| Letters
in Drug Design & Discovery
ISSN: 1570-1808
Letters in Drug Design &
Discovery
Volume 4, Number 6, September 2007
Inhibition of Human Leucocyte Elastase by Novel Thieno
1,3-oxazin-4-ones and Thieno-1,3-thioxazin-4-ones
Pp. 386-393
N.A. Santagati, L. Salerno, C. Di Giacomo, L. Vanella
and S. Ronsisvalle
[Abstract]
Synthesis and In Vitro Biochemical Evaluation
of a Series of Compounds as Potential Inhibitors of Estrone
Sulfatase (ES) and the Role of pKa in
both the Synthesis and the Inhibitory Activity of the Potential
Inhibitors Pp. 394-398
C.P. Owen, M. Patel, C.K Patel, T. Cartledge and S. Ahmed
[Abstract]
Synthesis and In Vitro Biochemical Evaluation
of a Series of Cycloalkyl Esters of 4-Sulfamoylated Benzoic
Acid as Inhibitors of Estrone Sulfatase (ES) Pp.
399-403
C.P. Owen, C.K. Patel, T. Cartledge and S. Ahmed
[Abstract]
Synthesis and Anti-HSV-1 Activity of 1,4-dihydro-4
oxoquinoline Ribonucleosides Pp. 404-409
C.V.B. dos S. Canuto, C.R.B. Gomes, I.P. Marques, L.V.
Faro, F. da C. Santos, I.C. de P.P. Frugulhetti, T.M.L. e
Souza, A.C. Cunha, G.A. Romeiro,V.F. Ferreira and M.C.B.V.
de Souza
[Abstract]
Classification and Prediction of Tripeptides Inhibiting
HIV-1 Tat/TAR-RNA Interaction using a Self-Organizing Map
Pp. 410-416
A. Givehchi, V. Ludwig, O. Boden, A. Krebs, U. Scheffer,
M. Göbel and G. Schneider
[Abstract]
Structure-Based Quantitative Structure Activity Relationship
Analysis of Omuralide Analogs in the 20S Proteasome: A Covalent
Inhibitor COMBINE Study Pp. 417-421
J.L. Wang, A. Datta and G.H. Lushington
[Abstract]
The Molecular Basis of COX-2 Versus COX-1
Selectivity of Lumiracoxib by Molecular Docking Studies Pp.
422-425
C.M. Corrêa, A.F. de Paula, G.M.S. da Silva,
C.M.R. Sant’Anna, C.A. M. Fraga and E.J. Barreiro
[Abstract]
A Cationic Liposomal Vincristine Formulation with
Improved Vincristine Retention, Extended Circulation Lifetime
and Increased Anti-Tumor Activity Pp. 426-433
M.S. Webb, N.L. Boman, D. Masin, D. Yapp, E.
Ramsay, G.N.C. Chiu, P.R. Cullis and M.B. Bally
[Abstract]
Isoform-Selective Regulation of Adenylyl Cyclase
by Forskolin Derivatives: Prediction of Selectivity by Computer-Based
Analysis Pp. 434-441
H. Eguchi, K. Iwatsubo and Y. Ishikawa
[Abstract]
Preparation and Biological Activities of Heteroarotinoids
Pp. 442-445
A. Wada, Y. Mizuguchi, H. Miyake, M. Niihara, M. Ito,
K. Nakagawa and T. Okano
[Abstract]
Lamotrigine as an Effective Treatment for Behavioral
Disorders Pp. 446-452
R. Moretti, P. Torre, C. Vilotti and R.M. Antonello
[Abstract]
Release Kinetics of Ampicillin, Biocompatibility
Tests with a Fibroblast Strain of a Zirconia Gel Glass Pp.
453-459
M. Catauro, M.G. Raucci and M.A. Continenza
[Abstract]
Abstracts
[Back to top]
Inhibition of Human Leucocyte Elastase by
Novel Thieno-1,3-oxazin-4-ones and Thieno-1,3-thioxazin-4-ones
N.A. Santagati, L. Salerno, C. Di Giacomo, L. Vanella
and S. Ronsisvalle
In this paper we report the synthesis and the inhibition on
Human Leucocyte Elastase (HLE) of a new series of thieno[2,3-d][1,3]oxazin-
or thioxazin-4-ones 3a-o and thieno[3,2-d][1,3]oxazin-
or thioxazin-4-ones 6a-d. New derivatives
have inhibitory activity in the micromolar range and among
them, 2-(3-trifluoromethylphenylamino)-4H-thieno[2,3-d][1,3]oxazin-4-one
3h and 5,6-dimethyl-2-(4-nitrophenylamino)-4H-thieno[2,3-d][1,3]thioxazin-4-one
3o were the most interesting.
[Back to top]
Synthesis and In Vitro Biochemical Evaluation
of a Series of Compounds as Potential Inhibitors of Estrone
Sulfatase (ES) and the Role of pKa in
both the Synthesis and the Inhibitory Activity of the Potential
Inhibitors
C.P. Owen, M. Patel, C.K Patel, T. Cartledge and S. Ahmed
We report the results of our study into a series of 3,5-dibrominated
derivatives of esters of 4-[(aminosulfonyl)oxy]benzoate as
potential inhibitors of estrone sulfatase (ES). The results
suggest that the compounds are weak inhibitors as a result
of the incorporation of the bromine atoms which reduce the
stability of the compound.
[Back to top]
Synthesis and In Vitro Biochemical Evaluation
of a Series of Cycloalkyl Esters of 4-Sulfamoylated Benzoic
Acid as Inhibitors of Estrone Sulfatase (ES)
C.P. Owen, C.K. Patel, T. Cartledge and S. Ahmed
SWe report the results of the synthesis and biochemical evaluation
of esters of 4-[(aminosulfonyl)oxy]benzoate as potential inhibitors
of estrone sulfatase (ES). Modelling the compounds shows that
steric interaction between the inhibitor and the active site
is a major factor responsible for the weak inhibitory activity
observed within the synthesised compounds.
[Back to top]
Synthesis and Anti-HSV-1 Activity of 1,4-dihydro-4-oxoquinoline
Ribonucleosides
C.V.B. dos S. Canuto, C.R.B. Gomes, I.P. Marques, L.V.
Faro, F. da C. Santos, I.C. de P.P. Frugulhetti, T.M.L. e
Souza, A.C. Cunha, G.A. Romeiro,V.F. Ferreira and M.C.B.V.
de Souza
Oxoquinolineribonucleosides 1a-j were prepared. These substances
were screened for antiviral activity on HSV-1 virus infection,
assessed by virus yield assay. The chlorosubstituted ribonucleosides
1b and 1g were the best inhibitors of HSV-1 yield with EC50
of 1.5 ± 0.06 µM and 1.7 ± 0.08 µM,
respectively. Compound 1b presented the best selectivity index
(SI) with an SI value of 1000.
[Back to top]
Classification and Prediction of Tripeptides Inhibiting
HIV-1 Tat/TAR-RNA Interaction using a Self-Organizing Map
A. Givehchi, V. Ludwig, O. Boden, A. Krebs, U. Scheffer,
M. Göbel and G. Schneider
A self-organizing map (SOM) was used for identification of
synthetic tripeptides to HIV-1 TAR-RNA. This virtual screening
strategy identified a phenanthrene-Arg-Arg sequence with an
IC50 value of 5 µM. The SOM technique
was shown to be applicable to RNA-ligand finding following
an entirely ligand-based approach.
[Back to top]
Structure-Based Quantitative Structure Activity Relationship
Analysis of Omuralide Analogs in the 20S Proteasome: A Covalent
Inhibitor COMBINE Study
J.L. Wang, A. Datta and G.H. Lushington
The structure activity relationship of omuralide-based 20S
proteasome inhibitors is assessed via a COMBINE model
incorporating covalent inhibitors. Reasonable correlation
(R2 = 0.84) and predictivity (Q2 = 0.66)
is obtained relative to experiment. The model confirms prior
SAR assertions and suggests lead refinements involving polar
substitution onto the lactacystin ring.
[Back to top]
The Molecular Basis of COX-2 Versus COX-1
Selectivity of Lumiracoxib by Molecular Docking Studies
C.M. Corrêa, A.F. de Paula, G.M.S. da Silva,
C.M.R. Sant’Anna, C.A. M. Fraga and E.J. Barreiro
A molecular rational basis for the COX-2/COX-1 selectivity
of lumiracoxib using molecular docking approach is described.
The COX-2 docking analysis for lumiracoxib and the diclofenac
analogue revealed a similar binding mode, in contrast with
the COX-1 docking analysis which revealed a different binding
orientation for both inhibitors.
[Back to top]
A Cationic Liposomal Vincristine Formulation with
Improved Vincristine Retention, Extended Circulation Lifetime
and Increased Anti-Tumor Activity
M.S. Webb, N.L. Boman, D. Masin, D. Yapp, E.
Ramsay, G.N.C. Chiu, P.R. Cullis and M.B. Bally
A critical characteristic of optimized liposomal delivery
systems is controlled drug release. This report describes
the use of the monoacyl cationic lipids stearylamine (SA)
and sphingosine (SPH), in conjunction with a transmembrane
pH gradient, to enhance retention of the anticancer agent
vincristine within liposomes administered intravenously to
mice. The addition of SA to liposomes composed of distearoylphosphatidylcholine
(DSPC) and cholesterol (Chol), to achieve a final composition
of DSPC/Chol/SA at ratios of 45/45/10 (mol/mol/mol), caused
a significant improvement in vincristine retention in the
circulation of mice when combined with a transmembrane pH
gradient of 5 units. Specifically, the presence of SA in liposomes
having an internal pH (pHi)
of 2.0 had a plasma vincristine AUC of 41.8 mg•h/100
mL plasma, compared to a vincristine AUC in the plasma of
28.0 mg•h/100 mL for identical liposomes lacking SA;
an increase of 49%. Similar effects were observed with 10
mol% of the cationic lipid SPH. Comparison to control formulations
lacking SA or SPH, or with smaller pH gradients (3 units),
showed that improved vincristine retention required both the
cationic lipid and the larger pH gradient. The presence of
SA or SPH significantly improved vincristine pharmacokinetics
due to the increased drug retention, but did not adversely
alter the liposome pharmacokinetics. Enhanced retention of
vincristine using SPH and a transmembrane pH gradient was
associated with significant increases in anti-tumor activity
against the murine P388 leukemia. The results are directly
relevant to the use of charged lipid components to improve
the drug retention/release attributes and the use of cationic
lipids to promote accumulation at tumor-associated vascular
endothelium.
[Back to top]
Isoform-Selective Regulation of Adenylyl Cyclase by
Forskolin Derivatives: Prediction of Selectivity by Computer-Based
Analysis
H. Eguchi, K. Iwatsubo and Y. Ishikawa
TAdenylyl cyclase is a membrane-bound enzyme that catalyzes
the conversion of ATP to cAMP upon various hormonal stimulations.
Isoform-selectivity among forskolin derivatives that forskolin
and its derivatives are a direct activator of adenylyl cyclase,
can be predicted mostly by the distribution of the negative
electrostatic potential of each derivative.
[Back to top]
Preparation and Biological Activities of Heteroarotinoids
A. Wada, Y. Mizuguchi, H. Miyake, M. Niihara, M. Ito,
K. Nakagawa and T. Okano
Retinoic acid analogs containing an aromatic ring fixed between
the 5 and 8 positions of retinoic acid, were synthesized by
a palladium-catalyzed cross-coupling reaction between boronic
acid and an alkenyltriflate or alkenyliodide. The biological
activities of the retinoic acid analogs were evaluated.
[Back to top]
Lamotrigine as an Effective Treatment for Behavioral
Disorders
R. Moretti, P. Torre, C. Vilotti and R.M. Antonello
Lamotrigine is thought to act at voltage-sensitive sodium
channels to stabilize neuronal membranes and inhibit the release
of excitatory amino acid neurotransmitters (e.g. glutamate,
aspartate) that are thought to play a role in the generation
and spread of epileptic seizures. In placebo-controlled clinical
studies, lamotrigine has been shown to be effective in reducing
seizure frequency and the number of days with seizures when
added to existing antiepileptic drug therapy in adult patients
with partial seizures, with or without generalized tonic-clonic
seizures, that are not satisfactorily controlled. Lamotrigine
has emerged as a first line treatment for bipolar depression,
which is an area of weakness for other mood stabilizers, with
positive effect for resistant bipolar disorders and rapid
cycling bipolar disorders. We review the Literature on the
topic with a specific interest on bipolar disorders.
[Back to top]
Release Kinetics of Ampicillin, Biocompatibility Tests
with a Fibroblast Strain of a Zirconia Gel Glass
M. Catauro, M.G. Raucci and M.A. Continenza
Biocompatibility remains the central theme for biomaterials
applications in medicine. It is generally accepted that this
term does not indicate only absence of a cytotoxic effect
but also positive effects in the sense of biofunctionality,
i.e. promotion of biological processes considering the intended
aim of the application of a biomaterial.
Biocompatibility of zirconia gel glass was studied using in
vitro testing methods, the incubation period was 7, 14,
21 days. The bioactivity of the synthesized material had been
shown by the formation of a layer of hydroxyapatite on the
surface of ZrO2-Y2O3(5wt%)
samples soaked in a fluid simulating the composition of the
human blood plasma (SBF), as observed by SEM and EDS microscopy.
Studies of drug delivery kinetics were also carried out. The
amount of sodium ampicillin released has been detected by
UV-VIS spectroscopy. The released kinetics seems to occur
in more than one stage. HPLC analysis had also been carried
out to ensure the integrity of ampicillin after the synthetic
treatment.
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