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Medicinal Chemistry
ISSN: 1573-4064
Medicinal Chemistry
Volume 1, Number 6, November 2005
Contents
Adenosine Phosphonoacetic Acid is Slowly Metabolized
by NDP Kinase Pp.529
Y. Chen, S. Morera, C. Pasti, A. Angusti, N. Solaroli,
M. Véron, J. Janin, S. Manfredini and D. Deville-Bonne
[Abstract] [Purchase
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Investigation into the Interaction of the Phosphoporin
PhoE with Outer Membrane Lipids: Physicochemical Characterization
and Biological Activity Pp.537
J. Andrä, H. de Cock, P. Garidel, J. Howe and K.
Brandenburg
[Abstract] [Purchase
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Competitive Reactions of L-Methionine and 5’-GMP
Towards Platinum (II) Complexes Pp.547
T. Soldatovic, P. Canovic, D. Canovic and Z.D. Bugarcic
[Abstract] [Purchase
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The Role of Copper in Development of Drug Resistance
in Murine Carcinoma Pp.563
S. Majumder, P. Dutta and S. K. Choudhuri
[Abstract] [Purchase
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Isolation of Bioactive Natural Products from Myxomycetes
Pp.575
M. Ishibashi
[Abstract] [Purchase
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Quinaldine Derivatives: Preparation and Biological
Activity Pp.591
J. Jampilek, M. Dolezal, J. Kunes, V. Buchta, L. Silva
and K. Kralova
[Abstract] [Purchase
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8-(Heteroaryl)phenalkyl-1-Phenyl-1,3,8 triazaspiro[4.5]decan-4-ones
as Opioid Receptor Modulators Pp.601
A.D. Jordan, M.J. Orsini, S.A. Middleton, P.J. Connolly,
D.E. Brenneman, K. Pan and A.B. Reitz
[Abstract] [Purchase
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Comparison of Radiohaloanalogues of Meta-Iodobenzylguanidine
(MIBG) for a Combined Gene- and Targeted Radiotherapy Approach
to Bladder Carcinoma Pp.611
N.E. Fullerton, M. Boyd, S.C. Ross, S.L. Pimlott, J. Babich,
D. Kirk, M.R. Zalutsky and R.J. Mairs
[Abstract] [Purchase
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Antitumour Antibiotics with Potent Activity Against
Multidrug Resistant (MDR) Staphylococcus aureus:
A New Approach to Targeting Resistant Bacteria Pp.619
M.A. Casely-Hayford, N.Ortuzar Kerr, E. Smith, S. Gibbons
and M. Searcey
[Abstract] [Purchase
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Resveratrol Enhances UVA-Induced DNA Damage in HaCaT
Human Keratinocytes Pp.629
M. Seve, F. Chimienti, S. Devergnas, M. Aouffen, T. Douki,
J. Chantegrel, J. Cadet and A. Favier
[Abstract] [Purchase
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The Rationale and Development of New Drugs to Treat
HIV Infection Pp.635
J. Stebbing, E. Hatzimichael, M. Bower and A. Winston
[Abstract] [Purchase
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Site- and Cell-Type- Specific Induction of Intestinal
Inducible Nitric Oxide Synthase in a Rat Model of Endotoxemia
Pp.643
T. Takahashi, H. Fujii, H. Shimizu, E. Omori, K. Uehara,
M. Takeuchi, M. Matsumi, M. Yokoyama, R. Akagi and K. Morita
[Abstract] [Purchase
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Review Article
Identification and Evaluation of Molecular Properties
Related to Preclinical Optimization and Clinical Fate Pp.649
J.F. Blake
[Abstract] [Purchase
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Abstracts
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Adenosine Phosphonoacetic Acid is Slowly Metabolized by
NDP Kinase
Y. Chen, S. Morera, C. Pasti, A. Angusti, N. Solaroli,
M. Véron, J. Janin, S. Manfredini and D. Deville-Bonne
NDP kinase catalyzes the last step in the phosphorylation
of nucleotides. It is also involved in the activation by cellular
kinases of nucleoside analogs used in antiviral therapies.
Adenosine phosphonoacetic acid, a close analog of ADP already
proposed as an inhibitor of ribonucleotide reductase, was
found to be a poor substrate for human NDP kinase, as well
as a weak inhibitor with an equilibrium dissociation constant
of 0.6 mM to be compared to 0.025 mM for ADP. The X-ray structure
of a complex of adenosine phosphonoacetic acid and the NDP
kinase from Dictyostelium was determined to 2.0 Å
resolution showing that the analog adopts a binding mode similar
to ADP, but that no magnesium ion is present at the active
site. As ACP may also interfere with other cellular kinases,
its potential as a drug targeting NDP kinase or ribonucleotide
reductase is likely to be limited due to strong side effects.
The design of new molecules with a narrower specificity and
a stronger affinity will benefit from the detailed knowledge
of the complex ACP-NDP kinase.
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Investigation into the Interaction of the Phosphoporin
PhoE with Outer Membrane Lipids: Physicochemical Characterization
and Biological Activity
Jörg Andrä, Hans de Cock, Patrick Garidel,
Jörg Howe and Klaus Brandenburg
Outer membrane pore proteins such as phosphoporin (PhoE)
are important constituents of Gram-negative bacteria such
as Escherichia coli. We have studied the interaction
of PhoE with the membrane-forming lipids phosphatidylethanolamine
(PE) and phosphatidylglycerol (PG) from the inner and lipopolysaccharide
(LPS) from the outer leaflet of the outer membrane. These
investigations comprise functional aspects of the protein:lipid
interaction corresponding to the outer membrane system as
well as the activity of LPS:PhoE complexes in the infected
host after release from the bacterial surface. The interaction
of the lipids PE, PG, and LPS with PhoE was investigated by
analysing molecular groups in the lipids originating from
the apolar region (methylene groups), the interface groups
(ester), and polar groups (phosphates) applying Fourier-transform
infrared spectroscopy (FTIR), and by analysing the phase transition
behaviour of the lipids using FTIR and differential scanning
calorimetry (DSC). The activity of PhoE and LPS:PhoE complexes
was investigated in biological test systems (human mononuclear
cells and Limulus amebocyte lysate assay) and with
phospholipid model membranes using fluorescence resonance
energy transfer spectroscopy (FRET). The results show a strong
influence of PhoE on the mobility of the lipids leading to
a considerable fluidization of the acyl chains of LPS, but
much less to those from phospholipids: PhoE released from
the outer membrane still contains slight contaminations of
LPS, but its strong cytokine-inducing ability in mononuclear
cells, which is not found in the LPS-specific Limulus
amebocyte lysate test, indicates an LPS-independent mechanism
of cell activation.
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Competitive Reactions of L-Methionine and 5’-GMP
Towards Platinum (II) Complexes
Tanja Soldatovic, Predrag Canovic, Dragan Canovic
and Zivadin D. Bugarcic
The complex-formation reactions of the platinum(II) complexes,
[Pt(dien)H2O]2I, [PtCl(dien)]I
and [PtBr(dien)]I (dien is diethylenetriamine)
with some biologically relevant ligands such as inosine (INO),
inosine-5’-monophosphate (5’-IMP), guanosine-5’-monophosphate
(5’-GMP), glutathione (GSH) and L-methionine (S-meth),
were studied by UV-Vis (UV-Visible) spectrophotometry and
1H NMR spectroscopy. Reactions of the [PtCl(dien)]I
with L-methionine were studied in the presence and absence
of 5’-GMP. The rate constants clearly showed a kinetic
preference toward L-methionine. However, competitive reactions
of [PtCl(dien)]I with L-methionine and 5’-GMP
demonstrated initially rapid formation of [Pt(dien)(S-meth)]2I
followed by displacement of L-methionine by 5’-GMP.
In the later stages the concentration of [Pt(dien)(N7-GMP
)]2I is predominant.
The results are analyzed in reference to the anti-tumour activity
of Pt(II) complexes.
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The Role of Copper in Development of Drug Resistance in
Murine Carcinoma
S. Majumder, P. Dutta and S. K. Choudhuri
Multidrug resistance (MDR) is a major obstacle to successful
application of cancer chemotherapy and also a basic problem
in cancer biology. Studies on the molecular basis of MDR have
revealed that a number of proteins over express in multidrug
resistant cells viz., multidrug resistant MDR1 gene product
P-glycoprotein, the multidrug resistance-associated protein
(MRP) and enzymes associated with the glutathione (GSH) metabolism.
Decreased expression or altered activity of topoisomerase
II has also been implicated in MDR. In the present investigation
a number of changes in phase II detoxification parameters
have been noticed in drug resistant cells but the novel aspect
of the present report is the observation that the metal copper
is involved in drug resistance. Although copper plays important
roles in many human and other biological systems and even
in the treatment of cancer but the relation of Cu and drug
resistance has not so far been studied in detailed. The present
report describes the novel findings that the level of copper
increases with the development of drug resistance in Ehrlich
ascites carcinoma and in Lewis lung carcinoma cells and also
in serum of mice bearing drug resistant cancer cells compared
to mice bearing drug sensitive cells; the work indicates the
important aspect of treating drug resistant cancer patients
by lowering Cu level in the cancerous cells and serum prior
to treatmentz
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Isolation of Bioactive Natural Products from Myxomycetes
Masami Ishibashi
The Myxomycetes (true slime molds) are an unusual group
of primitive organisms that may be assigned to one of the
lowest classes of eukaryotes. As their fruit bodies are very
small and it is very difficult to collect much quantity of
slime molds, few studies have been made on the chemistry of
myxomycetes. Cultivation of the plasmodium of myxomycetes
in a practical scale for natural products chemistry studies
is known only for very limited species. Here is described
a review on the recent results on isolation of bioactive natural
products from myxomycetes obtained in these two years in the
laboratories. Spore germination experiments were studied of
hundreds of field-collected myxomycetes collected in Japan
and succeeded in laboratory culture of plasmodia of several
myxomycetes in a practical scale for natural products chemistry
studies. As a result, pyrroloiminoquinones, polyene yellow
pigments, and a peptide lactone from cultured plasmodia of
Didymium iridis, Physarum rigidum and P. melleum,
respectively were isolated. New naphthoquinone pigments, cycloanthranilylprolines,
tyrosine-kinase inhibitory bisindoles, and a cytotoxic triterpenoid
aldehyde lactone were also isolated from field-collected fruit
bodies of Cribraria purpurea, Fuligo candida,
Tubifera casparyi, and Tubifera dimorphotheca,
respectively.
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Quinaldine Derivatives: Preparation and Biological Activity
Josef Jampilek, Martin Dolezal, Jiri Kunes, Vladimir
Buchta, Luis Silva and Katarina Kralova
The series of quinaldine derivatives were prepared, some
of them by means of novel synthetic methods. The synthetic
approach, analytical and spectroscopic data of all newly synthesized
compounds are presented. The prepared compounds were tested
for their in vitro antifungal activity as well as
for their photosynthesis-inhibiting activity (the inhibition
of photosynthetic electron transport in spinach chloroplasts
(Spinacia oleracea L.) and the reduction of chlorophyll
content in Chlorella vulgaris Beij.). Structure-activity
relationships among the chemical structure, the physical properties
and the biological activities of the evaluated compounds are
discussed in the article.
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8-(Heteroaryl)phenalkyl-1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-ones
as Opioid Receptor Modulators
Alfonzo D. Jordan, Michael J. Orsini, Steven A. Middleton,
Peter J. Connolly, Douglas E. Brenneman, Kevin Pan and Allen
B. Reitz
A series of N-biarylalkyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-ones
were prepared and evaluated for biological activity at opioid
(μ,
δ, κ) and opioid receptor like-1 (ORL-1)
G-protein coupled receptors. Substitution on the biaryl moiety
produced enhanced affinity for the μ-opioid
receptor.
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Comparison of Radiohaloanalogues of Meta-Iodobenzylguanidine
(MIBG) for a Combined Gene- and Targeted Radiotherapy Approach
to Bladder Carcinoma
Natasha E. Fullerton, Marie Boyd, Susan C. Ross, Sally
L. Pimlott, John Babich, David Kirk, Michael R. Zalutsky and
Robert J. Mairs
Targeted radiotherapy using radiolabelled meta-iodobenzylguanidine
(MIBG) is a promising treatment option for bladder cancer,
restricting the effects of radiotherapy to malignant cells
thereby increasing efficacy and decreasing morbidity of radiotherapy.
We investigated the efficacy of a combined gene therapy and
targeted radiotherapy approach for bladder cancer using radiolabelled
MIBG. The effectiveness of alternative radiohalogens and alternative
preparations of radiolabelled MIBG for this therapeutic strategy
were compared.
Bladder cancer cells, EJ138, were transfected with a gene
encoding the noradrenaline transporter (NAT) under the control
of a tumour specific telomerase promoter, enabling them to
actively take up radiolabelled MIBG. This resulted in tumour-specific
cell kill. Uptake and retention of radioactivity in cells
transfected with the NAT gene were compared with that obtained
in cells transfected with the sodium iodide symporter (NIS)
gene. Substantially greater uptake and longer retention of
radioactivity in NAT-transfected cells was observed. Carrier-added
(c.a.) [131I]MIBG, no-carrier added (n.c.a.) [131I]MIBG,
and [211At]-labelled benzylguanidine (i.e. [211At]
meta-astatobenzylguanidine (MABG)) were compared with respect
to efficiency of induction of cell kill. N.c.a[131I]MIBG
was more cytotoxic than c.a.[131I]MIBG. However,
the α-emitter [211At]MABG was, by three orders
of magnitude, more effective in causing tumour cell kill than
the β-emitter [131I]MIBG. We conclude that
NAT gene transfer combined with the administration of n.c.a.[131I]MIBG
or [211At]MABG, is a promising novel treatment
approach for bladder cancer therapy.
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Antitumour Antibiotics with Potent Activity Against Multidrug
Resistant (MDR) Staphylococcus aureus: A New Approach to Targeting
Resistant Bacteria
M.A. Casely-Hayford, N.Ortuzar Kerr, E. Smith, S.
Gibbons and M. Searcey
As hospital reports of strains of resistant bacteria are
continuing to increase, a new approach is required for the
identification of small molecules with antibacterial activity.
Natural products that bind covalently to their biological
target have been largely unexplored, although in the field
of cancer chemotherapy, such molecules have been shown to
counter resistance developed through efflux mechanisms. The
azinomycins are potent antitumour agents that alkylate DNA
and one of the natural products, compound 1, is a mono-alkylator
that has been reported to retain potent antitumour activity.
All four diastereomers of 1 were synthesized via
a route involving late stage introduction of the epoxide stereocentre
and separation of the resulting compounds. A non-alkylating
analogue and a potential alkylator that cannot intercalate
were also made. All four diastereomers are potent antibacterial
agents in cell lines containing efflux-based resistance mechanisms.
MIC values in the range of 0.25–1.0 μg/ml
were observed. Comparison with the antitumour activity of
the compounds suggests that the antibacterial activity stems
from a similar mechanism of action involving DNA alkylation.
As the ultimate molecular target of the azinomycins is unknown,
bacterial strains may represent an interesting route for the
discovery of the downstream mechanisms affected by DNA alkylation.
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Resveratrol Enhances UVA-Induced DNA Damage in HaCaT Human
Keratinocytes
M. Seve, F. Chimienti, S. Devergnas, M. Aouffen, T.
Douki, J. Chantegrel, J. Cadet and A. Favier
Resveratrol, a polyphenolic phytoalexin, is a very effective
antioxidant that also exhibits strong antiproliferative and
anti-inflammatory properties. Recent studies have provided
support for the use of resveratrol in human cancer chemoprevention,
in combination with either chemotherapeutic drugs or cytotoxic
factors for a most efficient treatment of drug refractory
tumor cells. Resveratrol is also widely used in topical preparations,
as a chemoprotective compound against development of several
cutaneous disorders, including skin cancer. Nevertheless,
the combined effect of resveratrol and UVA irradiation on
cellular toxicity and DNA damage has never been assessed.
The aim of this work was to investigate the effect of resveratrol
on cell fate in immortalized human keratinocytes HaCaT cells.
The results indicated that resveratrol potentiates the production
of significant amounts of 8-oxo-7,8-dihydro-2'-deoxyguanosine
in UVA-irradiated genomic DNA. Moreover, the combination of
resveratrol with UVA significantly enhances the induction
of DNA strand breaks and cell death in HaCaT keratinocytes.
The conclusion is a potential hazardous effect of topical
application of resveratrol, particularly on regions exposed
to sunlight.
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The Rationale and Development of New Drugs to Treat
HIV Infection
Justin Stebbing, Eleftheria Hatzimichael, Mark Bower and Alan
Winston
Fewer than one million HIV infected individuals are currently
receiving antiretroviral therapy. Present antiretroviral therapy
costs between $10,000 and $20,000 per year, which provides
excellent value for money in developed countries with a cost
of about $10,000 per life year saved; this compares very favourably
with other therapies in chronic use. Recent studies have demonstrated
a dramatic decline in HIV and AIDS related morbidity and mortality
across developed countries and these reductions have been
sustained since the introduction of highly active antiretroviral
therapy (HAART) since 1996. The use of HAART has been associated
with specific toxicities related to the drug class, problems
with adherence with the subsequent emergence of viral isolates
and resistance associated mutations. The replacement of older
therapies with newer drugs that avoid cross resistance even
within the same class of antiretroviral, represents a new
hope in retroviral targeting.
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Site- and Cell-Type- Specific Induction of Intestinal
Inducible Nitric Oxide Synthase in a Rat Model of Endotoxemia
T. Takahashi, H. Fujii, H. Shimizu, E. Omori, K. Uehara, M.
Takeuchi, M. Matsumi, M. Yokoyama, R. Akagi and K. Morita
The intestine is one of the major organs that are involved
in sepsis. The inducible isoform of nitric oxide synthase
(iNOS) is known to play a critical role in the pathogenesis
of septic tissue injury by generating excess amount of nitric
oxide (NO) in response to cytokines and endotoxin. In this
study, we examined changes in gene expression of iNOS in various
regions of the intestine as well as the distribution of iNOS
protein in the intestinal cells in a rat model of endotoxemia
produced by intraperitoneal injection of lipopolysaccharide
(LPS; 10 mg/kg). While iNOS mRNA was undetectable in the intestine
of untreated control animals, it underwent marked induction
following LPS treatment. Induction of iNOS mRNA in the ileum
was marked and biphasic, while it was also marked but monophasic
in the jejunum. The induction of iNOS mRNA was maximal in
the ileum. The administration of interleukin-6 (IL-6) upregulated
intestinal iNOS gene expression specifically in the ileum.
Consistent with enhanced iNOS gene expression, iNOS protein
was markedly expressed in the ileum after LPS treatment, exclusively
in the mucosal epithelium both at crypt and villus cells,
although more prominently in the former. These findings suggested
that intestinal iNOS expression was upregulated both at transcriptional
and protein levels not only in a site-specific, but also in
a cell type-specific manner in a rat model of endotoxemia,
possibly through increasing serum IL-6 levels. Differential
regulation of iNOS expression along the longitudinal and crypt-villus
axes of the gut might be a determinant of the pattern of sepsis-induced
intestinal damage.
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Identification and Evaluation of Molecular Properties
Related to Preclinical Optimization and Clinical Fate
James F. Blake
The economic case for fundamental changes that are required
to ensure long term viability of the pharmaceutical industry
demands a close look at which compounds are advanced into
clinical development. This perspective will cover recent efforts
that have had the greatest influence on defining the optimal
range of physical properties of compounds that are intended
to act as human therapeutic agents. Our focus will be on models
and properties that are most amenable to change via
synthetic design, are potentially fixable in the lead optimization
process, and have the greatest impact on overall attrition
in clinical development. In particular, we will examine the
optimal physicochemical properties for oral absorption based
on solubility, permeability, and a few easily computed parameters.
Additionally, the fate of compounds that have entered clinical
trials provides a compelling case for adhering to the defined
properties ranges. Finally, emerging data suggests that there
has been a shift in the leading causes of compound attrition,
and attention should now be focused on building toxicological
models to guide drug discovery efforts.
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