Mini-Reviews in Medicinal Chemistry, Volume 4, No. 4, 2004
Contents
Pro-Nucleotide Development
and Delivery of Biologically Active Nucleotide Analogues
Executive
Editor: Chris Meier
The Role of Thymidine Kinases in the
Activation of Pyrimidine Nucleoside Analogues
Pp. 341-350
Structural Requirements for Efficient
Phosphorylation of Nucleotide Analogs by Human Thymidylate Kinase Pp. 351-359
Arnon
Lavie and Manfred Konrad
Antiviral Nucleoside Analogs Phosphorylation
by Nucleoside Diphosphate Kinase Pp. 361-369
S.
Gallois-Montbrun, M. Veron and D. Deville-Bonne
Aryloxy Phosphoramidate Triesters as
Pro-Tides Pp. 371-381
Dominique
Cahard, Christopher McGuigan and Jan Balzarini
“Lock-in”-cycloSal-Pronucleotides – A New
Generation of Chemical Trojan Horses? Pp. 383-394
Chris
Meier, Manuel F.H. Ruppel, Dalibor Vukadinovic and Jan Balzarini
SATE Pronucleotide Approaches: An Overview Pp. 395-408
S.
Peyrottes, D. Egron, I. Lefebvre, G. Gosselin, J.-L. Imbach and C. Perigaud
Designing a Pronucleotide Stratagem: Lessons
from Amino Acid Phosphoramidates of Anticancer and Antiviral Pyrimidines Pp. 409-419
Dan
P. Drontle and Carston R. Wagner
Discovery and Validation of a New Family of
Antioxidants: The Aminopyrazine Derivatives Pp. 421-435
M.L.N.
Dubuisson, J.-F. Rees and J. Marchand-Brynaert
Bioactive Carbohydrates and Recently
Discovered Analogues as Chemotherapeutics Pp. 437-459
Tanja
M. Wrodnigg and Friedrich K. (Fitz) Sprenger
Abstracts
[Back to top] The Role of Thymidine Kinases in the
Activation of Pyrimidine Nucleoside Analogues
Ashraf
S. Al-Madhoun, Werner Tjarks and Staffan Eriksson
Deoxynucleoside
analogues need activation by deoxynucleoside kinases to serve as antiviral or
anticancer agents. Here we review the properties of cellular cytoplasmic
thymidine kinase 1, mitochondrial thymidine kinase 2, the multisubstrate
deoxynucleoside kinase from Drosophila melanogaster and Herpes virus 1
thymidine kinase. Important substrate activity relationships will be discussed.
[Back to top] Structural Requirements for Efficient
Phosphorylation of Nucleotide Analogs by Human Thymidylate Kinase
Arnon
Lavie and Manfred Konrad
Successive
phosphorylation of nucleoside analog prodrugs to their triphosphate forms is
required for the pharmacological activity of these compounds in the
chemotherapeutic treatment of viral infections and cancer. Human thymidylate
kinase (TMPK), apart from its essential physiological role in the biosynthesis
of TTP, is also required for the activation of thymidine analogs, such as the
clinically used anti-HIV prodrugs AZT and d4T. This enzyme is rate determining
in the three-step cascade of AZT phosphorylation. Our structural work on human,
yeast and E. coli TMPKs, in conjunction with sequence homology analyses
and biochemical data, has demonstrated that three loops are crucial for the
function of this enzyme: the first is the highly conserved P-loop motif, which
binds and positions the phosphoryl groups of ATP, the second critical loop
contains the DR(Y/H) motif that supplies a catalytic arginine and is also
important for the binding and positioning of the magnesium ion complexed to
ATP, and the third loop is the so-called Lid-region that is a flexible stretch
which closes on ATP when it binds. Modifications of the sugar moieties of
nucleoside monophosphates are shown to exert drastic effects on the enzyme's
conformation and, thus, reduced activity. Our structural work on several TMPKs
has formed the basis for generating mutants of human TMPK that are about 100
times more efficient in phosphorylating AZTMP. These enzyme variants could
potentially be introduced into HIV-targeted cells in order to significantly
improve AZT's antiviral activity.
[Back to top] Antiviral Nucleoside Analogs Phosphorylation
by Nucleoside Diphosphate Kinase
S.
Gallois-Montbrun, M. Veron and D. Deville-Bonne
The reaction of
NDP kinase was studied in vitro with several antiviral derivatives,
using kinetic steady state and presteady state analysis. The enzyme is highly
efficient with natural nucleotides but most of the analogs are slow substrates.
The catalytic efficiency, also related to the affinity of the analog, is mainly
dependent on the presence of a 3'-OH group on the ribose moiety.
[Back to top] Aryloxy Phosphoramidate Triesters as
Pro-Tides
Dominique Cahard, Christopher McGuigan and Jan Balzarini
We herein describe
the development of aryloxy phosphoramidate triesters as an effective pro-tide
motif for the intracellular delivery of charged bio-active antiviral nucleoside
monophosphates. The review covers the discovery of such aryl phosphoramidates,
their mechanism of action and structure-activity relationships. The application
of this strategy to a range of antiviral nucleosides is highlighted.
[Back to top] “Lock-in”-cycloSal-Pronucleotides – A New
Generation of Chemical Trojan Horses?
Chris
Meier, Manuel F.H. Ruppel, Dalibor Vukadinovic and Jan Balzarini
The cycloSal-concept
is one example of a successful nucleotide delivering system (pronucleotide).For
several nucleoside analogues, the cycloSal-approach improved the
antiviral potency and the applicability of the nucleosides could be broadened.
Here, a conceptional extension of the original design of the cycloSalsystem
will be discussed.
[Back to top] SATE Pronucleotide Approaches: An Overview
S.
Peyrottes, D. Egron, I. Lefebvre, G.
Gosselin, J.-L. Imbach and C. Perigaud
This review depicts
in vitro and in vivo results obtained with nucleotide prodrugs
(pronucleotides) bearing S-acyl-2-thioethyl (SATE) groups as
esterase-labile phosphate protections. New developments are illustrated by the
design of mononucleoside mixed phosphoester derivatives leading to the
selective intracellular delivery of the corresponding 5'-mononucleotide through
two different enzyme-mediated activation steps.
[Back to top] Designing a Pronucleotide Stratagem: Lessons
from Amino Acid Phosphoramidates of Anticancer and Antiviral Pyrimidines
Dan
P. Drontle and Carston R. Wagner
Phosphoramidate
pronucleotides have proven to be an effective strategy for the intracellular
delivery of nucleoside 5'-monophosphates. This review will summarize our
efforts to understand the in vitro and in vivo behavior of phosphoramidate
monoesters of 3'-azido-3'-deoxythymidine (AZT), 3'-fluoro-3'- deoxythymidine
(FLT) and 5-fluoro-2'-deoxyuridine (FUdR). Insights drawn from these studies
have proved valuable for the future design of phosphoramidate-based
pronucleotides.
[Back to top] Discovery and Validation of a New Family of
Antioxidants: The Aminopyrazine Derivatives
M.L.N.
Dubuisson, J.-F. Rees and J. Marchand-Brynaert
Coelenteramine
(2-amino-1,4-pyrazine derivative), one of the metabolites of the oxidative
degradation of coelenterazine (imidazolopyrazinone derivative), is endowed with
excellent antioxidative properties towards ROS/RNS, like its mother-compound.
This crucial discovery, made during the study of natural bioluminescent
compounds (luciferins), has stimulated the development of synthetic
aminopyrazine derivatives as new leads in medicinal chemistry in the field of
antioxidant-based therapies. Synthetic approaches, theoretical evaluation,
radical scavenging properties in acellular and cellular tests, and in vivo evaluation
are described, and illustrated with representative aminopyrazines. Tested
compounds were inhibitors of lipid peroxidation and good quenchers of
peroxynitrite. They efficiently protect isolated LDL against radical-induced
damages. They prevent cell constituents (membranes, DNA) against injuries by
various oxidative stressors (UV irradiation, hydroperoxide treatment, oxidized
LDL toxicity). Lastly, aminopyrazines are remarkably active in the
"hamster cheek pouch" assay (in vivo protection against
ischemia-reperfusion damages).
[Back to top] Bioactive Carbohydrates and Recently
Discovered Analogues as Chemotherapeutics
Tanja
M. Wrodnigg and Friedrich K. (Fitz) Sprenger
Infectious diseases such as tuberculosis,
malaria, the “simple flu” or HIV and HBV, are killing more than 50,000 people a
day according to estimations by the World Health Organisation (WHO).
Consequently, the development of biologically active agents in general, such as
antibiotics and chemotherapeutics, is of great importance. Hand in hand with
the understanding of the mechanisms of biological agents, structures carrying
sugar moieties have become increasingly important during the last decades. This
review will cover the most recent developments in the field of new antibiotics
and synthetic agents containing carbohydrates which are active against
tuberculosis and malaria. In addition, compounds having antiviral,
antibacterial and anticancer properties will be examined. Compounds such as
aminoglycosides, iminosugars, carbacycles, nucleosides, and other selected
substance classes will be considered.