Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 5, Number 13, 2005
Contents
Nucleoside and Nucleotide Therapeutics:
Recent Targets in Medicinal Chemistry
Guest Editor: Claire Simons
Editorial Pp.1189
Recent Advances in Antiviral Nucleoside and Nucleotide
Therapeutics Pp.1191
Claire Simons, Qinpei Wu and Thet Thet Htar
[Abstract]
Mitochondrial Thymidine Kinase Inhibitors
Pp.1205
María-Jesús Pérez-Pérez, Ana-Isabel
Hernández, Eva-María Priego, Fátima Rodríguez-Barrios,
Federico Gago, María-José Camarasa and Jan Balzarini
[Abstract]
MraY Inhibitors as Novel Antibacterial Agents Pp.1221
Christophe Dini
[Abstract]
Transition States and Inhibitors of the Purine Nucleoside
Phosphorylase Family Pp.1237
Erika A. Taylor Ringia and Vern L. Schramm
[Abstract]
PNP Anticancer Gene Therapy Pp.1259
Yang Zhang, William B. Parker, Eric J. Sorscher and Steven
E. Ealick
[Abstract]
Purine Derivatives as Ligands for A3 Adenosine
Receptors Pp.1275
Bhalchandra V. Joshi and Kenneth A. Jacobson
[Abstract]
Abstracts
[Back to top]
Editorial
Nucleoside And Nucleotide Therapeutics: Recent Targets In
Medicinal Chemistry
The field of nucleoside/nucleotide therapeutics is a challenging
area of research owing to the combination of carbohydrate,
heterocyclic and phosphate chemistry, all of which have their
own peculiar requirements of synthesis, stereochemistry and
handling. However this combination results in a diverse area
with respect to drug structure and drug target, resulting
in an array of clinical applications. Nucleoside therapeutics
were established in the 1960s with the naturally occurring
nucleoside antibiotics, e.g. showdomycin and pyrazofurin,
displaying potent antibacterial and anticancer activities.
The advent of HIV/AIDS in the 1980s saw an explosion of interest
in nucleoside/nucleotides as inhibitors after the licensing
of the nucleoside reverse transciptase inhibitors AZT, ddC,
ddI and d4T. This increased interest has seen a range of sugar
and base modifications achieved using elegant methodology.
Nucleosides and nucleotides have become synonymous with antiviral
therapy and the first review documents recent progress in
this field. A greater understanding of the viral genome/life
cycle, epidemiology and pathogenesis of viral infections,
and the mechanism of action and mechanism of resistance to
described antiviral agents, has enabled the advancement of
antiviral therapeutics. The development of acyclic, carbocyclic
and L-nucleosides continues to generate potent antiviral agents,
with the D-nucleosides containing substantially modified sugar,
e.g. entecavir and cyclopropavir, and/or heterocyclic
base moieties, e.g. ring–expanded nucleosides
(RENs) and bicyclic nucleoside analogues (BCNAs). Very promising
results have been shown with third generation antisense oligonucleotides,
antisense chimeric locked nucleic acid (LNA), short interfering
(si)RNA and antisense peptide nucleic acid (PNA). Further
development, leading to clinical application of the nucleotide/oligonucleotide
therapeutics, is concerned with the development of prodrug
technology, efficient delivery systems and modifications to
improve stability.
A key goal in the design of nucleoside/nucleotide drugs is
limited toxicity. Mitochondrial toxicity is associated with
prolonged treatments with nucleoside derivatives (e.g.
AZT and FIAU); implicated in mitochondrial toxicity is mitochondrial
thymidine kinase (TK-2), an enzyme instrumental in the activation
of deoxynucleoside analogues with biological and therapeutic
properties to their corresponding deoxynucleoside monophosphates.
The second review describes recent literature covering different
aspects of TK-2 including kinetic and binding studies as well
as inhibitor design. TK-2 inhibitors have potential as valuable
tools to unravel the role of TK-2 in mitochondrial dNTP pools
and homeostasis, and may also help to clarify the contribution
of TK-2-catalyzed phosphorylation of nucleoside derivatives
with mitochondrial toxicity.
An exciting target in antibacterial therapy is MraY, an enzyme
involved in the final steps of the cytoplasmic synthesis of
peptidoglycan, and is the subject of the third review. The
major source of future development of MurY inhibitors resides
in the nucleoside based inhibitors group. This group has been
subdivided into classes: Tunicamycins, Ribosamino-uridines,
Uridylpeptides and Capuramycins. Analysis of the pharmacological
behaviour observed of compounds within these classes, shows
that broad-spectrum antibacterial activity, including relevant
resistant strains and in vivo efficacy without toxicity
are achievable. Among them, Caprazamycins, Muraymycins, Riburamycins
and Capuramycins present the most promising profiles, with
activity against Gram-positive bacteria (MRSA and/or MSSA)
and Mycobacterium spp. observed. Further optimization
of their physico-chemical properties, while maintaining a
good level of activity against MraY, should result in these
outstanding antibacterial nucleosides entering the clinic.
The fourth and fifth reviews are both concerned with purine
nucleoside phosphorylase (PNP), an enzyme involved in the
catabolism and recycling of nucleosides. One review describes
the development of transition state analogue inhibitors as
novel nucleoside antibiotics whilst the second describes the
progress in the development of E. coli PNP anticancer
gene therapy. The transition state inhibitor approach is based
on the prediction that chemically stable analogues of a transition
state complex are able to convert the energy of enzymatic
rate acceleration (kcat/knon) into binding
energy. Transition state (TS) analogues developed for PNP
exhibit differential inhibition specificity for bovine, human,
and malarial PNPs, for which transition state structures have
been reported, and Mycobacterium tuberculosis. Transition
state determination and the subsequent development of transition
state analogue inhibitors, which help to elucidate the geometric
and electronic conformations that are necessary to fully implement
design of TS analogues, are described with impressive inhibitory
activity obtained for the Immucillin derivatives, which display
picomolar slow-onset dissociation constants.
Escherichia coli PNP catalyzes the cleavage of 9-(2-deoxy-β-D-ribofuranosyl)-6-methylpurine
(MeP-dR), while human PNP does not. MeP-dR is well tolerated
while the cleavage product, 6-methylpurine (MeP), is highly
cytotoxic. This clinical profile allows an anticancer gene
therapy strategy in which solid tumors are transfected with
the gene for E. coli PNP. Tumor cells expressing
E. coli PNP will liberate MeP and be killed. Furthermore,
MeP released from the cell via the purine transport system
will enter nearby cells, resulting in bystander killing of
tumor cells. The review describes the progress in the development
of E. coli PNP anticancer gene therapy, the structural
basis for activity of nucleoside phosphorylases and future
directions for the development of activating enzymes for suicide
gene therapy is also reviewed.
The final review describes the development of purine derivatives
as ligands for A3 adenosine receptors. Selective
agonists and antagonists for A3 adenosine receptors
(ARs) are being explored for the treatment of a variety of
disorders, including brain and heart ischemic conditions,
cancer, and rheumatoid arthritis. Highly selective ligands
have been designed, using both empirical approaches and a
semi-rational approach based on molecular modeling. Key structural
features determining A3AR interaction and conformational
preferences of the ribose moiety are described, with a series
of ring constrained (N)-methanocarba 5'-uronamide derivatives
reported to be highly selective A3AR agonists.
I am indebted to the eminent researchers at the forefront
of research in the nucleoside/nucleotide field who generously
gave their time and knowledge in contributing to this special
issue, which highlights the continuing value, clinical potential
and therapeutic diversity of this field of research.
Dr. Claire Simons
Medicinal Chemistry Division,
Welsh School of Pharmacy,
Cardiff University,
King Edward VII Avenue,
Cardiff CF10 3XF,
UK
[Back to top]
Recent Advances in Antiviral Nucleoside and Nucleotide
Therapeutics
Claire Simons, Qinpei Wu and Thet Thet Htar
Recent developments in nucleoside/nucleotide therapeutics
and antiviral drug targets are described covering progress
in the development of nucleoside/nucleotide mimetics for the
treatment of influenza virus, human immunodeficiency virus
type 1, hepatitis B and C virus, herpes virus infections;
including herpes simplex virus, cytomegalovirus and varicella
zoster virus infections, and the highly pathogenic poxviruses
(variola, vaccinia and mokey pox) and filoviruses (Ebola and
Marburg).
[Back to top]
Mitochondrial Thymidine Kinase Inhibitors
María-Jesús Pérez-Pérez, Ana-Isabel
Hernández, Eva-María Priego, Fátima Rodríguez-Barrios,
Federico Gago, María-José Camarasa and Jan Balzarini
Mitochondrial thymidine kinase or TK-2 belongs to the family
of mammalian deoxynucleoside kinases (dNKs) that catalyze
the phosphorylation of deoxynucleosides to their corresponding
deoxynucleoside monophosphates by γ-phosphoryl
transfer of ATP. These enzymes are instrumental in the activation
of deoxynucleoside analogues with biological and therapeutic
properties. Moreover, dNKs are fundamental to maintain dNTPs
pools for DNA synthesis and repair. TK-2 has a mitochondrial
localization and is the only thymidine kinase that is physiologically
active in non-proliferating and resting cells. Several recent
investigations point to an important role of TK-2 in the maintenance
of mitochondrial dNTPs pools. Indeed, mutations in the gene
encoding TK-2 have been associated with mitochondrial DNA
(mtDNA) depletion that mostly affects skeletal muscle. Moreover,
TK-2 has been suggested to be implicated in mitochondrial
toxicity associated to prolonged treatments with nucleoside
analogues (i.e AZT for the treatment of AIDS patients). In
this scenario, TK-2 inhibitors could be a useful tool to further
clarify both the physiological role of TK-2 in the maintenance
of mitochondrial dNTP pools, and the possible contribution
of TK-2 to the mitochondrial toxicity of pyrimidine nucleoside
analogues. In the present article we review the most recent
literature covering different aspects of TK-2 as well as published
TK-2 inhibitors, with special emphasis on acyclic nucleoside
analogues that have been described by our research groups
and whose prototype compound is 1-[(Z)-4-(triphenylmethoxy)-2-butenyl]thymine.
[Back to top]
MraY Inhibitors as Novel Antibacterial Agents
Christophe Dini
MraY presents all necessary biological requirements to be
considered as a target of interest for the discovery of novel
antibacterials. Furthermore, several inhibitors aimed at this
enzyme have been discovered. Amphomycin, which is currently
used as a topical antibacterial in the veterinary industry
is one of them, but the major source of future developments
resides in the nucleoside based inhibitors group. This group
has been subdivided into classes: Tunicamycins, Ribosamino-uridines,
Uridylpeptides and Capuramycins. Analysis of pharmacological
behaviours observed with several compounds within these classes,
shows that broad-spectrum antibacterial activity, including
relevant resistant strains and in vivo efficacy without toxicity
are achievable. Among them, Caprazamycins, Muraymycins, Riburamycins
and Capuramycins present the most promising profiles.
[Back to top]
Transition States and Inhibitors of the Purine Nucleoside
Phosphorylase Family
Erika A. Taylor Ringia and Vern L. Schramm
Purine nucleoside phosphorylase (PNP), an enzyme involved
in the catabolism and recycling of nucleosides, is under investigation
for the development of novel antibiotics. One method used
for the design of inhibitors is transition state analysis.
Chemically stable analogues of a transition state complex
are predicted to convert the energy of enzymatic rate acceleration
(kcat/knon) into binding energy. Transition
state structures have been reported for the bovine (Bos taurus),
human (Homo sapiens), and malarial (Plasmodium falciparum)
PNPs. All three enzymes proceed through SN1-like
mechanisms and have transition states with substantial ribooxocarbenium
ion character. Bovine PNP proceeds through an early SN1-like
transition state, whereas the human and malarial PNPs proceed
through more dissociative transition state. Transition state
analogues developed for PNP exhibit differential inhibition
specificity for these three enzymes based upon their distinct
reaction rates (kcat), mechanisms, and substrate
specificity. The most powerful inhibitors of these three enzymes
have picomolar dissociation constants, two of which are Immucillin-H
and DADMe-Immucillin-H. MT-Immucillin-H was also developed
as a specific inhibitor for P. falciparum PNP by virtue of
its unique utilization of 5’-methylthio substrates.
Although the transition state for tuberculosis (Mycobacterium
tuberculosis) PNP is yet to be determined, inhibition values
support a mechanism with a dissociative transition state like
those of its human and plasmodial counterparts. Comparison
of the transition states and substrate specificity of various
PNPs permits the design of species-specific inhibitors for
use as therapeutic agents.
[Back to top]
PNP Anticancer Gene Therapy
Yang Zhang, William B. Parker, Eric J. Sorscher and Steven
E. Ealick
Escherichia coli purine nucleoside phosphorylase (PNP) catalyzes
the cleavage of 9-(2-deoxy-β-D-ribofuranosyl)-6-methylpurine
(MeP-dR), while human PNP does not. MeP-dR is well tolerated
while the cleavage product, 6-methylpurine (MeP), is highly
cytotoxic. This clinical profile suggests an anticancer gene
therapy strategy in which solid tumors are transfected with
the gene for E. coli PNP. Tumor cells expressing E. coli PNP
will liberate MeP and be killed. Furthermore, MeP released
from the cell via the purine transport system will enter nearby
cells, resulting in bystander killing of tumor cells. To reduce
toxicity resulting from activation of MeP-dR by intestinal
tract flora, we redesigned the E. coli PNP active site to
cleave prodrugs that are not cleaved by wild type E. coli
PNP. It is possible that the variation of substrate specificity
among enzymes that cleave nucleosides will have broader application
in the gene therapy approach to prodrug activation. Here we
review progress in the development of E. coli PNP anticancer
gene therapy. We also review the structural basis for activity
of nucleoside phosphorylases and suggest future directions
for the development of activating enzymes for suicide gene
therapy.
[Back to top]
Purine Derivatives as Ligands for A3 Adenosine
Receptors
Bhalchandra V. Joshi and Kenneth A. Jacobson*
Selective agonists and antagonists for A3 adenosine
receptors (ARs) are being explored for the treatment of a
variety of disorders, including brain and heart ischemic conditions,
cancer, and rheumatoid arthritis. This review covers both
the structure activity relationships of nucleoside agonist
ligands and selected antagonists acting at this receptor and
the routes of synthesis. Highly selective agonists have been
designed, using both empirical approaches and a semi-rational
approach based on molecular modeling. The prototypical A3
agonists IB-MECA 10 and the more receptor-subtype-selective
Cl-IB-MECA 11, both of which have affinity in binding to the
receptor of ~ 1 nM, have been used widely as pharmacological
probes in the elucidation of the physiological role of this
receptor. In addition to the exploration of the effects of
structural modification of the adenine and ribose moieties
on A3AR affinity, the effects of these structural
changes on the intrinsic efficacy have also been studied in
a systematic fashion. Key structural features determining
A3AR interaction include the N6-benzyl
group, 2-position substitution such as halo, substitution
of ribose (e.g., the (N)-methanocarba ring system, various
2'- and 3'-substitutions and 4'-thio substitution of oxygen).
Conformational studies of the ribose moiety and its equivalents
indicate that the ring oxygen is not required and the North
(N) ring conformation is preferred in binding to the A3AR.
Using these observations, a series of ring constrained (N)-methanocarba
5'-uronamide derivatives was recently reported to be highly
selective A3AR agonists, the most notable amongst
them was MRS3558 113 having a Ki value in binding to the human
A3 receptor of 0.3 nM.
|
