| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 16, Number 1, 2009
Contents
Some Recent Approaches to the Synthesis of 2-Substituted Benzofurans
Pp. 1-20
Lidia De Luca, Giammario Nieddu, Andrea
Porcheddu and Giampaolo Giacomelli
[Abstract] [Full
text article] [PMID:
19149560 PubMed - indexed for MEDLINE]
Topological Polar Surface Area: A Useful
Descriptor in 2D-QSAR Pp. 21-41
S. Prasanna and R.J. Doerksen
[Abstract] [Full
text article]
[PMID:
19149561 PubMed - indexed for MEDLINE]
Recent Progress in the Discovery of Macrocyclic
Compounds as Potential Anti-Infective Therapeutics Pp.
42-65
D. Obrecht, J.A. Robinson, F. Bernardini,
C. Bisang, S.J. DeMarco, K. Moehle and F.O. Gombert
[Abstract] [Full
text article] [PMID:
19149562 PubMed - indexed for MEDLINE]
Targeting Ion Channels in Cancer: A Novel
Frontier in Antineoplastic Therapy Pp. 66-93
A. Arcangeli, O. Crociani, E. Lastraioli,
A. Masi, S. Pillozzi and A. Becchetti
[Abstract] [Full
text article] [PMID:
19149563 PubMed - indexed for MEDLINE]
Endothelial Dysfunction in Diabetes:
From Mechanisms to Therapeutic Targets Pp.
94-112
Maria Assunta Potenza, Sara Gagliardi, Carmela
Nacci, Maria Rosaria Carratu’ and Monica Montagnani
[Abstract] [Full
text article] [PMID:
19149564 PubMed - indexed for MEDLINE]
Role of Iron Deficiency and Overload
in the Pathogenesis of Diabetes and Diabetic Complications
Pp. 113-129
Qiuju Liu, Liang Sun, Yi Tan, Guanjun Wang,
Xu Lin and Lu Cai
[Abstract] [Full
text article] [PMID:
19149565 PubMed - indexed for MEDLINE]
Abstracts
[Back to top] [PMID:
19149560 PubMed - indexed for MEDLINE]
Some Recent Approaches to the Synthesis of 2-Substituted Benzofurans
Lidia De Luca, Giammario Nieddu, Andrea
Porcheddu and Giampaolo Giacomelli
[Full
text article]
In their structural multiplicity and in the extent to
which they occur in nature the derivatives of benzofuran are
significantly lesser than the isoelectronic analogue indoles.
However, these heterocyclic compounds show a variety of pharmacological
properties, and change of their structure offers a high degree
of diversity that has proven useful for the search of new
therapeutic agents. The broad spectrum of pharmacological
activity in individual benzofurans indicates that this series
of compounds is of an undoubted interest. From this point
of view, synthetic methods may be of very useful aid in the
production of specific structures characterized by given pharmacological
qualities. Moreover from a drug discovery perspective, synthesis
of chiral functionalized substituted benzofurans could be
more interesting because they might constitute starting materials
for the production of biologically active compounds. Taking
into account the actual tendency directed toward the development
of enantiomerically pure drugs, indeed there is a limited
number of papers related to the preparation of enantiomers
of benzofuran containing compounds, likely because of difficulties
in their preparation with conventional methods. In this context,
new approaches seem to expand the potentiality of the synthesis
of substituted benzofurans, providing also convenient routes
to enantiopure 2-substituted benzofurans.
[Back to top] [PMID:
19149561 PubMed - indexed for MEDLINE]
Topological Polar Surface Area: A Useful Descriptor in 2D-QSAR
S. Prasanna and R.J. Doerksen
[Full
text article]
Topological polar surface area (TPSA), which makes use
of functional group contributions based on a large database
of structures, is a convenient measure of the polar surface
area that avoids the need to calculate ligand 3D structure
or to decide which is the relevant biological conformation
or conformations. We demonstrate the utility of TPSA in 2D-QSAR
for 14 sets of diverse pharmacological activity data. Even
though a large pool of reports showing the importance of the
classic 2D descriptors such as calculated logP (ClogP) and
calculated molar refractivity (CMR) exists in the 2D-QSAR
literature, this is the first report to demonstrate the value
of TPSA as a relevant descriptor applicable to a large, structurally
and pharmacologically diverse set of classes of compounds.
We also address the limitations of applicability of this descriptor
for 2D-QSAR analysis. We observed a negative correlation of
TPSA with activity data for anticancer alkaloids, MT1 and
MT2 agonists, MAO-B and tumor necrosis factor-α
inhibitors and a positive correlation with inhibitory activity
data for telomerase, PDE-5, GSK-3, DNA-PK, aromatase, malaria,
trypanosomatids and CB2 agonists.
[Back to top] [PMID:
19149562 PubMed - indexed for MEDLINE]
Recent Progress in the Discovery of Macrocyclic Compounds
as Potential Anti-Infective Therapeutics
D. Obrecht, J.A. Robinson, F. Bernardini,
C. Bisang, S.J. DeMarco, K. Moehle and F.O. Gombert
[Full
text article]
Novel therapeutic strategies are urgently needed for
the treatment of serious diseases caused by viral, bacterial
and parasitic infections, because currently used drugs are
facing the problem of rapidly emerging resistance. There is
also an urgent need for agents that act on novel pathogen-specific
targets, in order to expand the repertoire of possible therapies.
The high throughput screening of diverse small molecule compound
libraries has provided only a limited number of new lead series,
and the number of compounds acting on novel targets is even
smaller. Natural product screening has traditionally been
very successful in the anti-infective area. Several successful
drugs on the market as well as other compounds in clinical
development are derived from natural products. Amongst these,
many are macrocyclic compounds in the 1-2 kDa size
range. This review will describe recent advances and novel
drug discovery approaches in the anti-infective area, focusing
on synthetic and natural macrocyclic compounds for which
in vivo proof of concept has been established. The review
will also highlight the Protein Epitope Mimetics (PEM) technology
as a novel tool in the drug discovery process. Here the structures
of naturally occurring antimicrobial and antiviral peptides
and proteins are used as starting points to generate novel
macrocyclic mimetics, which can be produced and optimized
efficiently by combinatorial synthetic methods. Several recent
examples highlight the great potential of the PEM approach
in the discovery of new anti-infective agents.
[Back to top] [PMID:
19149563 PubMed - indexed for MEDLINE]
Targeting Ion Channels in Cancer: A Novel Frontier in Antineoplastic
Therapy
A. Arcangeli, O. Crociani, E. Lastraioli,
A. Masi, S. Pillozzi and A. Becchetti
[Full
text article]
Targeted therapy is considerably changing the treatment
and prognosis of cancer. Progressive understanding of the
molecular mechanisms that regulate the establishment and progression
of different tumors is leading to ever more specific and efficacious
pharmacological approaches.
In this picture, ion channels represent an unexpected, but
very promising, player. The expression and activity of different
channel types mark and regulate specific stages of cancer
progression. Their contribution to the neoplastic phenotype
ranges from control of cell proliferation and apoptosis, to
regulation of invasiveness and metastatic spread. As is being
increasingly recognized, some of these roles can be attributed
to signaling mechanisms independent of ion flow.
Evidence is particularly extensive for K+
channels. Their expression is altered in many primary human
cancers, especially in early stages, and they frequently exert
pleiotropic effects on the neoplastic cell physiology. For
instance, by regulating membrane potential they can control
Ca2+ fluxes and thus the
cell cycle machinery. Their effects on mitosis can also depend
on regulation of cell volume, usually in cooperation with
chloride channels. However, ion channels are also implicated
in late neoplastic stages, by stimulating angiogenesis, mediating
the cell-matrix interaction and regulating cell motility.
Not surprisingly, the mechanisms of these effects are manifold.
For example, intracellular signaling cascades can be triggered
when ion channels form protein complexes with other membrane
proteins such as integrins or growth factor receptors.
Altered channel expression can be exploited for diagnostic
purposes or for addressing traceable or cytotoxic compounds
to specific neoplastic tissue. What is more, recent evidence
indicates that blocking channel activity impairs the growth
of some tumors, both in vitro and in vivo.
This opens a new field for medicinal chemistry studies, which
can avail of the many available tools, such as blocking antibodies,
antisense oligonucleotides, small interfering RNAs, peptide
toxins and a large variety of small organic compounds. The
major drawback of this approach is that some ion channel blockers
produce serious side effects, such as cardiac arrhythmias.
Therefore, drug developing efforts aimed at producing less
harmful compounds are needed and we discuss possible approaches
toward this goal. Finally, we propose that a novel therapeutic
tactic could be developed by unlocking ion channels from multiprotein
membrane signaling complexes.
[Back to top]
[PMID:
19149564 PubMed - indexed for MEDLINE]
Endothelial Dysfunction in Diabetes: From Mechanisms to Therapeutic
Targets
Maria Assunta Potenza, Sara Gagliardi, Carmela
Nacci, Maria Rosaria Carratu’ and Monica Montagnani
[Full
text article]
Micro- and macrovascular complications are major causes
of disability and death in patients with diabetes mellitus.
Functional impairment of endothelial activity precedes the
development of morphological alterations during the progression
of diabetes. This endothelial dysfunction results from reduced
bioavailability of the vasodilator nitric oxide (NO), mainly
due to accelerated NO degradation by reactive oxygen species
(ROS). Although hyperglycemia, insulin resistance, hyperinsulinemia
and dyslipidemia independently contribute to endothelial dysfunction
via several distinct mechanisms, increased oxidative
stress seems to be the first alteration triggering several
others.
Mechanisms proposed to explain glucose- and lipid-induced
vascular alterations in diabetes include accelerated formation
of advanced glycation end-products (AGEs), protein kinase
C activation, inflammatory signaling and oxidative stress.
Insulin resistance with impaired PI 3-kinase effects decreases
insulin mediated production of NO and reduces vasodilation,
capillary recruitment and antioxidant properties of endothelium.
Compensatory hyperinsulinemia enhances activation of intact
MAP-kinase pathways and contributes to pro-atherogenic events
by increasing secretion of endothelin-1 (ET-1), stimulating
expression of adhesion molecules such as VCAM-1 and E-selectin,
and inducing production of ROS.
Conventional therapies to reduce hyperglycemia, dyslipidemia
and insulin resistance may effectively improve endothelial
function and delay the onset of vascular complications. Novel
therapeutic approaches designed to inhibit AGEs formation,
reduce PKC activation, decrease inflammatory signals and restore
the ox/redox balance of endothelium may be predicted to ameliorate
vascular function in diabetic state.
This review summarizes the current knowledge on the most important
mechanisms involved in endothelial dysfunction during diabetes.
In addition, novel therapeutic strategies that may result
from recently identified targets are also described.
[Back to top]
[PMID: 19149565 PubMed - indexed for MEDLINE]
Role of Iron Deficiency and Overload in the Pathogenesis
of Diabetes and Diabetic Complications
Qiuju Liu, Liang Sun, Yi Tan, Guanjun Wang,
Xu Lin and Lu Cai
[Full
text article]
Iron is one of the essential minerals that are required
for a variety of molecules to maintain their normal structures
and functions and for cells to live, grow, and proliferate.
The homeostasis of iron results from a tightly coordinated
regulation by different proteins involved in uptake, excretion
and intracellular storage/trafficking. Although it is essential,
iron can also be toxic once in excess amounts. Through Fenton
reaction, iron as a transit mineral can generate various reactive
oxygen or nitrogen species; therefore, abnormal metabolism
of iron can lead to several chronic pathogenesis. Oxidative
stress is one of the major causative factors for diabetes
and diabetic complications. Increasing evidence has indicated
that iron overload not only increases risks of insulin resistance
and diabetes, but also causes cardiovascular diseases in non-diabetic
and diabetic subjects. Temporal iron deficiency was found
to sensitize insulin action, but chronic iron deficiency with
anemia can accelerate the development of cardiovascular diseases
in non-diabetic and diabetic patients. In this review, therefore,
we will first outline iron homeostasis, function, and toxicity,
and then mainly summarize the data regarding the roles of
iron deficiency and overload in the pathogenesis of diabetes
and diabetic complications, as well as the possible links
of iron to diabetes and diabetic complications. In the end,
the possible therapy using iron chelators for diabetes and
diabetic complications will also be discussed.
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