Letters in Drug Design & Discovery, Volume 2, No. 3, 2005
Contents
Role of a2-Antiplasmin in Cardiovascular
System Pp.172-176
En Shu, Hiroyuki Matsuno, Yasuo Kitajima and Osamu Kozawa
Peptide Mimetic Factor VIIa
Inhibitor: Importance of Hydrophilic Pocket in S2 Site to Improve Selectivity
Against Thrombin Pp.177-181
S. Kadono, A. Sakamoto, Y. Kikuchi, M. Oh-eda, N. Yabuta,
T. Koga, K. Hattori, T. Shiraishi, M. Haramura, H. Kodama, T. Esaki, H. Sato,
Y. Watanabe, S. Itoh, M. Ohta and T. Kozono
A Cellular ELISA to Screen
Lectin-Like Compounds for Cancer Cell Binding Pp.182-188
C-P. Chang, W-C. Cheng and H-Y. Lei
A Facile Synthesis of C2-Substituted
Pyrrolo[2,3-f]quinolines with Cytotoxic Activity Pp.189-192
Andrew Tsotinis, Margarita Vlachou, Spyridon Zouroudis,
Andras Jeney, Ferenc Timar, David E. Thurston and Christos Roussakis
Impact of Oral Administration of
the Surface-Active Excipient Solutol HS 15 on the Pharmacokinetics of
Intravenously Administered Colchicine Pp.193-195
B. Bittner, R.C. Bravo Gonzalez, I. Walter and J. Huwyler
Evaluation of Thermal Cisplatin Sensitization
in Chicken DT40 Cells, Normal and Deficient, in DNA Homologous and
Nonhomologous Endjoining Repair Pp.196-200
G.P. Raaphorst and J- Maude Leblanc
Preliminary In vitro
Results Indicating Tartronic Acids as Aspartic Acid Mimetics in Vitronectin
Receptor Antagonists: Evidence for Increased Hydroxyapatite Affinity Pp.201-204
Diane B. Hauze, Kenneth L. Kees, Charles W. Mann, Horace
Fletcher III, Richard Murrills, Jeanne Matteo, Frederick Bex, Bheem Bhat and
Valerie Coleburn
An Approach Towards the
Quantitative Structure-Activity Relationships for Sulfamate-Based Estrone
Sulfatase Inhibitors Pp.205-218
Rajeshwar P. Verma
Pyrazinobenzodiazepines as Potent
Nonpeptide Vasopressin Receptor Antagonists Pp.219-223
Jay M. Matthews, Dennis J. Hlasta, Patricia Andrade-Gordon,
Keith T. Demarest, Eric Ericson, Joseph W. Gunnet, William Hageman, Richard
Look, John B. Moore, and Bruce E. Maryanoff
Synthesis and Characterization of
a Novel Protein Tyrosine Phosphatase Inhibitor, 2-(Cyclobutylamino)- N-
(2-Furylmethyl)-2-Thioxoacetamide Pp.224-227
Y. Kobayashi-Matsunaga, T. Ishii, T. Hamaguchi, H. Osada
and M. Sato
Expression of a6b4 and a3b1 Integrins in Bullous Pemphigoid
and Pemphigus Vulgaris Pp.228-231
G. Giannelli, C. Foti, C. Divella, F. Marinosci, D.
Bonamonte and S. Antonaci
Molecular Modeling for
Quantitative Analysis of Molecular Interaction Pp.232-238
Toshihiko Hanai
Ascorbic Acid as Modulator of
Immune Function in Sepsis Pp.239-244
V.M. Victor
Difficulties in the Management of
Frontal Dementia: Therapeutics Strategies Pp.245-249
Rita Moretti, Paola Torre, Rodolfo M. Antonello, Tatiana Cattaruzza
and Giuseppe Cazzato
Design of a New Phosphate Binder,
Anion Exchange Resin, Based on Microcalorimeter Measurements Pp.250-254
Hiroyoshi Inoue and Sho-ichi Yamagishi
Abstracts
[Back to top] Role of a2-Antiplasmin in Cardiovascular
System
En Shu, Hiroyuki Matsuno, Yasuo Kitajima and Osamu Kozawa
Inhibition of the blood fibrinolytic system (plasminogen/plasmin)
occurs either at the level of plasminogen activators, regulated by specific
plasminogen activator inhibitors (PAIs) or at the level of plasmin, mainly
regulated by a2-antiplasmin (a2-AP).
In this contribution, we focused on the roles of a2-AP
in acute myocardial infarction and vascular remodeling associated with
cardiovascular diseases. Our findings have identified a new target for the
development of new therapeutics for the clinical therapy of cardiovascular
diseases.
[Back to top] Peptide Mimetic Factor VIIa
Inhibitor: Importance of Hydrophilic Pocket in S2 Site to Improve Selectivity
Against Thrombin
S. Kadono, A. Sakamoto, Y. Kikuchi, M. Oh-eda, N. Yabuta,
T. Koga, K. Hattori, T. Shiraishi, M. Haramura, H. Kodama, T. Esaki, H. Sato,
Y. Watanabe, S. Itoh, M. Ohta and T. Kozono
X-ray structure analysis of human factor VIIa/soluble tissue factor in
complex with a peptide mimetic inhibitor reveals that Asp60, Tyr94, and Thr98
in the S2 site play an important role for the improvement of selectivity
against thrombin.
[Back to top] A Cellular ELISA to Screen
Lectin-Like Compounds for Cancer Cell Binding
C-P. Chang, W-C. Cheng and H-Y. Lei
Lectins are carbohydrate-binding proteins that can modulate cellular
activity through cell membrane glycoproteins. A cell-based binding was set up
to screen the lectin-like substances in natural products. Lectins, after
binding to tumor cells, are detected with a biotinylated
carbohydrate-polyacrylamide complex by ELISA. Sugar specificity can also be
determined within the assay.
[Back to top] A Facile Synthesis of C2-Substituted
Pyrrolo[2,3-f]quinolines with Cytotoxic Activity
Andrew Tsotinis, Margarita
Vlachou, Spyridon Zouroudis, Andras Jeney, Ferenc Timar, David E. Thurston and
Christos Roussakis
An expeditious four-step synthesis of the 1H-pyrrolo[2,3-f]quinoline-2-carboxamides
(5a-h) is described. Readily available 6-quinolinecarboxaldehyde is
converted to the parent acid (6) by nucleophilic attack of the
azido-ester (9) and intramolecular cyclization of (10) followed
by hydrolysis of the methyl ester (11). The cytotoxicity of the target
molecules (5a-h) was evaluated in four tumour cell lines in vitro.
One compound (5d) showed sufficient activity (IC50 = 10.2 µM)
in the human non-small cell lung cell line NSCLCN16- L16 to be worthy of
further study.
[Back to top] Impact of Oral Administration of
the Surface-Active Excipient Solutol HS 15 on the Pharmacokinetics of
Intravenously Administered Colchicine
B. Bittner, R.C. Bravo
Gonzalez, I. Walter and J. Huwyler
Formulation ingredients may influence the pharmacokinetics of
co-administered drugs. We investigated whether oral pre-dosing with the
‘inactive’ formulation ingredient Solutol affects the pharmacokinetic profile
of intravenously administered colchicine in rats. Colchicine was administered
intravenously to male Wistar rats as solution in isotonic sodium chloride (NaCl
0.9%, control group) at 1.5 mg/kg. A second group of rats received the
intravenous dose of colchicine 20 minutes after oral pre-dosage with 4 mg/kg of
a 90:10 (v/v) mixture of NaCl 0.9% and Solutol HS 15 (Solutol). At
predetermined time points, plasma and urine were collected from the animals and
analyzed for colchicine and its demethylated metabolites by LC/MS-MS. After
oral pre-treatment with Solutol, colchicine plasma clearance (Cl) was decreased
by a factor of two and its maximum plasma concentration (cmax) was
almost twofold increased as compared to the control group. Moreover, the amount
of parent colchicine excreted into urine within 24 hours after administration
did increase twentyfold in the Solutol treated group. Renal excretion of
colchicine metabolites was slightly increased. We conclude that absorption of
Solutol and/or its degradation products into the systemic circulation seems to
be a major contributor to the observed effects. Our results suggest that oral
administration of formulation ingredients may alter the distribution kinetics
of drugs, which are co-administered orally as well as intravenously.
[Back to top] Evaluation of Thermal Cisplatin
Sensitization in Chicken DT40 Cells, Normal and Deficient, in DNA Homologous
and Nonhomologous Endjoining Repair
G.P. Raaphorst and J- Maude
Leblanc
Hyperthermia has been shown in many studies to be a strong sensitizer
for cisplatin treatment and this sensitization may be in part due to the
inhibition of DNA repair processes. We have set out to test this in cells with
specific gene knockouts for known repair processes. The chicken DT40 cell
system was used with a parental line (DT40) and knockouts of homologous
recombination (HR) repair DT40Rad54, nonhomologous recombination endjoining
(NHEJ) repair (DT40Ku70) and a double knockout mutant DT40Ku70Rad54. The
results show that thermal cisplatin sensitization was achieved in all cell lines
when hyperthermia at 45oC for 1.5h was given before cisplatin
treatment and 42oC hyperthermia was given concurrently with
cisplatin treatment. The data show that inhibition of the HR repair system did
not significantly affect sensitization, while inhibition of NHEJ reduced
thermal sensitization at low cisplatin doses and short treatments and for
concurrent treatments. These data indicate that there may be a partial
involvement of NHEJ in thermal cisplatin sensitization under specific treatment
conditions.
[Back to top] Preliminary In vitro Results Indicating Tartronic
Acids as Aspartic Acid Mimetics in Vitronectin Receptor Antagonists: Evidence
for Increased Hydroxyapatite Affinity
Diane B. Hauze, Kenneth L.
Kees, Charles W. Mann, Horace Fletcher III, Richard Murrills, Jeanne Matteo,
Frederick Bex, Bheem Bhat and Valerie Coleburn
A series of tartronic acid analogs of a non-peptide RGD mimetic were
prepared and evaluated both for antagonism of the vitronectin receptor and for
affinity to hydroxyapatite, the main inorganic component of bone matrix. The
hydroxy bis acid unit was found to be optimal for both receptor binding and
hydroxyapatite affinity, while the N-terminus affected only receptor binding
affinity.
[Back to top] An Approach Towards the Quantitative Structure-Activity
Relationships for Sulfamate-Based Estrone Sulfatase Inhibitors
Rajeshwar P. Verma
Estrone sulfatase (ES) is a membrane-bound enzyme that is responsible for
maintaining high levels of estrogens in breast cancer cells. This may be due to
the conversion of estrone-sulfate into estrone by estronesulfatase, which acts
as a pool of potentially available estrogens. There is now abundant evidence
that estrogens have a pivotal role in the growth and development of
hormone-dependent breast cancer. Thus, inhibitors of ES should have
considerable therapeutic potential for the treatment of hormone-dependent
breast cancer. Recently, a large number of sulfamate-based steroidal and
non-steroidal ES inhibitors have been developed. The sulfamate moiety is
believed to be involved in the irreversible inhibition of ES. In the present
paper, we have undertaken quantitative structure-activity relationships for
different series of non-steroidal sulfamate-based compounds in order to
understand the chemical-biological interactions governing their inhibitory
potency against ES. QSAR results have shown that the inhibitory potency against
ES for these nonsteroidal sulfamate-based compounds is largely dependent on
their hydrophobicity and molar refractivity.
[Back to top] Pyrazinobenzodiazepines as Potent Nonpeptide Vasopressin
Receptor Antagonists
Jay M. Matthews, Dennis J. Hlasta, Patricia Andrade-Gordon,
Keith T. Demarest, Eric Ericson, Joseph W. Gunnet, William Hageman, Richard
Look, John B. Moore and Bruce E. Maryanoff
We have identified a novel series of tricyclic pyrazinobenzodiazepines,
represented by general structure 2, as potent vasopressin receptor antagonists.
For example, 3 binds with high affinity to human V2 receptors and is
very selective relative to V1a receptors. Compound (R)-(+)-3
exhibited pronounced aquaretic activity in rats and dogs on oral
administration.
[Back to top] Synthesis and Characterization of a Novel Protein Tyrosine
Phosphatase Inhibitor, 2-(Cyclobutylamino)- N-
(2-Furylmethyl)-2-Thioxoacetamide
Y. Kobayashi-Matsunaga, T.
Ishii, T. Hamaguchi, H. Osada and M. Sato
The synthesis and biological activities of a series of
2-amino-2-thioxoacetamide derivatives are described. These compounds have
inhibitory effects against the protein tyrosine phosphatase activity of CD45.
Compound 4i inhibited the PCA reaction in vivo.
[Back to top] Expression of a6b4 and a3b1 Integrins in Bullous Pemphigoid and Pemphigus Vulgaris
G. Giannelli, C. Foti, C.
Divella, F. Marinosci, D. Bonamonte and S. Antonaci
Bullous pemphigoid and pemphigus vulgaris are blistering diseases. Our results show that expression of the integrins a6b4 a3b1is altered in both diseases: a6b4 to a greater extent in the former and a3b1 in the latter disease, respectively. Instead, the extracellular matrix examined resulted normally expressed.
[Back to top] Molecular Modeling for Quantitative Analysis of Molecular
Interaction
Toshihiko Hanai
The binding affinity (log nK) between human serum albumin and
acidic drugs was quantitatively analyzed using a computational chemical method
with several model phases. A flat guanidino-phase was the most efficient for
calculating log nK values, and docking was easily performed. A flowerpot
type model phase bonded a guanidine group at the center bottom demonstrating
that ion-ion interaction was the main driving force. A large molecule pushed
aside the hydrophobic wall of log P = 5, and reached the guanidino
group. Ionized acidic compounds may reach the guanidino group inside a protein
by ion-ion interaction through a narrow channel of length 10Å.
[Back to top] Ascorbic Acid as Modulator of Immune Function in Sepsis
V.M. Victor
Oxidative stress is a major contributing factor to high mortality rates
associated with several diseases such as sepsis. This condition can be controlled
to a certain degree by antioxidants for instance ascorbic acid (vitamin C).
This review focuses on the potential treatment of sepsis by ascorbic acid and
its effects on the immune cell function.
[Back to top] Difficulties in the Management of Frontal Dementia:
Therapeutics Strategies
Rita Moretti, Paola Torre, Rodolfo M. Antonello, Tatiana
Cattaruzza and Giuseppe Cazzato
Frontal dementia gives rise to characteristic behavioral changes, which
include altered emotions, profound alterations in personality and social
conduct, and behavioral alterations constitute core and supportive symptoms
laid out in the diagnostic criteria. There are some behavioral symptoms which
are considered specific for frontal dementia, being present in at least 50% of
cases. These includes loss of basic emotions and social embarrassment,
selfishness, disinhibition, irritability, neglect, apathy, altered preference
for sweet foods, with a tendency to continue eating for as long as food is
present, or to steal food from other’s plates, motor and verbal stereotypies,
wandering, and an absence of insightfulness. Albeit anatomical pathways are
well known, there is no known therapy to prevent the advance of frontal
dementia. The circuits involve a number of transmitters, receptor subtypes, and
second messengers that can be potentially mediated pharmacologically. Though,
rational treatments are currently limited. We present the possible actual and
future therapeutic choices on the basis of anatomical and biochemical
substrates.
[Back to top] Design of a New Phosphate Binder, Anion Exchange Resin, Based on
Microcalorimeter Measurements
Hiroyoshi Inoue and Sho-ichi Yamagishi
It has been suggested that resin wettability is advantageous for
dietary phosphate binding in the gastrointestinal tract. To evaluate the effect
of anion exchange resin wetting properties on in vivo phosphate binding
ability, four types of ethylene glycol dimethacrylate cross-linking
4-vinylpyridinium anion exchange resins (EGDMA-4VP) were synthesized.