple solutions in transition-state analogue design are available to convert the energy of catalytic rate enhancement to binding energy in human PNP.uman PNP catalyzes the phosphorolysis of 6-oxypurine nucleosides and deoxynucleosides to generate α-D-(deoxy) ribose 1-phosphate and the purine base. The purine is recycled or oxidized to uric acid for excretion. A rare genetic deficiency of PNP reveals that the enzyme is essential for recycling d-guanosine and formation of free purines leading to uric acid synthesis. PNP deficiency causes the presence of elevated concentrations of d-guanosine in the blood resulting in apoptosis of dividing T-cells due to the metabolic accumulation of dGTP, an inhibitor of ribonucleotide reductase (1, 2). Inhibitors of PNP have been used for the treatment of T-cell cancers and autoimmune disorders where T-cell clones are misdirected against self-antigens causing disorders, including psoriasis, rheumatoid arthritis, and multiple sclerosis (2, 3). PNP inhibitors are also in clinical trials for gout because formation of purine base precursors for uric acid formation requires PNP in humans.Knowledge of enzymatic transition-state structure is obtained from the experimental approach of kinetic isotope effects combined with quantum-chemical models (4). This analysis provides an atomic view of the difference in bond-vibrational environment between the reactants and th...

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Section: Discussionmentioning

confidence: 93%

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confidence: 99%

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Four generations of transition-state analogues for human purine nucleoside phosphorylase

Shi

Rinaldo-Matthis

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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103

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“…Inhibitor 16 was synthesized using methods previously described (46). The iminoribitol-, pyrrolidine-, and serinol-based inhibitors were synthesized by an extension of published methods for the synthesis of immucillin-H, 4Ј-deaza-1Ј-aza-2Ј-deoxy-1Ј-(9-methylene)-immucillin-H, and serinol-N-(9-methylene)-immucillin-H, respectively (see supplemental data) (40,(47)(48)(49). The identities of all inhibitors were confirmed by high-resolution mass spectrometry.…”

Section: Methodsmentioning

confidence: 99%

Transition State Analogues of Plasmodium falciparum and Human Orotate Phosphoribosyltransferases

Zhang

Evans

Clinch

et al. 2013

Journal of Biological Chemistry

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Background: Human and malaria orotate phosphoribosyltransferases (OPRTs) in the de novo pyrimidine biosynthesis pathway are characterized by ribocation transition states with fully dissociated leaving orotate groups. Results: Transition state analogues with varied ribocation substitutions, different linkers, and distinct leaving groups exhibited nanomolar binding affinities for the OPRT enzymes. Conclusion: Components crucial for inhibitor binding to the OPRT active sites have been identified, and powerful inhibitors were characterized. Significance: Transition state analogues of OPRTs provide new insights into the nature of potential antimalarials and anticancer agents.

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“…20 Subsequently, amine 20 was reacted with benzoyl chloride and Et 3 N as base, in THF, to give amide 21 in 88% yield. Cyclization of amide 21 using tBuOK in THF afforded the unstable diketone 22, which was immediately converted to the 7-N-benzoyl analogue 10 by condensation with 13 13 (Scheme 3).…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Structure–Activity Relationship Study of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor 2-Amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101) and Absolute Configurational Assignment Using Infrared and Vibrational Circular Dichroism Spectroscopy in Combination with ab Initio Hartree–Fock Calculations

Huynh

Shim²,

Bohr³

et al. 2012

J. Med. Chem.

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The excitatory amino acid transporters (EAATs) play essential roles in regulating the synaptic concentration of the neurotransmitter glutamate in the mammalian central nervous system. To date, five subtypes have been identified, named EAAT1–5 in humans, and GLAST, GLT-1, EAAC1, EAAT4, and EAAT5 in rodents, respectively. In this paper, we present the design, synthesis, and pharmacological evaluation of seven 7-N-substituted analogues of UCPH-101/102. Analogue 9 inhibited EAAT1 in the micromolar range (IC50 value 20 μM), whereas analogues 8 and 10 were inactive (IC50 values >100 μM). The diastereomeric pairs 11a/11b and 12a/12b were separated by HPLC and the absolute configuration assigned by VCD technique in combination with ab initio Hartree–Fock calculations. Analogues 11a (RS-isomer) and 12b (RR-isomer) inhibited EAAT1 (IC50 values 5.5 and 3.8 μM, respectively), whereas analogues 11b (SS-isomer) and 12a (SR-isomer) failed to inhibit EAAT1 uptake (IC50 values >300 μM).

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Third-Generation Immucillins: Syntheses and Bioactivities of Acyclic Immucillin Inhibitors of Human Purine Nucleoside Phosphorylase

Cited by 68 publications

References 51 publications

Four generations of transition-state analogues for human purine nucleoside phosphorylase

Four generations of transition-state analogues for human purine nucleoside phosphorylase

Transition State Analogues of Plasmodium falciparum and Human Orotate Phosphoribosyltransferases

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