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Literature DB >> 19170524

Third-generation immucillins: syntheses and bioactivities of acyclic immucillin inhibitors of human purine nucleoside phosphorylase.

Keith Clinch¹, Gary B Evans, Richard F G Fröhlich, Richard H Furneaux, Peter M Kelly, Laurent Legentil, Andrew S Murkin, Lei Li, Vern L Schramm, Peter C Tyler, Anthony D Woolhouse.

Abstract

ImmH (1) and DADMe-ImmH (2) are potent inhibitors of human purine nucleoside phoshorylase (PNP), developed by us and currently in clinical trials for the treatment of a variety of T-cell related diseases. Compounds 1 and 2 were used as templates for the design and synthesis of a series of acyclic immucillin analogues (8-38) in order to identify simplified alternatives to 1 and 2. SerMe-ImmG (8) and DATMe-ImmG (9) displayed the lowest inhibition constants of 2.1 and 3.4 pM, respectively, vs PNP. It was postulated that the flexible natures of 8 and 9 enabled them to adopt conformations resembling those of 1 and 2 within the active site of PNP and that the positioning of two hydroxyl groups was critical for picomolar activity. SerMe-ImmH (10, K(d) = 5.2 pM) was shown to be orally available in mice with a long biological residence time on blood PNP.

Entities: CellLine Chemical Disease Gene Species

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Year: 2009 PMID： 19170524 PMCID： PMC2698043 DOI： 10.1021/jm801421q

Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446

36 in total

Review 1. Enzymatic transition states: thermodynamics, dynamics and analogue design.

Authors: Vern L Schramm
Journal: Arch Biochem Biophys Date: 2005-01-01 Impact factor: 4.013

2. Energetic mapping of transition state analogue interactions with human and Plasmodium falciparum purine nucleoside phosphorylases.

Authors: Andrzej Lewandowicz; Erika A Taylor Ringia; Li-Min Ting; Kami Kim; Peter C Tyler; Gary B Evans; Olga V Zubkova; Simon Mee; Gavin F Painter; Dirk H Lenz; Richard H Furneaux; Vern L Schramm
Journal: J Biol Chem Date: 2005-06-16 Impact factor: 5.157

3. A highly efficient organocatalyst for direct aldol reactions of ketones with aldehydes [corrected].

Authors: Zhuo Tang; Zhi-Hua Yang; Xiao-Hua Chen; Lin-Feng Cun; Ai-Qiao Mi; Yao-Zhong Jiang; Liu-Zhu Gong
Journal: J Am Chem Soc Date: 2005-06-29 Impact factor: 15.419

4. Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine.

Authors: G B Elion; P A Furman; J A Fyfe; P de Miranda; L Beauchamp; H J Schaeffer
Journal: Proc Natl Acad Sci U S A Date: 1977-12 Impact factor: 11.205

5. Novel acyclonucleotides: synthesis and antiviral activity of alkenylphosphonic acid derivatives of purines and a pyrimidine.

Authors: M R Harnden; A Parkin; M J Parratt; R M Perkins
Journal: J Med Chem Date: 1993-05-14 Impact factor: 7.446

6. One-third-the-sites transition-state inhibitors for purine nucleoside phosphorylase.

Authors: R W Miles; P C Tyler; R H Furneaux; C K Bagdassarian; V L Schramm
Journal: Biochemistry Date: 1998-06-16 Impact factor: 3.162

7. Synthesis of a transition state analogue inhibitor of purine nucleoside phosphorylase via the Mannich reaction.

Authors: Gary B Evans; Richard H Furneaux; Peter C Tyler; Vern L Schramm
Journal: Org Lett Date: 2003-10-02 Impact factor: 6.005

8. Nucleoside-phosphorylase deficiency in a child with severely defective T-cell immunity and normal B-cell immunity.

Authors: E R Giblett; A J Ammann; D W Wara; R Sandman; L K Diamond
Journal: Lancet Date: 1975-05-03 Impact factor: 79.321

9. Synthesis of second-generation transition state analogues of human purine nucleoside phosphorylase.

Authors: Gary B Evans; Richard H Furneaux; Andrzej Lewandowicz; Vern L Schramm; Peter C Tyler
Journal: J Med Chem Date: 2003-11-20 Impact factor: 7.446

Review 10. Acyclovir: discovery, mechanism of action, and selectivity.

Authors: G B Elion
Journal: J Med Virol Date: 1993 Impact factor: 2.327

27 in total

1. Acyclic immucillin phosphonates: second-generation inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase.

Authors: Keith Z Hazleton; Meng-Chiao Ho; Maria B Cassera; Keith Clinch; Douglas R Crump; Irving Rosario; Emilio F Merino; Steve C Almo; Peter C Tyler; Vern L Schramm
Journal: Chem Biol Date: 2012-06-22

Review 2. Enzymatic transition states, transition-state analogs, dynamics, thermodynamics, and lifetimes.

Authors: Vern L Schramm
Journal: Annu Rev Biochem Date: 2011 Impact factor: 23.643

3. Oligonucleotide transition state analogues of saporin L3.

Authors: Jennifer M Mason; Hongling Yuan; Gary B Evans; Peter C Tyler; Quan Du; Vern L Schramm
Journal: Eur J Med Chem Date: 2016-10-27 Impact factor: 6.514

4. Synthesis and evaluation of eight- and four-membered iminosugar analogues as inhibitors of testicular ceramide-specific glucosyltransferase, testicular β-glucosidase 2, and other glycosidases.

Authors: Jae Chul Lee; Subhashree Francis; Dinah Dutta; Vijayalaxmi Gupta; Yan Yang; Jin-Yi Zhu; Joseph S Tash; Ernst Schönbrunn; Gunda I Georg
Journal: J Org Chem Date: 2012-03-20 Impact factor: 4.354

Review 5. Computational methods for de novo protein design and its applications to the human immunodeficiency virus 1, purine nucleoside phosphorylase, ubiquitin specific protease 7, and histone demethylases.

Authors: M L Bellows; C A Floudas
Journal: Curr Drug Targets Date: 2010-03 Impact factor: 3.465