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Medicinal Chemistry
ISSN: 1573-4064
Medicinal Chemistry
Volume 4, Number 6, November
2008
Contents
Non-Invasive Markers of Liver Fibrosis in
HCV Mono-Infected and in HIV/HCV Co-Infected Subjects
Pp. 513-519
M. Bongiovanni and M. Casana
[Abstract]
Hemoglobin Enhances the Biological Activity
of Synthetic and Natural Bacterial (Endotoxic) Virulence Factors:
A General Principle Pp. 520-525
J. Howe, W. Richter, L. Hawkins, M. Rössle,
C. Alexander, K. Fournier, J.P. Mach, T. Waelli, R.M. Gorczynski,
A.J. Ulmer, H. Brade, A. Zamyatina, P. Kosma, E.T. R. and
K. Brandenburg
[Abstract]
Effects of Vitamin E and C on Placental
Oxidative Stress: An In Vitro Evidence for the Potential
Therapeutic or Prophylactic Treatment of Preeclampsia
Pp. 526-530
G. Fiore and A. Capasso
[Abstract]
Synthesis of Chiral 3-Methyl- and 3-Methyl-N-propargyl-1,2,3,4-tetrahydroisoquinoline
and Prevention of MPP+-Induced
Cytotoxicity Pp. 531-538
T. Saitoh, A. Yamashita, K. Abe, K. Ogawa,
M. Kitabatake, K. Taguchi and Y. Horiguchi
[Abstract]
Syntheses, Urease Inhibition, and Antimicrobial
Studies of Some Chiral 3-Substituted-4-amino-5-thioxo-1H,4H-1,2,4-triazoles
Pp. 539-543
T. Akhtar, S. Hameed, K.M. Khan and
M.I. Choudhary
[Abstract]
Disturbance of Apolipoprotein B100 Containing
Lipoprotein Metabolism in Severe Hyperlipidemic and Lipodystrophic
HIV Patients on Combined Antiretroviral Therapy: Evidences
of Insulin Resistance Effect Pp. 544-550
K. Ouguerram, Y. Zair, S. Billon, M. Chétiveaux,
C. Brunet-François, K. Ngohou-Bach, C. Allavena, V.
Reliquet, B. Milpied, T. Magot, F. Raffi and M. Krempf
[Abstract]
Down-Regulation of Notch1 Expression is Involved in HL-60
Cell Growth Inhibition Induced by 4-Hydroxynonenal, a Product
of Lipid Peroxidation Pp. 551-557
S. Pizzimenti, G. Barrera, E. Calzavara,
L. Mirandola, C. Toaldo, M.U. Dianzani, P. Comi and R.
Chiaramonte
[Abstract]
Synthesis and Biological Evaluation of
2-aroyl-4-phenyl-5-hydroxybenzofurans as a New Class of Antitubulin
Agents Pp. 558-564
R. Romagnoli, P.G. Baraldi, T. Sarkar, C.L.
Cara, O.C. Lopez, M.D. Carrion, D. Preti, M. Tolomeo, J. Balzarini
and E. Hamel
[Abstract]
NMDA Agonists and Antagonists Induce
Renal Culture Cell Toxicity Pp. 565-571
J.C. Leung, N. Ragland, T. Marphis and D.M.
Silverstein
[Abstract]
Hemin Treatment Abrogates Monocrotaline-Induced
Pulmonary Hypertension Pp. 572-576
K. Shimzu, T. Takahashi, T. Iwasaki, H.
Shimizu, K. Inoue, H. Morimatsu, E. Omori, M. Matsumi, R.
Akagi and K. Morita
[Abstract]
Synthesis of 4-amino-5-cyano-2, 6-Disubstituted
Pyrimidines as a Potential Antifilarial DNA Topoisomerase
II Inhibitors Pp. 577-585
A. Kumar, J.K. Saxena and P.M.S.
Chauhan
[Abstract]
Synthesis and Anti-Inflammatory Activity
of Chalcones and Related Mannich Bases Pp.
586-596
Kouskoura Maria, Hadjipavlou-Litina Dimitra
and Giakoumakou Maria
[Abstract]
Inhibition of Inflammation by a p38 MAP
Kinase Targeted Cell Permeable Peptide Pp. 597-604
J. Fu, X. Meng, J. He and J. Gu
[Abstract]
2-Arylbenzimidazoles as Antiviral and
Antiproliferative Agents-Part 1 Pp. 605-615
G. Vitale, A. Carta, M. Loriga, G. Paglietti,
P. La Colla, B. Busonera, D. Collu and R. Loddo
[Abstract]
Enhancement of Escherichia coli
and Staphylococcus aureus Antibiotic Susceptibility
Using Sesquiterpenoids Pp. 616-623
M. Simões, S. Rocha, M.A. Coimbra
and Maria J. Vieira
[Abstract]
A Comparison of the Biological Properties
of Small Molecular Weight Agonists and Antagonists of CD200:CD200R
Interactions Pp. 624-631
Reg Gorczynski, Ivo Boudakov and Ismat
Khatri
[Abstract]
Abstracts
[Back to top]
Non-Invasive Markers of Liver Fibrosis in HCV Mono-Infected
and in HIV/HCV Co-Infected Subjects
M. Bongiovanni and M. Casana
Non-invasive markers of liver fibrosis have been recently
developed as a possible alternative to liver biopsy. The clinical
management of hepatic diseases is dependent on the extent
of liver fibrosis. Liver biopsy remains the gold standard
but severe complications are found in about 0.5% of cases.
Studies involving sequential liver biopsies are impractical,
costly, and risky. Therefore non-invasive markers of liver
fibrosis could be useful. These drawbacks justify an intensive
research on non-invasive alternatives. Several serum markers
are either directly involved in fibrosis remodelling or are
indirectly associated with the presence of significant liver
fibrosis. More recently, fibrosis scores calculated from statistical
models have been described. This review describes the role
of non-invasive markers in assessing hepatic fibrosis in both
HCV mono-infected and HIV/HCV co-infected subjects.
[Back to top]
Hemoglobin Enhances the Biological Activity of Synthetic and
Natural Bacterial (Endotoxic) Virulence Factors: A General
Principle
J. Howe, W. Richter, L. Hawkins, M. Rössle,
C. Alexander, K. Fournier, J.P. Mach, T. Waelli, R.M. Gorczynski,
A.J. Ulmer, H. Brade, A. Zamyatina, P. Kosma, E.T. R. and
K. Brandenburg
Although hemoglobin (Hb) is mainly present in the cytoplasm
of erythrocytes (red blood cells), lower concentrations of
pure, cell-free Hb are released permanently into the circulation
due to an inherent intravascular hemolytic disruption of erythrocytes.
Previously it was shown that the interaction of Hb with bacterial
endotoxins (lipopolysaccharides, LPS) results in a significant
increase of the biological activity of LPS. There is clear
evidence that the enhancement of the biological activity of
LPS by Hb is connected with a disaggregation of LPS. From
these findings one questions whether the property to enhance
the biological activity of endotoxin, in most cases proven
by the ability to increase the cytokine (tumor-necrosis-factor-α,
interleukins) production in human mononuclear cells, is restricted
to bacterial endotoxin or is a more general principle in nature.
To elucidate this question, we investigated the interaction
of various synthetic and natural virulence (pathogenicity)
factors with hemoglobin of human or sheep origin. In addition
to enterobacterial R-type LPS a synthetic bacterial lipopeptide
and synthetic phospholipid-like structures mimicking the lipid
A portion of LPS were analysed. Furthermore, we also tested
endotoxically inactive LPS and lipid A compounds such as those
from Chlamydia trachomatis. We found that the observations
made for endotoxically active form of LPS can be generalized
for the other synthetic and natural virulence factors: In
every case, the cytokine-production induced by them is increased
by the addition of Hb. This biological property of Hb is connected
with its physical property to convert the aggregate structures
of the virulence factors into one with cubic symmetry, accompanied
with a considerable reduction of the size and number of the
original aggregates.
[Back to top]
Effects of Vitamin E and C on Placental Oxidative Stress:
An In Vitro Evidence for the Potential Therapeutic
or Prophylactic Treatment of Preeclampsia
G. Fiore and A. Capasso
Preeclampsia (PE) is a multisystem disorder that remains
a major cause of maternal and foetal morbidity and death.
To date, no treatment has been found that prevents the development
of the disease. Endothelial dysfunction is considered to underlie
its clinical manifestations, such as maternal hypertension,
proteinuria and edema; and oxidative stress has been increasingly
postulated as a major contributor to endothelial dysfunction
in PE.
A large body of research has investigated the potential role
of antioxidant nutrients in the prevention of PE in women
at high increased risk of the disease. Therefore, the present
study was primarly designed to assess the potential benefit
of antioxidant supplementation on markers of placental oxidative
stress in an in vitro model of PE, since we previously
found that endothelin-1 (ET-1) is able to trigger the placental
secretion of stress molecules. In this regard, we evaluated
the effects of vitamin C, vitamin E and N-acetylcysteine (NAC),
alone or in combination, in placental villi culture after
exposure to ET-1. The effect of antioxidant nutrients on trophoblast
cells proliferation and vitality was also evaluated.
The results obtained suggest that in a pathophysiological
condition, such as PE, the deleterious effect of reactive
oxygen species may be counteract by an antioxidant therapy,
and there is the need to investigate the optimum dosing and
timing of antioxidants administration, since an inappropriate
antioxidant treatment in pregnant women may have deleterious
consequences, reducing placental cells proliferation until
to cell death.
[Back to top]
Synthesis of Chiral 3-Methyl- and 3-Methyl-N-propargyl-1,2,3,4-tetrahydroisoquinoline
and Prevention of MPP+-Induced
Cytotoxicity
T. Saitoh, A. Yamashita, K. Abe, K. Ogawa,
M. Kitabatake, K. Taguchi and Y. Horiguchi
The chemical structure of selegiline, a commercially
available drug for Parkinson’s disease (PD), resembles
that of 1,2,3,4-tetrahydroisoquinoline (TIQ), an endogenous
parkinsonism-inducing compound. In the present study, we evaluated
the direct cytotoxicity of (R)- and (S)-3-methyl-TIQ
(3-MeTIQ) and (R)- and (S)-3-methyl-N-propargyl-TIQ
(3-Me-N-propargyl-TIQ), as selegiline-mimetic TIQ
derivatives, and their ability to prevent 1-methyl-4-phenylpyridinium
iodide (MPP+)-induced cell
death. Synthesis of optically-pure 3-MeTIQs was achieved via
the super acid-induced cyclization of chiral N-benzyl-N-[1-methyl-2-(phenylsulfinyl)ethyl]formamide
using a Pummerer-type cyclization reaction as the key step
in producing excellent yields. Subsequent N-propargylation
of chiral 3-MeTIQs using propynylbromide gave the corresponding
3-Me-N-propargyl-TIQs. In our in vitro experiments,
the direct cytotoxicity of chiral 3-MeTIQs and 3-Me-N-propargyl-TIQs
was almost identical, with no relationship to optical chirality
except for (S)-3-Me-N-propargyl-TIQ, which
had significantly weaker direct cytotoxicity than the other
3-MeTIQ derivatives. However, the decreased viability of PC12
cells induced by treatment with MPP+
was accelerated by the coexistence of 3-MeTIQs and inhibited
by 3-Me-N-propargyl-TIQs without any participation
of the stereochemistry at the 3-postion. These results suggest
that the N-propargyl group is necessary for protection
of cells against the toxicity of MPP+.
Furthermore, the stereochemistry of the 3-position appears
to partially participate in the direct cytotoxicity of 3-Me-N-propargyl-TIQs.
[Back to top]
Syntheses, Urease Inhibition, and Antimicrobial Studies of
Some Chiral 3-Substituted-4-amino-5-thioxo-1H,4H-1,2,4-triazoles
T. Akhtar, S. Hameed, K.M. Khan and
M.I. Choudhary
Chiral 3-substituted-4-amino-5-thioxo-1H,4H-1,2,4-triazoles
(5a-i) were synthesized. The target molecules
were prepared by cyclization of the corresponding dithiocarbazinic
acids, obtained from hydrazides, in the presence of hydrazine
hydrate. The chiral hydrazides were in turn synthesized form
L-amino acids. The structures of all the compounds were confirmed
by modern spectroscopic techniques and purity ascertained
by elemental analysis. The synthesized compounds 5a-i
were evaluated for urease inhibition and found to exhibit
varying degrees of urease inhibition activity showing IC50
values ranging from 22.0 ±
0.5 to 43.8 ±
0.3 μM.
Compound 5b was found to be the most active,
exhibiting IC50 = 22.0 ±
0.5 μM
comparable to the standard, thiourea (IC50
= 21.0 ±
0.1 μM).
Triazoles 5a-i were also screened for their
antimicrobial properties and promising antibacterial activities
were observed against five pathogenic bacteria. However, all
the compounds were devoid of any antifungal activity.
[Back to top]
Disturbance of Apolipoprotein B100 Containing Lipoprotein
Metabolism in Severe Hyperlipidemic and Lipodystrophic HIV
Patients on Combined Antiretroviral Therapy: Evidences of
Insulin Resistance Effect
K. Ouguerram, Y. Zair, S. Billon, M. Chétiveaux,
C. Brunet-François, K. Ngohou-Bach, C. Allavena, V.
Reliquet, B. Milpied, T. Magot, F. Raffi and M. Krempf
The aim was to study the mechanisms involved in the dyslipidemia
associated with lipodystrophy in HIV infected patients on
antiretroviral therapy (ART).
We investigated the in vivo kinetics of apolipoprotein
B100 (apoB) containing lipoproteins using a 14 h primed constant
infusion of [5,5,5,2H3]
leucine and compartmental modelling in normolipidemic without
lipodystrophy (7 patients, NLD) or dyslipidemic with lipodystrophy
(7 patients, LD) treated with ART.
Subjects in group LD showed higher plasma triglycerides (5.73±3.58
vs 1.29±0.54
g/L, p<0.005),
total cholesterol (2.98±0.95
vs 1.74±0.26
g/L, p<0.05),
apoB (1.49±1.11
vs 0.51±0.11
g/L, p<0.005)
and apolipoprotein CIII in apoB containing lipoproteins (117.7±42.2
vs 22.6±23.9
g/L, p<0.005).
LD subjects exhibited an insulin resistant as observed by
higher HOMA (3.44±1.62
vs 1.60±0.61,
p<0.05).
They exhibited an increase in VLDL (1.24±0.33
vs 0.80±0.21
mg/kg/h, p<0.05),
decrease in IDL (0.20±0.10
vs 0.48±0.24
mg/kg/h, p<0.05)
and no difference in LDL (0.38±0.19
vs 0.45±0.25
mg/kg/h) production rate. LD subject also showed a dramatic
decrease in transformation of VLDL to IDL (0.013±0.010
vs 0.258±0.206
h-1, p<0.005)
and IDL to LDL (0.088±0.093
vs 0.366±0.189
h-1, p<0.05)
and a decrease in fractional catabolic rate (FCR) of VLDL
(0.199±0.132
vs 0.555±0.398
h-1, p<0.05),
IDL (0.110±0.08
vs 0.523±0.275
h-1, p<0.05)
and LDL (0.010±0.005
vs 0.025±0.014
h-1, p<0.05).
These disturbances, overproduction and an overall delayed
catabolism of apoB, are similar to those observed using the
same protocol in insulin resistant subjects. Our study suggests
that metabolic disturbance of apoB100 observed in lipodystrophic
HIV in combined antiretroviral therapy are consecutive to
insulin resistance induced by the treatment.
[Back to top]
Down-Regulation of Notch1 Expression is Involved in HL-60
Cell Growth Inhibition Induced by 4-Hydroxynonenal, a Product
of Lipid Peroxidation
S. Pizzimenti, G. Barrera, E. Calzavara,
L. Mirandola, C. Toaldo, M.U. Dianzani, P. Comi and R.
Chiaramonte
The role of the Notch1 pathway has been well assessed
in leukemia. Notch1 mutations are the most common
ones in T acute lymphoblastic leukaemia patients which carry
either oncogenic Notch1 forms or ineffective ubiquitin ligase
implicated in Notch1 turnover. Abnormalities in the Notch1-Jagged1
system have been reported also in acute myelogenous leukaemia
(AML) patients where Jagged1 is frequently over-expressed.
Moreover, activating Notch1 mutations, as well, can occur
in human AML and in leukemia cases with lineage infidelity.
As a result, Notch1 signalling inhibition is an attractive
goal in leukaemia therapy. Blockage/delay in cell differentiation
and/or increase of proliferation are the main results of Notch1
signalling activation in several leukemic cell lines. Moreover,
specific genes involved in cell growth control have been identified
as Notch1 transcriptional targets, i.e. Cyclin D1 and c-Myc.
4-Hydroxynonenal (HNE), an aldehyde produced during lipid
peroxidation, is involved in several pathological and physiological
conditions, including inflammation; atherosclerosis; and neurodegenerative
and chronic liver diseases. Moreover HNE has an antiproliferative/
differentiative effect in several cell lines, by affecting
the expression of key genes, such as oncogenes (e.g. c-Myc,
c-Myb), cyclins and telomerase.
This prompted us to study the effect of HNE on Notch1 expression
and its related signalling in HL-60 cells, a leukemic cell
line widely used for differentiation studies. RT-PCR as well
as Western blot assay showed Notch1down-regulation in HNE-treated
HL-60 cells. The expression of Hes1, a Notch1 target gene,
was concomitantly down-regulated by HNE treatment, reflecting
Notch1 signalling inhibition.
DAPT, an inhibitor of Notch activity, when added contemporary
to HNE, further increased cell growth inhibition, without
affecting apoptosis. Moreover, DAPT treatment reversed the
HNE-induced differentiation. Overall these results suggest
that Notch1 is a target for HNE and its down regulation is
a key event in HNE-mediated inhibition of cell proliferation
in the HL-60 cell line. By contrast our data do not support
a role for Notch1 in HNE- induced differentiation or apoptosis.
[Back to top]
Synthesis and Biological Evaluation of 2-aroyl-4-phenyl-5-hydroxybenzofurans
as a New Class of Antitubulin Agents
R. Romagnoli, P.G. Baraldi, T. Sarkar, C.L.
Cara, O.C. Lopez, M.D. Carrion, D. Preti, M. Tolomeo, J. Balzarini
and E. Hamel
Microtubules are among the most successful targets for
development of compounds useful for anticancer therapy. Continuing
our project to develop new small molecule antitumor agents,
two new series of derivatives based on the 2-aroyl-4-phenylbenzofuran
molecular skeleton were synthesized and evaluated for antiproliferative
activity, inhibition of tubulin polymerization and cell cycle
effects. SAR were elucidated with various substitutions on
the benzoyl moiety at the 2-position of the benzofuran ring.
The most promising compound in this series, the (5-hydroxy-4-phenylbenzofuran-2-yl)(4
methoxyphenyl)methanone derivative (3d),
has significant growthb inhibitory activity in the submicromolar
range against the Molt4, CEM and HeLa cancer cell lines and
interacts with tubulin by binding to the colchicine site.
Exposure to 3d led to the arrest of K562
cells in the G2-M phase of the cell cycle and to the induction
of apoptosis.
[Back to top]
NMDA Agonists and Antagonists Induce Renal Culture Cell Toxicity
J.C. Leung, N. Ragland, T. Marphis and D.M.
Silverstein
The NMDA receptor (NMDAR) is expressed in the renal proximal
tubule. NMDAR agonists and antagonists induce cell toxicity
in the central nervous system (CNS). We studied the effect
of NMDAR agonists and antagonists on renal cell survival in
renal culture cells: proximal tubule-like opossum kidney (OK)
and distal-tubule-like madine darby canine kidney cells (MDCK)
cells. Low dose glutamate had no effect on cell survival.
However, 10 mM glutamate induced a 14-fold increase in cell
death compared to control cells. Addition of low or high doses
of the NMDAR agonist glycine had no effect on cell toxicity.
Exposure of cells to the non-competitive NMDAR blocker MK-801
or the competitive NMDAR antagonist CPP induced a time and
dose-dependent increase in cell death and apoptosis. The presence
of fetal bovine serum in the pre-incubation media attenuated
the toxicity caused by MK-801 and CPP. The deleterious effect
of NMDAR antagonists on cell survival was specific for OK
cells; these substances had no effect on MDCK cell survival.
Finally, pre-treatment of OK cells with the renal cytoprotective
glycine completely blunted the affect of MK-801 on renal cell
survival. We conclude that excessive stimulation or blockade
of the renal NMDAR results in cell death.
[Back to top]
Hemin Treatment Abrogates Monocrotaline-Induced Pulmonary
Hypertension
K. Shimzu, T. Takahashi, T. Iwasaki, H.
Shimizu, K. Inoue, H. Morimatsu, E. Omori, M. Matsumi, R.
Akagi and K. Morita
Treatment of rats with monocrotaline (MCT), a pyrrolizidine
alkaloid plant toxin, is known to cause pulmonary hypertension
(PH), and it has been used as a useful experimental model
of PH. Recent findings suggested that pulmonary inflammation
may play a significant role in the pathogenesis of MCT-induced
PH. We also demonstrated that, following MCT administration
to rats, there was a significant and sustained increase in
the pulmonary expression of heme oxygenase-1 (HO-1), which
is known to be induced by various oxidative stresses, including
inflammation and free heme, and is thought to be essential
in the protection against oxidative tissue injuries. In this
study, we administered hemin (ferripro-toporphyrin chloride,
30 μmol/kg
b.w., subcutaneously), a potent inducer of HO-1, every 3 days
to rats following subcutaneous administration of MCT (60 mg/kg)
and examined its effect on MCT-induced PH and pulmonary inflammation.
MCT administration caused pulmonary arterial wall thickening
with marked elevation of right ventricular pressure, in association
with prominent pulmonary inflammation as revealed by the increase
in gene expression of tumor necrosis factor-α
and the number of infiltrated neutrophils in the lung. In
contrast, hemin treatment of MCT-administered animals, which
led to a further increase in pulmonary HO-1 mRNA expression,
significantly ameliorated MCT-induced PH as well as tissue
inflammation. These findings suggest that hemin treatment
ameliorates MCT-induced PH possibly mediated through induction
of pulmonary HO-1 which leads to the attenuation of pulmonary
inflammation.
[Back to top]
Synthesis of 4-amino-5-cyano-2, 6-Disubstituted Pyrimidines
as a Potential Antifilarial DNA Topoisomerase II Inhibitors
A. Kumar, J.K. Saxena and P.M.S.
Chauhan
A novel series of 4-amino-5-cyano-2, 6-disubstituted
pyrimidines have been synthesized and evaluated for their
in vitro antifilarial DNA topoisomerase II activity
against filarial parasite Setaria Cervi. In particular
compounds bearing 4-chloro-phenyl substitutent at position-6,
exhibited strong inhibition at 40 μg/mL
and 5 μg/mL
concentration. The present study based on the biological results
obtained, suggests that the nature of substitutent at position-4
in the phenyl ring directly affects DNA topoisomerase II inhibitory
activity. Most of the compounds have shown better topoisomerase
II inhibitory activity than the standard antifilarial drug
(DEC) and the topoisomerase II inhibitors (Novobiocin, Nalidixic
acid).
[Back to top]
Synthesis and Anti-Inflammatory Activity of Chalcones and
Related Mannich Bases
Kouskoura Maria, Hadjipavlou-Litina Dimitra
and Giakoumakou Maria
Chalcones and Mannich bases have been reported to present
antiinflammatory activities as well as inhibitory activities
on several factors implicated in inflammation disorders.
A series of chalcones and some related Mannich bases were
prepared by Claisen-Schmidt condensation of appropriate acetophenones
with appropriate aromatic aldehyde. Mannich bases were derived
from chalcones, with formaldehyde and the corresponding amine.
The compounds were tested in vitro for their ability
to inhibit various enzymes involved in the arachidonic acid
cascade, for their antioxidant behaviour and in vivo
for anti-inflammatory activity.
Some chalcones and Mannich bases present strong anti-inflammatory
and antioxidant activities. Almost all the tested compounds
present high inhibitory activity on lipid peroxidation. Some
compounds showed potent inhibitory effect on superoxide anion
formation. Among the tested compounds 5 and
6 showed the highest lipoxygenase (LO) inhibitory
activity. All the tested compounds inhibit both the proteolytic
and esteratic activities of trypsin and chymotrypsin.
The results indicated that the anti-inflammatory effects of
the compounds were partially mediated, through their antioxidant
activity. Attempts to correlate quantitatively structure with
activity revealed that lipophilicity and molar refractivity
influence the biological response.
[Back to top]
Inhibition of Inflammation by a p38 MAP Kinase Targeted Cell
Permeable Peptide
J. Fu, X. Meng, J. He and J. Gu
p38 MAPK has been the key therapeutic target for multiple
inflammation diseases. However, the clinical applications
of p38 inhibitors, most of which target on the ATP binding
groove in the kinase, have been held back, largely because
of their limited specificity and severe side-effects. An alternative
strategy to generate highly selective p38 inhibitor is to
block the specific interaction in the p38 signal pathway.
Based on the hypothesis that specific binding peptides targeting
on the docking groove would interfere the intrinsic interaction
between p38 and its partners, we have designed a fusion peptide
containing 12aa p38 docking sequence derived from MKK3b and
11aa HIV-TAT transmembrane sequence to form a cell permeable
peptide. The peptide specifically binds to p38, and aborts
its interaction with upstream kinase as well as downstream
substrates, and thus to inhibit p38 phosphorylation and its
signaling. Furthermore, the induction and secretion of TNFα
and other inflammatory factors by LPS are blocked in peptide
treated cells and mice. Finally the peptide has been shown
to significantly inhibit ear oedema in mice. Therefore, the
peptide holds great potential as an anti-inflammation agent
for the treatment of inflammation and its related diseases.
[Back to top]
2-Arylbenzimidazoles as Antiviral and Antiproliferative Agents-Part
1
G. Vitale, A. Carta, M. Loriga, G. Paglietti,
P. La Colla, B. Busonera, D. Collu and R. Loddo
Being involved in an anti-Flaviviridae Project, and because
of the role played by benzimidazole derivatives as promising
inhibitors of the HCV helicase and RNA polymerase, as well
as of the Zn finger transcription factor, we synthesized a
new series of 2-arylbenzimidazoles and evaluated them for
antiviral activity, as well as for antiproliferative activity.
Compounds were tested in cell-based assays against viruses
representative of: i) two of the three genera of the Flaviviridae
family, i.e. Flaviviruses and Pestiviruses;
ii) other RNA virus families, such as Retroviridae,
Picornaviridae, Para-myxoviridae, Rhabdoviridae
and Reoviridae; iii) two DNA virus families (Herpesviridae
and Poxviridae). Compounds 15, 28
and 29 resulted moderately active only against
Yellow Fever Virus (a Flavivirus) (range 6-27 μM),
whereas none of the title benzimidazoles showed any antiviral
activity at concentrations not cytotoxic for the resting cell
monolayers.
Compounds were also tested for antiproliferative activity
against a panel of exponentially growing cell lines derived
from human haematological and solid tumors. Several new benzimidazoles
turned out active. Among them, compound 27
was the most potent against human haematologic and solid tumor
cells and turned out to be as potent as Etoposide and more
potent than 6-mercaptopurine (6-MP), used as reference antitumor
agents.
[Back to top]
Enhancement of Escherichia coli and Staphylococcus
aureus Antibiotic Susceptibility Using Sesquiterpenoids
M. Simões, S. Rocha, M.A. Coimbra
and Maria J. Vieira
The present work examines the potential of sesquiterpenoids
to sensitize Escherichia coli and Staphylococcus
aureus, and modulate their susceptibility to the standard
antibiotics ciprofloxacin, erythromycin, gentamicin and vancomycin.
It was tested samples of three sesquiterpenoids: guaiazulene,
nerolidol (racemic mixture of the cis and trans
isomers) and germacrene D enriched natural extract. Experiments
were conducted aiming to assess the antimicrobial effects
of the antibiotic-sesquiterpenoid combination on bacterial
growth inhibition, by the disc diffusion assay and the minimum
inhibitory concentration (MIC) assessment, the bactericidal
effects, the post-antibiotic effect (PAE) and the effect on
membrane permeability. The data related with the antimicrobial
activity evidenced, through the disc diffusion assay, an antibiotic
S. aureus antimicrobial activity enhancement by sesquiterpenoids
presence. The MIC value for E. coli decreased significantly
by sesquiterpenoids combination with ciprofloxacin, erythromycin
and gentamicin, and for S. aureus, with all four
selected antibiotics. This combination also increased the
PAE, with the exception of guaiazulene, which seemed to quench
antibiotic antimicrobial action. A moderate correlation between
antimicrobial action and impairment of cell membrane function
was detected for germacrene D enriched extract, and nerolidol,
as single treatments and in combination with antibiotic, while
a poor correlation was obtained for guaiazulene.
This study provides basis for the evaluation of sesquiterpenoids
as alternative or possible synergistic compounds for current
antimicrobial chemotherapeutics, showing the practical utility
of natural derived products to increase the susceptibility
of E. coli and S. aureus.
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A Comparison of the Biological Properties of Small Molecular
Weight Agonists and Antagonists of CD200:CD200R Interactions
Reg Gorczynski, Ivo Boudakov and Ismat
Khatri
Our laboratory and others have documented in some detail the
immunological consequences which follow from interaction of
the ubiquitously expressed molecule CD200 with its receptor(s)
CD200R (expressed predominantly on cells of myeloid and lymphoid
origin). In particular, there is evidence that these interactions
lead to immunosuppressive signals which modulate graft rejection
responses; decrease the manifestations of arthritis in rodent
models; diminish mast cell mediator release in models of allergic
disease; and favour the growth of tumors in both mice and
humans. The development of small molecular weight agonists
(and/or antagonists) of these interactions would thus likely
have significant clinical importance. The data reported herein
characterizes several such molecules in a number of rodent
models.
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