| Letters
in Drug Design & Discovery
ISSN: 1570-1808
Upcoming Articles
Telmisartan Blocks Advanced Glycation End Product (AGE)-Induced
Plasminogen Activator Inhibitor-1 (PAI-1) Gene Expression
in Endo-thelial Cells via Activation of Peroxisome
Proliferator-Activated Receptor-γ
PPAR-γ
Takanori Matsui, Kazuo Nakamura, Masayoshi Takeuchi and
Sho-ichi Yamagishi
[Abstract]
Synthesis and Biological Evaluation of Novel 6-Deoxy-β-D-Psicofuranosyl
Mercaptoheterocyclic Compounds
I.G. De Lade, F.G. Braga, R.M. Grazul, E.S. Coimbra and
A.D. Da Silva
[Abstract]
Microwave-Assisted Synthesis of Imido-Substituted
2-Chloro-1,4-naphtho-quinone Derivatives and their Cytotoxic
Activities on Three Human Prostate Cancer Cell Lines
Solomon Berhe, Yasmine Kanaan, Robert L. Copeland, Jr.,
Dwayne A. Wright, Leon H. Zalkow and Oladapo Bakare
[Abstract]
Antitumor Activity of Oxali-Titanocene Y in Xenografted CAKI-1
Tumors in Mice
Iduna Fichtner, Diana Behrens, James Claffey, Brendan Gleeson,
Megan Hogan, Denise Wallis, Holger Weber and Matthias Tacke
[Abstract]
Multidimensional Consensus QSAR: A Step towards Integrating
CoMFA, CoMSIA with Traditional QSAR Methodologies
P. Dewangan, S.M. Verma, A. Basu and Venkatesan J.
[Abstract]
Synthesis of a Novel Series of 8-HETE Analogs and
their Biological Evaluation Towards the PPAR Nuclear Receptors
Mélanie Liutkus, Catherine Dacquet, Valérie
Audinot-Bouchez, Jean Boutin, Daniel-Henri Caignard, Alain
Ktorza and René Grée
[Abstract]
Molecular Modeling of Flavonoid-β-Cyclodextrin
Complexes
Ying Zheng, Albert H.L. Chow and Ian S. Haworth
[Abstract]
Identification of GCP II Inhibitors Based on 4-Arylmethyl-3-(4-carboxyphenyl)-5-hydroxyisoxazole
Scaffold
M. Teusa, A. Jirgensons M. Dambrova, R. Mezhapuke, C. G. Parsons
and W. Danysz
[Abstract]
Structural and Morphological Studies of Cationic Liposomes-DNA
Complexes
Yan Sun, Itziar Miguéliz, Gemma Navarro and Conchita
Tros de Ilarduya
[Abstract]
Synthesis of 4-substituted-3-hydroxy-5-oxo-10-oxa-4-azatricyclo[5.2.1]dec-3-yl
Acetic Acid Ethyl Esters As Norcantharidin Analogues
Benjamin Sauer, Jayne Gilbert, Jennette A. Sakoff and Adam
McCluskey
[Abstract]
Buprenorphine and Methadone Maintenance Treatment
- Sexual Behaviour and Dysfunction Prevalence
S.M. Giacomuzzi, A. Khreis, Y. Riemer, K. Garber and M. Ertl
[Abstract]
Involvement of Serotonin in the Acute Dependence Produced
by μ,
and K Opioid Agonists
Anna Capasso
[Abstract]
Synthesis, Antibacterial Activity of 2,4-Disubstituted
Oxazoles and Thiazoles as Bioisosteres
Mohamed Kaspady, Venugopala Katharigatta Narayanaswamy, Mohana
Raju and Gopal Krishna Rao
[Abstract]
Computer-Aided Drug Design for Cancer-Causing H-Ras
p21 Mutant Protein
Mannu Jayakanthan, Gulshan Wadhwa, Thangavel Madhan Mohan,
Loganathan Arul, Ponnusamy Balasubramanian and Durai Sundar
[Abstract]
Evaluation of In-Vivo Anti-Implantation and
In-Vitro Anti-Proliferative Activities of Substituted
3-phenyl-4-phenylvinyl Benzopyranone Derivatives
Atul Gupta, Ramesh Sharma, Anil Kumar Balapure, Govind Keshri,
M.M. Singh and Suprabhat Ray
[Abstract]
Solution-Phase Parallel Synthesis of N-Arylisoquinuclidines
Ronald F. Borne, Mark S. Levi, M.O. Faruk Khan and Norman
H. Wilson
[Abstract]
Abstracts
[Back to top ]
Telmisartan Blocks Advanced Glycation End Product
(AGE)-Induced Plasminogen Activator Inhibitor-1 (PAI-1) Gene
Expression in Endo-thelial Cells via Activation of
Peroxisome Proliferator-Activated Receptor-γ
PPAR-γ
Takanori Matsui, Kazuo Nakamura, Masayoshi Takeuchi and
Sho-ichi Yamagishi
Advanced glycation end product (AGE) and receptor (RAGE) axis
play a central role in the pathogenesis of diabetic vascular
complications. Since peroxisome proliferator-activated receptor-γ
(PPAR-γ)
agonists have been reported to reduce RAGE gene expression
and subsequently suppress the downstream signalings in human
umbilical vein endothelial cells (HUVECs), we examined here
whether telmisartan, a unique angiotensin II type 1 receptor
blocker with PPAR-γ
agonistic activity, could inhibit the AGE-induced up-regulation
of plasminogen activator inhibitor-1 (PAI-1) mRNA levels in
HUVECs by suppressing RAGE gene expression. Telmisartan completely
blocked the AGE-induced RAGE gene up-regulation in HUVECs,
which was partly prevented by GW9662, an inhibitor of PPAR-γ.
Further, telmisartan was also found to inhibit up-regulation
of mRNA levels for PAI-1 in AGE-exposed HUVECs, which was
completely prevented by GW9662. These results suggest that
telmisartan inhibits the AGE-induced PAI-1 gene induction
in HUVECs by down-regulating RAGE expression via
PPAR-γ
activation. Our present study suggests that telmisartan works
as an anti-thrombogenic agent against AGEs, which may play
a protective role against vascular complications in diabetes.
[Back to top ]
Synthesis and Biological Evaluation of Novel 6-Deoxy-β-D-Psicofuranosyl
Mercaptoheterocyclic Compounds
I.G. De Lade, F.G. Braga, R.M. Grazul, E.S. Coimbra and
A.D. Da Silva
We report herein the synthesis of a series of eight novel
compounds based on the coupling of 6-mercaptopurine (4),
2-mercaptopyrimidine (5), 4-mercaptopyridine
(6) and 2-mercaptobenzimidazole (7)
with 6-deoxy-6-iodo-1,2:3,4-di-O-isopropylidene-β-D-psicofuranose
and subsequent deprotection. The compounds were evaluated
in vitro for activity against Leishmania amazonensis
and L. chagasi promastigotes and for cytotoxic activity
against Kb and Vero cells.
[Back to top ]
Microwave-Assisted Synthesis of Imido-Substituted
2-Chloro-1,4-naphtho-quinone Derivatives and their Cytotoxic
Activities on Three Human Prostate Cancer Cell Lines
Solomon Berhe, Yasmine Kanaan, Robert L. Copeland, Jr.,
Dwayne A. Wright, Leon H. Zalkow and Oladapo Bakare
The anticancer activities of six imido-substituted
2-chloro-1,4-naphthoquinone derivatives on one androgen-dependent,
LNCaP, and two androgen-independent, PC3 and DU145, human
prostate cancer cell lines are reported. The open chain imides
(2-4) showed more potency in all three cell
lines. In addition the microwave-assisted synthesis of five
of these compounds is reported.
[Back to top ]
Antitumor Activity of Oxali-Titanocene Y in Xenografted
CAKI-1 Tumors in Mice
Iduna Fichtner, Diana Behrens, James Claffey, Brendan Gleeson,
Megan Hogan, Denise Wallis, Holger Weber and Matthias Tacke
The para-methoxybenzyl-substituted titanocene
oxalate (Oxali-Titanocene Y) was tested in vitro
in an anti-angiogenesis assay against human umbilical vein
endothelial cells, HUVEC, delivering an IC50 value of 14 μM
and in a cytotoxicity assay against the human renal cancer
cells, CAKI-1, which demonstrated an IC50 value greater than
100 μM.
Then Oxali-Titanocene Y was given at 30 mg/kg/d, which is
the maximum tolerable dose, on five consecutive days per week
for three weeks to one cohort of eight CAKI-1 tumor-bearing
female NMRI:nu/nu mice, while a second cohort was treated
with solvent only. The titanocene-treated mouse cohort showed
a statistically significant tumor growth reduction with respect
to the solvent-treated control group with an optimal T/C value
of 38% at the end of the experiment. Immunohistological analysis
revealed that the expression of the proliferation marker Ki-67
was reduced by 30%. Furthermore, an anti-angiogenic activity
was identified by CD31 staining; the number of micro vessels
in a defined tumor area was significantly decreased due to
Oxali-Titanocene Y treatment.
[Back to top ]
Multidimensional Consensus QSAR: A Step towards
Integrating CoMFA, CoMSIA with Traditional QSAR Methodologies
P. Dewangan, S.M. Verma, A. Basu and Venkatesan J.
A consensus QSAR combining traditional 2D-QSAR with
CoMFA and CoMSIA was developed for N, N'- bis substituted
guanidines reported with NMDA receptor ion channel blocker
activity. Two new statistics r2wμp
(leverage weighted mean r2pred)
and r2μp
(mean r2pred)
were defined. A slight improvement in predictive ability was
observed for all the combinations while using r2wμp
(0.630, 0.691, 0.672) rather than r2μp
(0.622, 0.644, 0.658) however the approach has to be validated
using more datasets.
[Back to top ]
Synthesis of a Novel Series of 8-HETE Analogs
and their Biological Evaluation Towards the PPAR Nuclear Receptors
Mélanie Liutkus, Catherine Dacquet, Valérie
Audinot-Bouchez, Jean Boutin, Daniel-Henri Caignard, Alain
Ktorza and René Grée
A novel series of dual PPARα/γ
agonists was designed through the modification of our previously
described family of 8-HETE analogs. The combination of the
structural elements of this family and of the classical PPAR
ligands produced compounds with a quinoxaline core and two
sides chains. Structure-activity relationship studies have
been carried out on the new series and compounds belonging
to this new family have been tested in vitro on both
subtypes of PPAR nuclear receptors. Corresponding results
indicated a strong decrease in the activity towards both subtypes,
especially on PPARγ.
However, they have also clearly shown the central role of
the bottom side chain in the activity.
[Back to top ]
Molecular Modeling of Flavonoid-β-Cyclodextrin
Complexes
Ying Zheng, Albert H.L. Chow and Ian S. Haworth
Molecular modeling of flavonoid/β-cyclodextrin
complexes was used for rationalization of 1H-NMR
data. We describe an algorithm that allows exact definition
of the starting host-guest orientation. We used this algorithm
to build complexes of two flavonoids, quercetin and myricetin.
Subsequent molecular dynamics simulations yielded structures
consistent with NMR data for the flavonoid position in the
β-cyclodextrin
cavity.
[Back to top ]
Identification of GCP II Inhibitors Based on 4-Arylmethyl-3-(4-carboxyphenyl)-5-hydroxyisoxazole
Scaffold
M. Teusa, A. Jirgensons M. Dambrova, R. Mezhapuke, C. G. Parsons
and W. Danysz
Screening of a non-ionizable compound library and
hit optimization studies has resulted in a series of compounds
based on a 4-arylmethyl-3-(4-carboxyphenyl)-5-hydroxyisoxazole
scaffold with GCP II inhibitory activity in the low micromolar
range.
[Back to top ]
Structural and Morphological Studies of Cationic
Liposomes-DNA Complexes
Yan Sun, Itziar Miguéliz, Gemma Navarro and Conchita
Tros de Ilarduya
In this study we have prepared and characterized, in
terms of structure and morphology, different cationic lipid-DNA
complexes (lipoplexes). Condensation studies showing the ability
of cationic lipids to condense DNA are presented. The effect
of the presence of serum and the ligand transferrin (Tf) has
also been evaluated. Studies of negative stain transmission
electron microscopy (TEM), infrared spectroscopy (FTIR), differential
thermal analysis (DTA) and X-ray diffractometry have shown
stable complexes with different morphology and structural
rearrangements.
[Back to top ]
Synthesis of 4-substituted-3-hydroxy-5-oxo-10-oxa-4-azatricyclo[5.2.1]dec-3-yl
Acetic Acid Ethyl Esters As Norcantharidin Analogues
Benjamin Sauer, Jayne Gilbert, Jennette A. Sakoff and Adam
McCluskey
A novel library of eighteen 4-substituted-3-hydroxy-5-oxo-10-oxa-4-azatricyclo[5.2.1]dec-3-yl
acetic acid ethyl esters was generated in high yield in two
steps from norcantharidin, a known protein phosphatase 1 and
2A inhibitor that displays good anticancer activity. Interestingly
these analogues are bereft of anticancer and protein phosphatase
activity, but possess the attributes needed for medicinal
agents and could be used as scaffolds in other targets.
[Back to top ]
Buprenorphine and Methadone Maintenance Treatment
- Sexual Behaviour and Dysfunction Prevalence
S.M. Giacomuzzi, A. Khreis, Y. Riemer, K. Garber and M. Ertl
Buprenorphine maintenance treatment has become a
major intervention in the care and treatment of drug dependence
in Europe. Still little is known about sexual behaviour and
sexual dysfunction especially under buprenorphine or methadone
maintenance treatment. Our study aimed to evaluate patterns
of sexual behaviour and dysfunction prevalence within buprenorphine
and methadone maintenance treatment. Significant differences
between both groups could be observed regarding sexual excitation
disturbances and ability to orgasm. 33.3% of the methadone-maintained
group showed significantly higher sexual excitation disturbances
(p = 0.006). Future studies of sexual dysfunction in opioid-treated
persons should examine the potential benefits of dose reduction,
androgen replacement, and choice of opioid.
[Back to top ]
Involvement of Serotonin in the Acute Dependence
Produced by μ,
and K Opioid Agonists
Anna Capasso
Dependence can be induced and measured in vitro by using guinea-pig
ileum. Tissues from untreated animals, after a brief exposure
to opioids, show a strong naloxone-induced contracture indicating
that the cellular mechanisms of dependence may occur very
rapidly following occupation of receptors and that these mechanisms
operate within the myenteric plexus. The characteristics of
dependence development and the precipitation of withdrawal
by naloxone in the guinea-pig ileum are very similar to those
of acute dependence in experimental animals and man. Several
observations indicate that brain serotoninergic system has
been widely implicated in many of the pharmacological effects
of opioids. Although the role of serotonin in the development
of dependence has been previously reported the effects exerted
by chronic treatment of p-Chlorophenylalanine (p-CPA),
an inhibitor of tryptophan 5-hydroxylation which is the rate
limiting step in the synthesis of serotonin, on the acute
opiate withdrawal was investigated in vitro and whether
p-CPA interferences on opiate withdrawal take place
through μ
and/or κ
opioid receptors.
Following a 4 min in vitro exposure to the opioid
agonist (Morphine, DAGO or U50-488H), the guinea-pig isolated
ileum exhibited a strong contracture after the addition of
naloxone (80% of contraction vs. acetylcholine control).
By contrast, ilea from guinea-pigs treated for 6 days with
p-CPA (10 mg/Kg/i.p.), following a 4 min in vitro
exposure to the opioid agonist, did not show any contracture
after the addition of naloxone (0% of contraction vs. acetylcholine
control). The results of the present study confirm an important
functional interaction between the serotoninergic system and
opioid sys-tem.
[Back to top ]
Synthesis, Antibacterial Activity of 2,4-Disubstituted
Oxazoles and Thiazoles as Bioisosteres
Mohamed Kaspady, Venugopala Katharigatta Narayanaswamy, Mohana
Raju and Gopal Krishna Rao
Two series of 2-substituted aryl, heteroaryl and
alkyl, 4-substituted aryl 1,3-oxazole (2a-k)
and thiazole (4a-k) molecular scaffolds containing
divalent bioisosteres, viz., oxygen and sulphur were synthesized
by condensing substituted amides and thioamides with substituted
phenacyl bromide in absolute ethanol medium. The structure
of newly synthesized compounds was characterized by analytical
and spectral (IR, 1H-NMR,
13C-NMR and LC-MS) methods.
The synthesized compounds were evaluated for qualitative (zone
of inhibition) and quantitative antibacterial activity (MIC)
by agar cup plate and micro-titration methods, respectively.
Preliminary pharmacological observations revealed that some
of the sub-stituents such as 2-alkyl and heteroaryl at second
position, chloro and bromo at the fourth position of the aryl
moiety and a divalent sulphur atom in the five-membered heterocyclic
ring system influenced significantly the antibacterial activity
when compared to its bioisostere counterpart 2-substituted
aryl, heteroaryl and alkyl, 4-substituted aryl 1,3-oxazole
sys-tems.
[Back to top ]
Computer-Aided Drug Design for Cancer-Causing
H-Ras p21 Mutant Protein
Mannu Jayakanthan, Gulshan Wadhwa, Thangavel Madhan Mohan,
Loganathan Arul, Ponnusamy Balasubramanian and Durai Sundar
GTP-bound mutant form H-Ras (Harvey-Ras) proteins
are found in 30% of human tumors. Activation of H-Ras is due
to point mutation at positions 12, 13, 59 and/or 61 codon.
Mutant form of H-Ras proteins is continuously involved in
signal transduction for cell growth and proliferation through
interaction of downstream-regulated protein Raf. In this paper,
we have reported the virtual screening of lead compounds for
H-Ras P21 mutant protein
from ChemBank and DrugBank databases using LigandFit and DrugBank-BLAST.
The analysis resulted in 13 hits which were docked and scored
to identify structurally active leads that make similar interaction
to those of bound complex of H-Ras P21
mutant-Raf. This approach produced two different leads, 3-Aminopropanesulphonic
acid (docked energy -3.014 kcal/mol) and Hydroxyurea (docked
energy -0.009 kcal/mol) with finest Lipinski’s rule-of-five.
Their docked energy scores were better than the complex structure
of H-Ras P21 mutant protein
bound with Raf (1.18 kcal/mol). All the leads were docked
into effector region forming interaction with ILE36, GLU37,
ASP38 and SER39.
[Back to top ]
Evaluation of In-Vivo Anti-Implantation
and In-Vitro Anti-Proliferative Activities of Substituted
3-phenyl-4-phenylvinyl Benzopyranone Derivatives
Atul Gupta, Ramesh Sharma, Anil Kumar Balapure, Govind Keshri,
M.M. Singh and Suprabhat Ray
A series of substituted 3-phenyl-4-phenylvinyl benzopyranone
derivatives (11a-e) was evaluated for their
anti-implantation activity in mature female Sprague-Dawley
rat model. Compounds were further evaluated for anti-proliferative
activity in human adenocarcenoma breast cancer cell line (MCF-7
cancer cell line). The tested compounds showed significant
anti-proliferative activity with moderate anti-implantation
activity. The inhibitory concentration (IC50)
values of most active compounds 11 (c-e)
are 8.43 μM,
7.97 μM
and 7.91 μM
respectively and comparable to that of tamoxifen (5.10 μM),
a well known antiestrogen used for treatment of breast cancer.
[Back to top ]
Solution-Phase Parallel Synthesis of N-Arylisoquinuclidines
Ronald F. Borne, Mark S. Levi, M.O. Faruk Khan and Norman
H. Wilson
The naturally-occurring alkaloid ibogaine, found
in the West African shrub Tabernanthe iboga, possesses
the ability to diminish self-administration of substances
of abuse, such as cocaine, heroin and alcohol. The presence
of the isoquinuclidine ring system in the structure of ibogaine
became the lead for the design of a 16-member library of N-aryl
isoquinuclidines, where pyridine, pyrimidine and quinoline
ring systems were attached directly to the bicyclic nitrogen.
A solution-phase method for their synthesis is described.
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