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Anti-Inflammatory
& Anti-Allergy Agents in Medicinal Chemistry
ISSN: 1871-5230
Anti-Inflammatory & Anti-Allergy
Agents in Medicinal Chemistry
Volume 6, Number 4, November 2007
Contents
Chemical Approaches to Anti-Inflammatory
Discovery
Guest Editor: Balbina J. Plotkin
Editorial Pp. 252
Antibiotic or Anti-inflammatory Agent? The Double-Edged
Sword of Tetracyclines Pp. 253-263
K.K. Eklund and C. Sandler
[Abstract]
Ethanol and Inflammation Pp. 264-270
J. Goral
[Abstract]
Anti-inflammatory Sulfur-Containing Agents with Additional
Modes of Action Pp. 271-277
M.I. Konaklieva and B.J. Plotkin
[Abstract]
Salicylates and their Spectrum of Activity
Pp. 278-292
K.K. Wu
[Abstract]
The Anti-inflammatory Effect of Coumarin and its Derivatives
Pp. 293-306
D.J. Hadjipavlou-Litina, K.E. Litinas and C. Kontogiorgis
[Abstract]
Bioactivities of Iridoids Pp. 307-314
I.M. Villaseñor
[Abstract]
Nongenomic Actions of Retinoids: Role of Nur77 and
RXR in the Regulation of Apoptosis and Inflammation
Pp. 315-331
J.-Z. Zeng and X.-k. Zhang
[Abstract]
Abstracts
[Back to top]
Editorial
The one bullet-one target approach to drug design
where compounds exhibit a single specificity in action and
function is generally the preferred design. However, there
are multiple classes of agents with antiinflammatory activity
that are multi-function with activity across taxonomic kingdoms,
cell types and molecular targets. The aim of this volume is
to examine the structure-function relationship for antiinflammatory
agents which exhibit multiple activities.
For agents like the tetracyclines, which are bacteriostatic
antibiotics, their antiinflammatory activity was a secondary
find-ing. Tetracyclines in addition to inhibiting bacterial
protein synthesis, inhibit collagenases, proteolysis, angiogenesis,
apoptosis, bone metabolism and modulation of matrix metalloproteinase
activity. Based on this ability to inhibit various pro-inflammatory
pathways, tetracyclines are being used in the treatment of
rheumatoid arthritis, adult periodontal diseases and rosacea.
Ethanol, which is used as a bacterial disinfectant/antiseptic/cleanser,
is also one of the most commonly self-administered compounds
which can modify immune responses. However, these effects
of ethanol on the inflammatory response can be opposing depending
on dosage; low levels associated with an anti-inflammatory
effect and chronic consumption of high levels of ethanol linked
to augmentation of inflammatory responses.
Sulfur-containing compounds appear to target NF-kB, thus potentially
have broad impact on a variety of cellular mechan-isms, such
as proliferation, differentiation, angiogenesis and metastasis.
Also under development are new drugs utilizing thio-gold complexes.
These compounds have a broad range of clinical targets from
cellular (cancer), to viral (AIDS) and parasital (malaria).
Other compounds act across phyla as signaling molecules, thus
having multiple activities. Salicylate, a signaling molecule
in plants, also exhibits similar activity in mammalian cells
and microbial cells resulting in antithrombotic, anti-inflammatory,
anti-neoplastic, and anti-microbial actions. As with other
compounds such as the sulfur-containing compounds, salicylates
are active in controlling inflammation and tumor growth by
altering gene expression; they inhibit suppress the DNA binding
activi-ties of NF-kB, AP-1 and C/EBPβ
in a concentration dependent manner which may account for
their diverse spectrum of activi-ty.
Alternatively, compounds like coumarin reduce tissue edema
and inflammation by inhibiting prostaglandin biosynthesis
and fatty acid hydroperoxy-intermediates. It is to be expected
that coumarin might affect the formation and scavenging of
reactive substances derived from oxygen species (ROS) and
influence processes involving free radical-mediated injury,
as can flavonoids. Similarly, the anti-inflammatory iridoids
also showed anti-oxidant, anti-tumor, hepatoprotective, immunomodulatory,
antimicrobial, antinociceptive, neuroprotective, neurotogenic,
angiogenic, anxiolytic, osteoporotic, and anti-aging activities.
Like salicylates, the iridoids have also been part of herbal
medicine for generations.
Multiple anti-inflammatory activities can also be mediated
via various pathways in mammalian cells. This is exemplified
by the retinoid story wherein there are both genomic and non-genomic
mechanisms which contribute to the pleiotropic effects of
retinoids and receptors and exemplify both intracellular and
intercellular cross-talk. Thus, retinoids may serve as the
paradigm for the multiplicity of sometimes seemingly contradictory
activities of this group of antiinflammatory agents.
Balbina J. Plotkin
Guest Editor
Anti-Inflammatory & Anti-Allergy Agents in Medicinal
Chemistry
Midwestern University
Downers Grove, IL 60515
USA
[Back to top]
Antibiotic or Anti-inflammatory Agent? The Double-Edged Sword
of Tetracyclines
K.K. Eklund and C. Sandler
The tetracyclines are broad-spectrum bacteriostatic antibiotics
which interfere with the protein synthesis of bacteria at
the ribosomal level. More recently the nonantibiotic properties
of tetracyclines have attracted increasing interest. Since
the initial observations that tetracyclines inhibit collagenases,
extensive number of studies have shown that tetracyclines
have effects on inflammation, proteolysis, angiogenesis, apoptosis,
and bone metabolism. The mechanism of their action is complex
and not completely understood. It includes inhibition of free
radical formation and cytokine production, interference with
protein synthesis, and modulation of matrix metalloproteinase
activity. Chemically modified tetracyclines (CMTs) are tetracycline
derivates which lack the antibiotic activity of tetracyclines
but possess anti-inflammatory properties. The therapeutic
effects of tetracyclines and its analogues have been studied
in various inflammatory diseases. Encouraging results have
been obtained in the treatment of rheumatoid arthritis (RA)
and based on those results minocycline is currently used in
the treatment of selected RA patients. Doxycycline has been
approved for the treatment of adult periodontal diseases and
rosacea. The role of tetracyclines has been studied also in
cardiovascular diseases and neuroprotection but their true
potential in these diseases remains to be determined. In this
review the nonantibiotic properties of tetracycline and its
analogues will be examined and their potential for clinical
applications in inflammatory diseases will be discussed.
[Back to top]
Ethanol and Inflammation
J. Goral
Ethanol (alcohol) consumption can modify immune responses.
Moderate ethanol use is associated with lower production of
mediators of inflammation and has anti-inflammatory effect,
while ethanol abuse and alcoholism are linked with augmentation
of inflammatory responses. Ethanol exposure can result in
functional alterations of macrophages and other cells of the
innate immune system. These cells recognize microbial antigens
through Toll-like receptors (TLRs). Molecular mechanisms underlying
the inflammatory responses stimulated via TLRs involve activation
of intracellular signaling pathways that include mitogen-activated
protein kinases (MAPKs) and transcription factor NFκB.
Growing evidence indicates that ethanol can affect these cellular
events in a manner that depends on the organ or cell type
and the pattern of ethanol administration (moderate or acute
versus chronic).
[Back to top]
Anti-inflammatory Sulfur-Containing Agents with Additional
Modes of Action
M.I. Konaklieva and B.J. Plotkin
Sulfur-containing compounds have proved to be excellent anti-inflammatory
agents. In this pharmacological class of compounds the sulfur
atom can be found both in reduced and oxidized state. We were
interested in outlining the roles of the sulfur moiety and
correlate its anti-inflammatory activity to other pharmacological
roles based on the mechanism of action of the sulfur groups.
[Back to top]
Salicylates and their Spectrum of Activity
K.K. Wu
Salicylate is a signaling molecule in plants. It also
exhibits signaling activities in mammalian cells. Experimental
and clinical data indicate that salicylates have a spectrum
of activities, including antithrombotic, anti-inflammatiory,
anti-neoplastic, and anti-microbial actions. Aspirin, a synthetic
derivative of salicylic acid, is widely used in treating human
diseases. The antithrombotic action is unique to aspirin and
not shared by other salicylates as only aspirin possesses
the property to acetylate COX-1. Other actions of salicylates
are attributed to salicylate, a major metabolite of aspirin
in vivo. Salicylates are active in controlling inflammation
and tumor growth by altering gene expressions. They suppress
the expression of pro-inflammatory genes by inhibiting the
DNA binding activities of transcription activators such as
NF-κB,
AP-1 and C/EBPβ.
Their actions appear to be concentration related. Salicylates
at high concentrations non-selectively inhibit the binding
activities of diverse transactivators. At pharmacological
concentrations, salicylates inhibit C/EBPβ
binding and C-Rel. Transcriptional suppression by salicylates
is mediated by kinase inhibition. Salicylates at high concentrations
inhibit diverse classes of kinases and, paradoxically, activate
some kinases. However, at micromolar concentrations, salicylates
inhibit p90 ribosomal S6 kinase (RSK) and p70 S6 kinase (S6K).
The mechanism by which salicylates inhibit kinases is unclear.
We propose that salicylates at mM concentrations non-selectively
inhibit ATP binding to kinases. At micromolar concentrations,
they inhibit substrate binding to a selective family of kinases
including RSK and S6K. Further structural analysis will yield
valuable information which will be useful in designing new
anti-inflammatory and anti-neoplastic drugs.
[Back to top]
The Anti-inflammatory Effect of Coumarin
and its Derivatives
D.J. Hadjipavlou-Litina, K.E. Litinas and C. Kontogiorgis
Inflammation is the primary host defense mechanism against
all forms of injury. Excessive or inadequate activation of
the system can have serious effects, as can the failure of
inactivation mechanisms.
Coumarins can reduce tissue edema and inflammation and inhibit
prostaglandin biosynthesis, which involves fatty acid hydroperoxy
intermediates. It is to be expected that coumarins might affect
the formation and scavenging of reactive sub-stances derived
from oxygen species (ROS) and influence processes involving
free radical-mediated injury, as can flavon-oids.
During these years a small number of (Q)SAR studies concerning
coumarins as NSAIDs has been presented and reviewed. In this
research we tried to examine the structure-function relationship
for coumarins, presenting anti-inflammatory activity. Coumarin
(1), the prototypical compound presents anti-inflammatory
activity. The hydroxyl-aromatic substituted derivatives (5-
or 6- or 7-hydroxy or the vicinal dihydroxy) seems to be potent
inhibitors of lipoxygenase. Several synthetic derivatives
simple or more complicated were found to be potent antiinflammatories/antioxidant
agents.
[Back to top]
Bioactivities of Iridoids
I.M. Villaseñor
Iridoids discussed in this review were chosen based on
their anti-inflammatory activity and their having various
different bioactivities. Harpagoside is the major iridoid
glycoside (0.5-1.6%) in Harpagophytum procumbens,
an herbal medicine for rheumatologic conditions. The stem
bark of C. ovata is used as an anti-inflammatory
drug and catalposide is the main constituent. Geniposide is
a main iridoid glucoside of Gardenia jasmoides, 56.2
mg / 500 mg extract. Gardenia fruits are used for the treatment
of anti-inflammatory, hepatic and gall bladder diseases. Catalpol,
known for its neuroprotective activity, is the major constituent
of the roots of Rehmannia glutinosa, which are traditionally
used for the treatment of auditory diseases such as tinnitus.
Aucubin, which is frequently found as a natural constituent
of many traditional medicinal plants, is used in the alleviation
of chronic allergic inflammatory disease. PicroLiv, an anti-inflammagen,
is a standardized fraction from the root and rhizome of Picrorhiza
kurroa containing picrosides I and II and kutkoside.
Both aucubin and PicroLiv have potent hepatoprotective activity.
[Back to top]
Nongenomic Actions of Retinoids: Role of Nur77 and RXR in
the Regulation of Apoptosis and Inflammation
J.-Z. Zeng and X.-k. Zhang
Recent advances have suggested that nongenomic action of retinoids
and their receptors represents an important mechanism by which
they exert therapeutic effects. Here we review rapid biological
responses triggered by retinoids and related molecules by
focusing on novel nongenomic mechanisms involving cytoplasmic
action of nuclear receptors Nur77 and retinoid X receptor
(RXR) in the regulation of apoptosis and inflammation. A class
of apoptosis-inducing compounds related to atypical retinoid
AHPN/CD437 has emerged as promising therapeutic agents. They
rapidly induce mitochondrial targeting of Nur77 and RXR and
conversion of Bcl-2 from a cellular protector to a killer.
Thus, understanding the nongenomic action of Nur77 and RXR
may provide a rational basis to guide the design and development
of new therapeutic agents for cancer, and skin, cardiovascular,
metabolic and central nervous disorders.
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