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Title: Synthesis of bis-Phosphate Iminoaltritol Enantiomers and Structural Characterization with Adenine Phosphoribosyltransferase

Journal Article · · ACS Chemical Biology
ORCiD logo [1];  [2]; ORCiD logo [2];  [3];  [2]; ORCiD logo [2]
  1. Victoria Univ. of Wellington, Lower Hutt (New Zealand)
  2. Albert Einstein College of Medicine, Bronx, NY (United States)
  3. Victoria Univ. of Wellington, Lower Hutt (New Zealand); The Univ. of Auckland (New Zealand)
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Phosphoribosyl transferases (PRTs) are essential in nucleotide synthesis and salvage, amino acid, and vitamin synthesis. Transition state analysis of several PRTs has demonstrated ribocation-like transition states with a partial positive charge residing on the pentose ring. Core chemistry for synthesis of transition state analogues related to the 5-phospho-α-d-ribosyl 1-pyrophosphate (PRPP) reactant of these enzymes could be developed by stereospecific placement of bis-phosphate groups on an iminoaltritol ring. Cationic character is provided by the imino group and the bis-phosphates anchor both the 1- and 5-phosphate binding sites. We provide a facile synthetic path to these molecules. Cyclic-nitrone redox methodology was applied to the stereocontrolled synthesis of three stereoisomers of a selectively monoprotected diol relevant to the synthesis of transition-state analogue inhibitors. These polyhydroxylated pyrrolidine natural product analogues were bis-phosphorylated to generate analogues of the ribocationic form of 5-phosphoribosyl 1-phosphate. A safe, high yielding synthesis of the key intermediate represents a new route to these transition state mimics. An enantiomeric pair of iminoaltritol bis-phosphates (L-DIAB and D-DIAB) was prepared and shown to display inhibition of Plasmodium falciparum orotate phosphoribosyltransferase and Saccharomyces cerevisiae adenine phosphoribosyltransferase (ScAPRT). As a result, the crystallographic inhibitor binding analysis of L- and D-DIAB bound to the catalytic sites of ScAPRT demonstrates accommodation of both enantiomers by altered ring geometry and bis-phosphate catalytic site contacts.

Research Organization:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC); National Inst. of Health
Grant/Contract Number:
AC02-06CH11357; GM41916; AI127807
OSTI ID:
1506527
Journal Information:
ACS Chemical Biology, Vol. 13, Issue 1; ISSN 1554-8929
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 2 works
Citation information provided by
Web of Science

References (47)

Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance journal December 2016
Transition State Structure of Salmonella typhimurium Orotate Phosphoribosyltransferase † journal January 1996
Transition States of Plasmodium falciparum and Human Orotate Phosphoribosyltransferases journal March 2009
Recycling Nicotinamide. The Transition-State Structure of Human Nicotinamide Phosphoribosyltransferase journal February 2013
Transition State Analogues of Plasmodium falciparum and Human Orotate Phosphoribosyltransferases journal November 2013
Electrophilic Aromatic Selenylation: New OPRT Inhibitors journal June 2010
Total syntheses of hyacinthacine A2 and 7-deoxycasuarine by cycloaddition to a carbohydrate derived nitrone journal March 2003
New Concise Total Synthesis of (+)-Lentiginosine and Some Structural Analogues journal August 2005
(1S,2S,7R,8aS)- and (1S,2S,7S,8aS)-trihydroxyoctahydroindolizine: Two new glycosidase inhibitors by nitrone cycloaddition strategy journal June 1996
Iterative Organometallic Addition to Chiral Hydroxylated Cyclic Nitrones:  Highly Stereoselective Syntheses of α,α‘- and α,α-Substituted Hydroxypyrrolidines journal October 2003
Nucleophilic Additions to Cyclic Nitrones en Route to Iminocyclitols – Total Syntheses of DMDP, 6-deoxy-DMDP, DAB-1, CYB-3, Nectrisine, and Radicamine B journal June 2008
A convenient approach toward the synthesis of enantiopure isomers of DMDP and ADMDP journal January 2009
Synthesis of enantiomerically pure hydroxylated pyrroline N-oxides from d-ribose journal March 2006
One-Pot Synthesis of Cyclic Nitrones and Their Conversion to Pyrrolizidines:  7a- e pi -Crotanecine Inhibits α-Mannosidases journal February 2006
Transition States, Analogues, and Drug Development journal January 2013
Biological Phosphoryl-Transfer Reactions: Understanding Mechanism and Catalysis journal July 2011
‘Irreversible’ slow-onset inhibition of orotate phosphoribosyltransferase by an amidrazone phosphate transition-state mimic journal December 2006
The l-enantiomers of d-sugar-mimicking iminosugars are noncompetitive inhibitors of d-glycohydrolase? journal January 2005
4-C-Me-DAB and 4-C-Me-LAB—enantiomeric alkyl-branched pyrrolidine iminosugars—are specific and potent α-glucosidase inhibitors; acetone as the sole protecting group journal January 2011
Transition state analogue inhibitors of protozoan nucleoside hydrolases journal November 1999
Imino- C -nucleoside Synthesis:  Heteroaryl Lithium Carbanion Additions to a Carbohydrate Cyclic Imine and Nitrone journal March 2004
The risk of mixing dilute hydrogen peroxide and acetone solutions journal March 2012
Fully Stereoselective Nucleophilic Addition to a Novel Chiral PyrrolineN-Oxide: Total Syntheses of (2S,3R)-3-Hydroxy-3-methylproline and Its (2R)-Epimer journal February 2004
Sequential Nucleophilic Addition/Intramolecular Cycloaddition to Chiral Nonracemic Cyclic Nitrones: A Highly Stereoselective Approach to Polyhydroxynortropane Alkaloids journal May 2011
Stereoselective synthesis of novel C-azanucleoside analogues by microwave-assisted nucleophilic addition of sugar-derived cyclic nitrones journal March 2011
Straightforward synthesis of enantiopure 2-aminomethyl and 2-hydroxymethyl pyrrolidines with complete stereocontrol journal February 2005
l-DMDP, l-homoDMDP and their C-3 fluorinated derivatives: synthesis and glycosidase-inhibition journal January 2011
Entropy-Controlled Selectivity in the Vinylation of a Cyclic Chiral Nitrone. An Efficient Route to Enantiopure Polyhydroxylated Pyrrolidines journal February 2001
Tunable Diastereoselection of Biased Rigid Systems by Lewis Acid Induced Conformational Effects: A Rationalization of the Vinylation of Cyclic Nitrones En Route to Polyhydroxylated Pyrrolidines journal August 2010
Kinetic Mechanism of Adenine Phosphoribosyltransferase from Leishmania donovani † journal March 2002
Purine Salvage Pathway in Mycobacterium tuberculosis journal March 2011
Transition-state inhibitors of purine salvage and other prospective enzyme targets in malaria journal July 2013
Synthesis of nitrones by methyltrioxorhenium catalyzed direct oxidation of secondary amines journal August 1996
Synthesis of Nitrones Using the Methyltrioxorhenium/Hydrogen Peroxide System journal January 1996
Methyltrioxorhenium (MTO) journal January 2004
Oxidation ofN,N-Disubstituted Hydroxylamines to Nitrones with Hydrogen Peroxide Catalyzed by Polymer-Supported Methylrhenium Trioxide Systems journal May 2004
Palladium-Catalyzed Coupling Reactions of Thioimidate N-Oxides: Access to α-Alkenyl- and α-Aryl-Functionalized Cyclic Nitrones journal December 2009
One-pot, three-component synthesis of five-membered cyclic nitrones by addition/cyclization/condensation domino reaction journal March 2010
Diastereoselective Synthesis of C3-Quaternary Indolenines Using α,β-Unsaturated N -Aryl Ketonitrones and Activated Alkynes journal April 2012
Synthesis of 2-Alkenyl-1-pyrrolin-1-oxidesand Polysubstituted Nitrones journal January 2003
Synthesis of hydrodipyrrins tailored for reactivity at the 1- and 9-positions journal January 2007
The synthesis of phosphopeptides journal January 2001
Structural Analysis of Adenine Phosphoribosyltransferase from Saccharomyces cerevisiae , journal August 2001
Continuous Fluorescence Assays for Reactions Involving Adenine journal November 2016
Tight binding enantiomers of pre-clinical drug candidates journal September 2015
Phaser crystallographic software journal July 2007
Closed Site Complexes of Adenine Phosphoribosyltransferase fromGiardia lamblia Reveal a Mechanism of Ribosyl Migration journal October 2002

Cited By (2)

The transition to magic bullets – transition state analogue drug design journal January 2018
Regiospecific formation of sugar-derived ketonitrone towards unconventional C -branched pyrrolizidines and indolizidines journal January 2019

Figures / Tables (10)

Figure 1(p. 5)figure Figure 1
Scheme 1(p. 6)figure Scheme 1
Scheme 2(p. 9)figure Scheme 2
Scheme 3(p. 10)figure Scheme 3
Scheme 4(p. 12)figure Scheme 4
Figure 2(p. 13)figure Figure 2
Table 1(p. 14)table Table 1
Figure 3(p. 16)figure Figure 3
Figure 4(p. 18)figure Figure 4
Figure 5(p. 20)figure Figure 5

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
peptides and proteins
transition states
nitrogen compounds
adenine
inhibitors