| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 17, Number 17, 2010
Contents
Editor’s Choice
Antibodies in Single-Chain Format Against
Tumour-Associated Antigens: Present and Future Applications
Pp. 1730-1755
L. Accardi and P. Di Bonito
[Abstract] [Purchase
Article] [PMID: 20345346 PubMed - indexed for MEDLINE]
Flavonoids Influence Epigenetic-Modifying
Enzyme Activity: Structure-Function Relationships and the
Therapeutic Potential for Cancer Pp. 1756-1768
E.R. Gilbert and D. Liu
[Abstract] [Purchase
Article] [PMID: 20345345 PubMed - indexed for MEDLINE]
Contributions of Computational Chemistry and Biophysical Techniques
to Fragment-Based Drug Discovery Pp. 1769-1794
Rafael Gozalbes, Rodrigo J. Carbajo and Antonio Pineda-Lucena
[Abstract]
[Purchase
Article] [PMID: 20345344 PubMed - indexed for MEDLINE]
Drug-Membrane Interactions: Significance for Medicinal
Chemistry Pp. 1795-1809
M. Lúcio, J.L.F.C. Lima and S. Reis
[Abstract]
[Purchase
Article] [PMID: 20345343 PubMed - indexed for MEDLINE]
Structure-Activity Relationship of Quaternary Acetylcholinesterase
Inhibitors – Outlook for Early Myasthenia Gravis Treatment
Pp. 1810-1824
M. Komloova, K. Musilek, M. Dolezal, F. Gunn-Moore
and K. Kuca
[Abstract] [Purchase
Article] [PMID: 20345342 PubMed - indexed for MEDLINE]
Tacrine Derivatives and Alzheimer’s Disease
Pp. 1825-1838
V. Tumiatti, A. Minarini, M.L. Bolognesi,
A. Milelli, M. Rosini and C. Melchiorre
[Abstract]
[Purchase
Article] [PMID: 20345341 PubMed - indexed for MEDLINE]
Clinical Impact of the Detection of BRAF Mutations
in Thyroid Pathology: Potential Usefulness as Diagnostic,
Prognostic and Theragnostic Applications Pp.
1839-1850
Sandra Lassalle, Véronique Hofman, Marius Ilie, Catherine
Butori, Alexandre Bozec, José Santini, Philippe Vielh
and Paul Hofman
[Abstract] [Purchase
Article] [PMID: 20345340 PubMed - indexed for MEDLINE]
New Drug Delivery Systems in Inflammatory Bowel Disease:
MMXTM and Tailored Delivery
to the Gut Pp. 1851-1857
G. Fiorino, W. Fries, S.A. De La Rue, A.C. Malesci, A. Repici
and S. Danese
[Abstract]
[Purchase
Article] [PMID: 20353384 PubMed - indexed for MEDLINE]
Abstracts
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[Purchase
Article] [PMID: 20345346 PubMed - indexed for MEDLINE]
Antibodies in Single-Chain Format Against Tumour-Associated
Antigens: Present and Future Applications
L. Accardi and P. Di Bonito
The recombinant antibodies in single-chain format (scFv) have
found broad applications in both therapeutic and diagnostic
fields. Tumour-associated antigens (TAAs) are proteins or
other molecular species expressed in a specific tumour type,
that can be targeted for diagnostic and immunotherapy purposes.
The possibility of obtaining highly selective and efficacious
scFvs makes them appropriate tools to target TAAs. The approach
utilised for targeting depends on the nature of TAAs and their
cell localisation. Tumour antigens displayed on the cell surface
can be recognised by scFvs coupled to radioisotopes, toxins
and enzymes to be used in cancer diagnosis and therapy. Intracellular
tumour antigens can be targeted by scFvs expressed as “intracellular
antibodies”. This review reports the existing scFv-based
formats, hints of their generation and pharmacokinetics, and
a description of the most promising TAAs. It also provides
an update of in vitro, preclinical and clinical studies
using scFvs against TAAs for cancer diagnosis and treatment,
with their merits and limits.
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Article] [PMID: 20345345 PubMed - indexed for MEDLINE]
Flavonoids Influence Epigenetic-Modifying Enzyme Activity:
Structure-Function Relationships and the Therapeutic Potential
for Cancer
E.R. Gilbert and D. Liu
Epigenetic modifications result in heritable changes in gene
expression without changes to the DNA sequence. The most common
forms of epigenetic regulation of gene expression are DNA
methylation and histone acetylation or methylation, all of
which are associated with chromatin remodeling. Results from
recent studies suggest that epigenetic changes are some of
the primary contributory factors of tumor-suppressor gene
silencing in cancer cells. Compounds that target epigenetic
regulators in the body may represent an attractive target
for chemoprevention. Flavonoids are polyphenolic phytochemicals
that exert a multitude of beneficial effects on human health.
In recent years, isoflavones, flavonols and catechins have
received much attention due to their ability to influence
activity of chromatin-modifying enzymes. Epigal-locatechin-3-gallate,
for example, was shown to inhibit activity of histone acetyltransferase
and DNA methyltransferase. In this review, we will highlight
the structure-function relationship between flavonoids and
epigenetic modifications, with an emphasis on the isoflavones,
flavonols and catechins, and their potential as anti-cancer
agents in this regard.
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Article] [PMID: 20345344 PubMed - indexed for MEDLINE]
Contributions of Computational Chemistry and Biophysical Techniques
to Fragment-Based Drug Discovery
Rafael Gozalbes, Rodrigo J. Carbajo and Antonio Pineda-Lucena
In the last decade, fragment-based drug discovery (FBDD) has
evolved from a novel approach in the search of new hits to
a valuable alternative to the high-throughput screening (HTS)
campaigns of many pharmaceutical companies. The increasing
relevance of FBDD in the drug discovery universe has been
concomitant with an implementation of the biophysical techniques
used for the detection of weak inhibitors, e.g. NMR, X-ray
crystallography or surface plasmon resonance (SPR). At the
same time, computational approaches have also been progressively
incorporated into the FBDD process and nowadays several computational
tools are available. These stretch from the filtering of huge
chemical data-bases in order to build fragment-focused libraries
comprising compounds with adequate physicochemical properties,
to more evolved models based on different in silico
methods such as docking, pharmacophore modelling, QSAR and
virtual screening. In this paper we will review the parallel
evolution and complementarities of biophysical techniques
and computational methods, providing some representative examples
of drug discovery success stories by using FBDD.
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Article] [PMID: 20345343 PubMed - indexed for MEDLINE]
Drug-Membrane Interactions: Significance for Medicinal
Chemistry
M. Lúcio, J.L.F.C. Lima and S. Reis
Generally drugs can act on the level of different biological
membranes as well as inside the cells that are limited by
membranes. Even in the latter situation, drugs must still
interact with the membrane in order to cross it and reach
their targets. For this reason, the efficiency of drugs to
interact with the membranes constitutes one of the most important
pharmacological features playing an essential role in their
biological activity.
Membranes are the gathering place of many proteins and lipids,
and are the structures where most cellular activities occur.
Although drugs bind to proteins and regulate their activity,
the membrane lipid phase is no less important. Great part
of compounds studied induces structural changes in the lipid
phase resulting structural defects, which in turn disturb
membrane function and indirectly modulate membrane proteins.
This paper reviews the clinical significance of drug-membrane
interaction studies with a special focus in the lipidic components
of the membrane and reinforcing the importance of these studies
in the field of medicinal chemistry since they constitute
stimulating opportunities for understanding drugs mode of
action and toxic effects and cannot be overlooked during drug
design and synthesis.
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Article] [PMID: 20345342 PubMed - indexed for MEDLINE]
Structure-Activity Relationship of Quaternary Acetylcholinesterase
Inhibitors – Outlook for Early Myasthenia Gravis Treatment
M. Komloova, K. Musilek, M. Dolezal, F. Gunn-Moore
and K. Kuca
Myasthenia gravis is a rare autoimmune neuromuscular junction
disorder mainly caused by antibodies being targeted against
the muscle acetylcholine receptors (AChRs). The loss of AChRs
leads to a defect in neuromuscular transmission resulting
in muscle weakness and fatigue. Although once an often fatal
illness, Myasthenia gravis can now be well managed with relatively
safe and effective treatments. However, the severe myasthenic
cases associated with thymus tumors remain often fatal exception
in the management of the disease. The early treatment includes
the use of acetyl-cholinesterase inhibitors (AChEI) which
enhance neuromuscular transmission. To ensure a peripheral
effect, charged molecules are used, particularly quaternary
ammonium salts. The structure of AChEIs has been continuously
modified to obtain the optimal ratio between AChE inhibition
and potential side-effects. This review summarizes progress
in the use of quaternary compounds as AChE inhibitors in
vitro with respect to their structure and inhibitory
ability. Namely, carbamic acid esters, piperidinium and pyridinium
salts, bisquaternary pyridinium salts and heterogeneous quaternary
inhibitors are all discussed. Among data found in the literature,
many compounds have shown promising inhibition of AChE when
compared to commercial standards (pyridostigmine, neostigmine).
Besides a promising inhibitory ability, selectivity for AChE
versus butyrylcholinesterase (BChE) for the most potent compounds
(sub-nanomolar IC50) was
also identified.
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Tacrine Derivatives and Alzheimer’s Disease
V. Tumiatti, A. Minarini, M.L. Bolognesi,
A. Milelli, M. Rosini and C. Melchiorre
To date, the pharmacotherapy of Alzheimer’s
disease (AD) has relied on acetylcholinesterase (AChE) inhibitors
(AChEIs) and, more recently, an N-methyl-D-aspartate receptor
(NMDAR) antagonist. AD is a multifactorial syndrome with several
target proteins contributing to its etiology. “Multi-target-directed
ligands” (MTDLs) have great potential for treating complex
diseases such as AD because they can interact with multiple
targets. The design of compounds that can hit more than one
specific AD target thus represents an innovative strategy
for AD treatment. Tacrine was the first AChEI introduced in
therapy. Recent studies have demonstrated its ability to interact
with different AD targets. Furthermore, numerous tacrine homo-
and heterodimers have been developed with the aim of improving
and enlarging its biological profile beyond its ability to
act as an AChEI. Several tacrine hybrid derivatives have been
designed and synthesized with the same goal. This review will
focus on and summarize the last two years of research into
the development of tacrine derivatives able to hit AD targets
beyond simple AChE inhibition.
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[Purchase
Article] [PMID: 20345340 PubMed - indexed for MEDLINE]
Clinical Impact of the Detection of BRAF Mutations
in Thyroid Pathology: Potential Usefulness as Diagnostic,
Prognostic and Theragnostic Applications
Sandra Lassalle, Véronique Hofman, Marius Ilie, Catherine
Butori, Alexandre Bozec, José Santini, Philippe Vielh
and Paul Hofman
A BRAF somatic mutation at residue 600 of the BRAF
protein (BRAFV600E) is highly prevalent in papillary thyroid
carcinomas (PTC). This mutation occurs in approximately 44%
(from 29% to 83%) of PTC depending on the different studies.
BRAFV600E is almost always found in PTC with a papillary or
a mixed follicular/papillary architecture, being rarer in
other subtypes of PTC. The discovery of the BRAFV600E mutation
in tissue and fine-needle aspiration (FNA) is diagnostic for
PTC and has been frequently associated with worse clinical
prognosis. However, some studies failed to reveal this prognostic
association. Transcriptional and post-transcriptional modulation
of PTC with a BRAF mutation has been evaluated in some recent
studies. Current therapeutic approaches targeting BRAF are
being tested in clinical trials, particularly in more aggressive
PTC. In this review, we will first discuss the diagnostic
value of a BRAF mutation for PTC diagnosis. The prognostic
role of a BRAFV600E mutation is then outlined and discussed
in the context of other well-accepted clinicopathological
prognostic parameters for PTC (age, gender, pTNM stage, histological
subtype). Finally, the currently and potentially used treatments
targeting BRAF in patients with PTC are presented.
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[Purchase
Article] [PMID: 20353384 PubMed - indexed for MEDLINE]
New Drug Delivery Systems in Inflammatory Bowel Disease:
MMXTM and Tailored Delivery
to the Gut
G. Fiorino, W. Fries, S.A. De La Rue, A.C. Malesci, A. Repici
and S. Danese
Inflammatory bowel diseases are chronic diseases that
affect the gastrointestinal tract. Mesalamine, corticosteroids,
immunosuppressants and biological agents are currently used
to treat these diseases. Due to inadequacies of the currently
available delivery systems, a large number of patients do
not respond to treatment, especially when they are affected
by distal colonic disease. Multimatrix (MMXTM)
technology comprises hydrophilic and lipophilic excipients,
enclosed within a gastro-resistant, pH-dependent coating.
This new delivery technology has been used to modify some
commonly used drugs, including mesalamine and budesonide,
as well as heparin, which are now being investigated for their
utility in the management of IBD.
Aim: The aim of this review is to explore the MMX
delivery technology and its efficacy for the treatment of
IBD.
Results: The results of various studies involving
MMX drugs have been published. Mesalamine MMX induces clinical
and endoscopic remission in patients with mild to moderate
ulcerative colitis (UC) compared with placebo. Positive results
have also been observed with MMX budesonide in two phase I
studies. In a pilot study involving ten patients with UC,
efficacy of heparin-MMX as an IBD therapy was observed.
Conclusion: MMX is a promising new delivery system
that can improve efficacy of current and new drugs, augmenting
targeting to the affected tract, thereby increasing response
and remission rates for those drugs in patients with IBD.
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