| Letters
in Drug Design & Discovery
ISSN: 1570-1808
Letters in Drug Design &
Discovery
Volume 4, Number 8, December 2007
Rapid Quantification of Neurons and Stem/Progenitor
Cells in the Adult Mouse Brain by Flow Cytometry
Pp. 532-539
N.A.K. Hellström, O. Zachrisson, H.G. Kuhn and C. Patrone
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Open Label Trial of Therapeutic Hepatitis B Vaccine
V-5 Immunitor (V5) Delivered by Oral Route Pp. 540-544
D. Batdelger, D. Dandii, V. Jirathitikal and A.S. Bourinbaiar
[Abstract] [Purchase
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Inhibition of Aromatase (AR) by Benzyl Azole-Based
Compounds Pp. 545-549
S. Adat, C.P. Owen and S. Ahmed
[Abstract] [Purchase
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Synthesis and Biological Evaluation of a New
Series of Benzothiazole-Benzothiadiazine Conjugates as Antibacterial
Agents Pp. 550-556
A. Kamal, S.K. Ahmed, K.S. Reddy, M.N.A. Khan, R.V.C.R.N.C.
Shetty, B. Siddhardha, U.S.N. Murty, A. China and V. Nagaraja
[Abstract] [Purchase
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3D-QSAR Analysis on Pyrrolopyridine Analogs as Mitogen Activated
Protein Kinase-Activated Protein Kinase 2 (MK-2) Inhibitors
Pp. 557-561
Z. Yang, P. Sun and W. Chen
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A Microplate based Screening of Benzimidazole Derivatives
on Hyaluronidase Inhibition at PH 7 and 3.5 Pp. 562-569
A. Kaessler, O. Algul and J. Jose
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Toward the Development of Inhibitors Directed
against Mammalian DDAH Proteins: Considerations
from Homology Modeling of DDAH-2 and DDAH Activity Tracing
in Tissue Homogenate Pp. 570-579
M. Knipp
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An Efficient Synthesis of Quinoline Derivatives: Bio Active
Studies Pp. 580-586
A. Kamal, K.S. Reddy, M.N.A. Khan, R.V.C.R.N.C.
Shetty, S.K. Ahmed, K.P. Kumar and U.S.N. Murthy
[Abstract]
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Structural and Electronic Characteristics
of a Series of Glycosidase Inhibitors Pp. 587-595
R.D. Anderson and M.C. Milletti
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Design, Synthesis and Biological Activity of A-C8/C-C2
Linked 6- Chloropurine-Pyrrolobenzodiazepine Hybrids as Anticancer
Agents Pp. 596-604
A. Kamal, N. Shankaraiah, K.L. Reddy, V. Devaiah, A. Juvekar
and S. Sen
[Abstract] [Purchase
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Design and Synthesis of a (N-Alkylaminoalkyl-Substituted)
Arylalkenyl-amide Drug Discovery Library Pp. 605-610
M. Urbano, S. Collina, D. Rossi, A.C. Baraglia,
S. Alcaro, A. Artese and O. Azzolina
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Rapid Quantification of Neurons and Stem/Progenitor
Cells in the Adult Mouse Brain by Flow Cytometry
N.A.K. Hellström, O. Zachrisson, H.G. Kuhn and C. Patrone
In order to develop novel therapies for the treatment of central
nervous system diseases, methods for rapid quantification
of different neural cell populations, from healthy or diseased
brains, are highly desirable. Today, the method of choice
to quantify different cell populations in the brain is immunohistochemistry.
This technique is precise and reliable, but is also very time
consuming and cost-intensive. In this paper, we describe a
rapid procedure where neurons and neural stem/progenitor cells
from the adult mouse are isolated, immediately fixed, and
quantified with different cell type specific markers by flow
cytometry.
Our results show that we can reproducibly detect and quantify
mature neurons with antibodies towards microtubuli associated
protein (MAP2) and neuronal nuclei (NeuN), both in hippocampus
and olfactory bulb. Stem/progenitor cell detection and quantification
were achieved using antibodies specific for bromodeoxyuridine
(BrdU) and doublecortin (DCX). The flow cytometric analysis
revealed fractions of positive cells corresponding to the
in vivo situation, confirmed and validated by traditional
immunohistochemistry and stereological counting procedures.
We conclude that the flow cytometric technique can be used
as a rapid screening method to accurately quantify neuronal
populations and to detect and quantify other brain cell types,
such as neural stem/progenitor cells.
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Open Label Trial of Therapeutic Hepatitis B Vaccine V-5 Immunitor
(V5) Delivered by Oral Route
D. Batdelger, D. Dandii, V. Jirathitikal and A.S. Bourinbaiar
We evaluated whether V-5 Immunitor (V5), tableted immunotherapeutic
preparation comprising heat-inactivated HBV antigens from
pooled blood of HBV- and HCV-infected donors, may produce
clinical benefit through induction of oral tolerance and reduction
of immune-mediated liver injury. Once daily dose of V5 was
administered per os to 10 patients with chronic hepatitis
B in an open label study that lasted one month. Every patient
who entered the study had elevated liver enzyme levels, which
at the end of study have decreased in 100% of analyzed patients.
The reduction was highly significant, from 112.4 to 44.4 U/L
(P=0.00009) and 118.8 to 46.1 U/L (P=0.0032), for ALT and
AST respectively. In addition, half of intent-to-treat patients
who were HBV surface antigen (HBsAg) positive at study entry,
became negative after one month on V5 (P=0.0098). All patients,
except one, reported complete recuperation from hepatitis-associated
clinical symptoms present at baseline (P=0.0016). No adverse
events were observed at any time. Favorable biochemical, virological
and clinical responses indicate that V5 is safe and effective
means for immunotherapy of chronic hepatitis B. Placebo-controlled,
randomized study is required to confirm these findings.
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Inhibition of Aromatase (AR) by Benzyl Azole-Based
Compounds
S. Adat, C.P. Owen and S. Ahmed
We report the results of the evaluation of a series of
benzyl imidazole-based compounds against the enzyme aromatase
(AR). The results show that the synthesised compounds were
potent inhibitors of AR in comparison to the standard compound
aminoglutethimide (AG).
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Synthesis and Biological Evaluation of a New Series
of Benzothiazole-Benzothiadiazine Conjugates as Antibacterial
Agents
A. Kamal, S.K. Ahmed, K.S. Reddy, M.N.A. Khan, R.V.C.R.N.C.
Shetty, B. Siddhardha, U.S.N. Murty, A. China and V. Nagaraja
A new series of benzothiazolo-benzothiadiazine hybrids (9a-g)
has been synthesized and evaluated for their antibacterial
activity against clinical isolates of Gram-positive and Gram-negative
bacteria. Some of these hybrids in this series exhibited antibacterial
activity comparable to ampicillin. In addition, some of the
compounds showed DNA gyrase inhibitory activity at a moderate
level compared to ciprofloxacin.
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3D-QSAR Analysis on Pyrrolopyridine Analogs as
Mitogen Activated Protein Kinase-Activated Protein Kinase
2 (MK-2) Inhibitors
Z. Yang, P. Sun and W. Chen
Mitogen-activated protein kinase-activated protein kinase
2 (MK-2) plays an important role in treatment of inflammatory
disease such as rheumatoid arthritis. CoMFA was conducted
on thirty-one analogs displaying variable inhibition of MK-2
to determine the structural requirements for potency in inhibiting
MK-2. The resulting model exhibited good q2
and r2 values up
to 0.549 and 0.973 for CoMFA, the standard error of estimation
was 0.098. The contributions from the steric and electrostatic
fields were 0.586 and 0.414 respectively. The 3D-QSAR model
should be very useful for design of novel MK-2 inhibitors.
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A Microplate based Screening of Benzimidazole Derivatives
on Hyaluronidase Inhibition at PH 7 and 3.5
A. Kaessler, O. Algul and J. Jose
Two microplate assays for inhibitor testing were established
and used to identify new hyaluronidase inhibitors from a series
of benzimidazole derivatives. In vitro assays were
performed at pH 7 using a “stains-all” based assay
and at pH 3.5 using a Morgan-Elson assay. Twelve benzimidazole
derivatives were synthesized and tested on hyaluronidase inhibition
at a concentration of 100 μM
and IC50 values of the compounds
with an inhibition of more than 50 % were determined. The
most potent compound was 4b (Di(1H-benzo[d]imidazol-2-yl)methane)
with an IC50 value of 78
μM
at pH 7 and 72 μM
at pH 3.5, respectively.
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Toward the Development of Inhibitors Directed
against Mammalian DDAH Proteins: Considerations
from Homology Modeling of DDAH-2 and DDAH Activity Tracing
in Tissue Homogenate
M. Knipp
The cysteine hydrolase Nω,Nω-dimethyl-L-arginine
dimethylaminohydrolase-1 (DDAH-1) is an important regulator
of NO production through the degradation of endogenous Nω-methylated
arginines, that are competitive inhibitors for nitric oxide
synthase (NOS). Consequently, DDAH-1 is a target for pharmacological
drug design to regulate NO production. The appearance of a
second isoform DDAH-2, which was assigned through sequence
comparison, requires detailed knowledge about the properties
of both proteins. This study represents the first attempt
for a structural and functional characterization of DDAH-2.
However, lack in enzymatic activity together with structural
consideration based on a homology model places the designation
as a DDAH enzyme into question. On the other hand, it is shown
that DDAH-2 is a substrate for two protein-arginine methyltransferases,
CARM-1 and PRMT-6, which supports the participation of DDAH-2
in the metabolism of side-chain methylated arginines.
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An Efficient Synthesis of Quinoline Derivatives:
Bio Active Studies 580
A. Kamal, K.S. Reddy, M.N.A. Khan, R.V.C.R.N.C. Shetty,
S.K. Ahmed, K.P. Kumar and U.S.N. Murthy
A new method for the synthesis of quinolines has been
developed by employing various novel catalysts such as Al(OTf)3,
Gd(OTf)3, and TMSCl-NaI. Later, these compounds
were condensed with 3-hydrazino benzothiadiazines to obtain
quinoline derived [1,2,4]triazolo[1,5-b][1,2,4] benzothiadiazines.
Further, these new molecules have been evaluated for their
antibacterial activity and some of them have exhibited significant
antibacterial activity in comparison to sulfadiazine.
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Structural and Electronic Characteristics
of a Series of Glycosidase Inhibitors
R.D. Anderson and M.C. Milletti
Molecular orbital calculations are used to determine structural
and electronic characteristics of a series of sugar mimics,
which are correlated with experimentally determined activity
toward glycosidases. Differences in activity between α-
and β
glycosidase correlate to the position of the HOMO surface
of the neutral form of the inhibitor. A correlation is also
found between relative activity and energy of the HOMO.
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Design, Synthesis and Biological Activity of A-C8/C-C2
Linked 6- Chloropurine-Pyrrolobenzodiazepine Hybrids as Anticancer
Agents
A. Kamal, N. Shankaraiah, K.L. Reddy, V. Devaiah, A. Juvekar
and S. Sen
New A-C8 and C-C2-linked 6-chloropurine-pyrrolo[2,1-c][1,4]benzodiazepine
hybrids have been prepared and evaluated for their anticancer
potential. The molecular modeling studies might be explained
in terms of effect of the molecule on binding in the minor
groove of DNA and also comparison to both A-C8/C-C2-position
of the PBD. These PBD conjugates have shown DNA-binding ability
and promising anticancer activity.
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Design and Synthesis of a (N-Alkylaminoalkyl-Substituted)
Arylalkenyl-amide Drug Discovery Library
M. Urbano, S. Collina, D. Rossi, A.C. Baraglia,
S. Alcaro, A. Artese and O. Azzolina
To discover new potential sigma ligands, a library of 64 members
based on a carbamidic scaffold was designed and a synthetic
protocol, based on PASPS and MAOS techniques, was developed
and optimized. Applying the developed protocol the library
compounds were obtained in high purity, suitable for biological
screening.
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