| Letters
in Drug Design & Discovery
ISSN: 1570-1808
Letters in Drug Design &
Discovery
Volume 5, Number 2, March 2008
Contents
CoMFA Study on Thiazolidine-2,4-diones for their Antihyperglycemic
Activity Pp. 79-87
B.R.P. Kumar, B.J. Desai, J. Vergheese, T.K. Praveen, B. Suresh
and M.J. Nanjan
[Abstract]
Artepillin C: A Review Pp. 88-92
G.O.D. Estrada, J.F.M. da Silva and O.A.C. Antunes
[Abstract]
Synthesis and Photobiological Properties
of Bromo- and Alkoxymethyl Furocoumarins Pp. 93-103
G. Viola, M. Boccalini, E. Fortunato, F. dall’Acqua
and S. Chimichi
[Abstract]
New Peptidic Neuroprotectants Against
NMDA Neurotoxicity: Syntheses and Biological Evaluations ofLinear
Complestatin Analogs Pp. 104-107
H-J. Park, S-W. Kim, Y-G. Shin, Y-J. Kim, J-K. Lee, S.B.
Kong and S-H. Yoon
[Abstract]
Inhibition of Human Melonoma Cell Proliferation Using Small
Molecule Uracil-DNA Glycosylase Inhibitors Pp. 108-110
M. Xiao, B-K. Zhu and Y.L. Jiang
[Abstract]
Phenylpyazoleanilides as a Potent Inhibitor of IL-15 Dependent
T Cell Proliferation. Part 1: A New Class of Orally Available
Immunomodulators Pp. 111-115
H. Ushio, S. Ishibuchi, K. Adachi, K. Oshita and K. Chiba
[Abstract]
Potent, Nonpeptide Inhibitors of Human
Mast Cel Tryptase. 2. Investigation of the Carboxamide Portion
of Spirocyclic Piperidine Amides Pp. 116-120
M.J. Costanzo, S.C. Yabut, H-C. Zhang, K.B. White, Y.
Wang,L.K. Minor, B.A. Tounge, A.N. Barnakov, F. Lewandowski,
C Milligan, J.C. Spurlino and B.E. Maryanoff
[Abstract]
Synthesis and Biological Activity of New Tricyclic
Purine Derivatives Obtained by Intramolecular N-7 Alkylation
Pp. 122-126
A.M.L. Carmo, F.G. Braga, M.L. De Paulaa, A.P. Ferreira,
H.C. Teixeira, A.D. da Silva and E.S. Coimbra
[Abstract]
Design and Synthesis of Novel Diaryl Heterocyclic
Derivatives as Selective Cyclooxygenase-2 Pp. 127-133
S.X. Li, X.D. Deng, F.L Jiang, Y.J. Zhao, W.S. Xiao, X.Z.
Kuang and X.M. Sun
[Abstract]
Mycophenolate Mofetil for the Treatment of Systemic Sclerosis
Pp. 134-136
Manisha Naik, Max Shenin and Chris T. Derk
[Abstract]
Synthesis and Antitubercular Evaluation
of N'-[(E) (hydroxy, methoxy and ethoxy-substituted-phenyl)
Methylidene]isonicotinohydrazide Derivatives Pp.
137-140
M. de L. Ferreira, L.N. de F. Cardoso, R.S.B. Gonçalves,
E.T. da Silva, M.C.S. Lourenço, F.R. Vicente and M.V.N.
de Souza
[Abstract]
Antitumor Activity of Titanocene Y in
Xenografted PC3 Tumors in Mice Pp. 141-144
C.M. Dowling, J. Claffey, S. Cuffe, I. Fichtner, C. Pampillón,
N.J. Sweeney, K. Strohfeldt, R.W.G. Watson and M. Tacke
[Abstract]
Dopamine Receptors are Involved in the
Control of Opioid Antinociception in Mice Pp. 145-147
A. Capasso
[Abstract]
Propofol and Systemic Inflammatory Response
in Abdominal Aortic Surgery Pp. 148-151
J.M. Rodríguez-López and F.S. Lozano
[Abstract]
Abstracts
[Back to top]
CoMFA Study on Thiazolidine-2,4-diones for
their Antihyperglycemic Activity
B.R.P. Kumar, B.J. Desai, J. Vergheese, T.K. Praveen, B. Suresh
and M.J. Nanjan
The present CoMFA study on thiazolidine-2,4-diones attempts
to quantitatively describe the structural features of the
compounds for high PPAR-γ
agonistic action. A set of 50 compounds was used for the analysis.
A training set and a test set were designed consisting of
39 and 11 compounds, respectively. All the molecules were
modeled and energy minimized using SYBYL 6.7 software. The
molecules were aligned using the most active analog as the
template by field fit method. PLS (partial least square) analysis
was performed on the training set and statistical parameters
like q2, r2,
F value and P value were calculated. A final model was generated
by excluding four outliers from the training set. Cross Validation
was done by leave one out method. The developed CoMFA model
showed a good external as well as internal predictivity in
most of the compounds with low residual values. The q2
value of the developed model was 0.549 and r2
value was 0.976. Contour plots generated from the steric and
electrostatic contributions of this model were used to derive
structure-activity relationships and to design a hypothetical
molecular structure, which can be used as a lead for design
and syntheses of newer molecules.
[Back to top]
Artepillin C: A Review
G.O.D. Estrada, J.F.M. da Silva and O.A.C. Antunes
This article presents a review on artepillin C, a diprenyl-p-hydroxycinnamic
acid derivative mainly isolated from Baccharis species,
and one of the principal phenolic acids present in Brazilian
propolis, covering aspects of its occurrence, synthesis, biological
activities and pharmacokinetics.
[Back to top]
Synthesis and Photobiological Properties of Bromo- and Alkoxymethyl
Furocoumarins
G. Viola, M. Boccalini, E. Fortunato, F. dall’Acqua
and S. Chimichi
Bromo- and alkoxymethyl-furocoumarins were synthesized
and evaluated for their ability to photoinduce cell death
in human tumoral cell culture. Bromo substituted compounds
resulted to be the most phototoxic compounds giving rise to
a significant induction of apoptosis at 24 h from irradiation
as demonstrated by a remarkable percentage of Annexin-V positive
cells. The DNA photocleavaging properties of these derivatives
were investigated using plasmid DNA as model. The results
indicate that bromo derivatives induce significant photodamage
to DNA. In particular, the effect is strongly evidenced after
treatment of photosensitized DNA by two base excision repair
enzymes, Fpg and Endo III.
[Back to top]
New Peptidic Neuroprotectants Against NMDA Neurotoxicity:
Syntheses and Biological Evaluations of Linear Complestatin
Analogs
H-J. Park, S-W. Kim, Y-G. Shin, Y-J. Kim, J-K. Lee, S.B.
Kong and S-H. Yoon
Linear peptide analogs of complestatin were synthesized
via solid phase peptide synthesis and tested in
vitro as inhibitors against N-methyl-D-aspartic
acid (NMDA) neurotoxicity as possible new peptidic neuroprotectants.
While none of the analogs were as potent as the parent compound
(IC50 = 2.5 µM), hexamer
11c and heptamer 1c, which
contain all D-amino acids, showed modestly potent neuroprotective
effects with IC50 values
of 23.8 µM and 22.5 µM, respectively. The results
indicate that the bicyclic ring structure of complestatin
plays an important role for its inhibitory activity, and the
D-stereochemistry of tryptophan (component F)
is important for the potency of the linear peptide analogs.
[Back to top]
Inhibition of Human Melonoma Cell Proliferation Using Small
Molecule Uracil-DNA Glycosylase Inhibitors
M. Xiao, B-K. Zhu and Y.L. Jiang
Four known small molecule uracil-DNA glycosylase (UNG)
inhibitors were synthesized and tested against human melanoma
cells, IgR3 and MM200. They were found to be effective against
cell proliferation at micromolar concentrations and to operate
through a nonapoptotic mechanism. Thus, small molecules that
target UNG may be useful as potential chemotherapeutic agents
against human melanoma.
[Back to top]
Phenylpyazoleanilides as a Potent Inhibitor of IL-15 Dependent
T Cell Proliferation. Part 1: A New Class of Orally Available
Immunomodulators
H. Ushio, S. Ishibuchi, K. Adachi, K. Oshita and K. Chiba
In research for a new immunomodulator, we discoverd a
novel hydroxypiperidine derivative 9h which
was a potent inhibitor of IL-15induced T cell activation.
Further modification of 9h gave a potent
and orally active agent 10 which was effective
in a mouse CIA model.
[Back to top]
Potent, Nonpeptide Inhibitors of Human Mast Cell Tryptase.
2. Investigation of the Carboxamide Portion of Spirocyclic
Piperidine Amides
M.J. Costanzo, S.C. Yabut, H-C. Zhang, K.B. White, Y.
Wang, L.K. Minor, B.A. Tounge, A.N. Barnakov, F. Lewandowski,
C. Milligan, J.C. Spurlino and B.E. Maryanoff
We have explored a series of spirocyclic piperidine amide
derivatives with respect to the N-acyl portion (viz. 6) for
inhibition of tryptase. Thus, we identified analogues 6nn
and 6oo as potent tryptase inhibitors (IC50<
10 nM) with excellent selectivity vs. trypsin. Other interesting
compounds (IC50 = 10-20 nM)
in this chemical series are 6k, 6m, 6ff,
and 6bbb. X-ray co-crystal structures of
6nn•tryptase and 6pp•tryptase
are reported.
[Back to top]
Synthesis and Biological Activity of New Tricyclic Purine
Derivatives Obtained by Intramolecular N-7 Alkylation
A.M.L. Carmo, F.G. Braga, M.L. De Paulaa, A.P. Ferreira,
H.C. Teixeira, A.D. da Silva and E.S. Coimbra
Intramolecular N-7 alkylation of 6-substituted purines
gave rise to a new series of tricyclic purine derivatives.
The new compounds were evaluated for their cytotoxicity, their
antileishmania activity together with their capacity to modulate
NO production in macrophages. As a result compound 1
exhibited a modest activity against KB cells. On the other
hand 4a was active against Leishmania
and it diminished NO production of BCG-induced J774A.1 cells.
[Back to top]
Design and Synthesis of Novel Diaryl Heterocyclic Derivatives
as Selective Cyclooxygenase-2
S.X. Li, X.D. Deng, F.L Jiang, Y.J. Zhao, W.S. Xiao, X.Z.
Kuang and X.M. Sun
In this work we reported the design, synthesis and evaluation
of the new diaryl heterocyclic derivatives based on the lead
compounds of Rofecoxib and Celecoxib by application of the
principle of isosterism. The in vivo pharmacological
evaluation of these new compounds lead us to select the compounds
(Ia) and (IIc) as a new
prototype which a substituent ortho to the methylsulfone or
sulfonamide group was introduced for further development,
more active that celecoxib at the same mass concentration.
[Back to top]
Mycophenolate Mofetil for the Treatment of Systemic Sclerosis
Manisha Naik, Max Shenin and Chris T. Derk
Mycophenolate mofetil, an inosine monophosphate dehydrogenase
inhibitor, that inhibits the de novo pathway of guanosine
nucleotide synthesis, inhibits proliferative responses of
T and B lymphocytes as well as antibody production by B-lymphocytes.
It is indicated for the prophylaxis of organ rejection after
allogeneic cardiac, hepatic and renal transplants. It has
also been recently used with good success in patients with
lupus nephritis. Based on these actions mycophenolate mofetil
appears to be a novel agent in the treatment of systemic sclerosis
[Back to top]
Synthesis and Antitubercular Evaluation of N'-[(E)-(hydroxy,
methoxy and ethoxy-substituted-phenyl) Methylidene]isonicotinohydrazide
Derivatives
M. de L. Ferreira, L.N. de F. Cardoso, R.S.B. Gonçalves,
E.T. da Silva, M.C.S. Lourenço, F.R. Vicente and M.V.N.
de Souza
The present article describes a series of eighteen N'-[(E)-(hydroxy,
methoxy and ethoxy substituted-phenyl)methylidene]isonicotinohydrazide
derivatives, which were synthesized and evaluated for their
in vitro antibacterial activity against Mycobacterium
tuberculosis, and the activity expressed as the minimum
inhibitory concentration (MIC) in μg/ml.
Compounds 2a, 2d-f, and 2h exhibited a significant activity
(0.31-1.25 μg/ml)
when compared with first line drugs such as isoniazid (INH)
and rifampicin (RIP) and could be a good start point to find
new lead compounds in the fight against multi-drug resistant
tuberculosis.
[Back to top]
Antitumor Activity of Titanocene Y in Xenografted PC3 Tumors
in Mice
C.M. Dowling, J. Claffey, S. Cuffe, I. Fichtner, C. Pampillón,
N.J. Sweeney, K. Strohfeldt, R.W.G. Watson and M. Tacke
Chemotherapeutic options for androgen-independent prostate
cancer are extremely limited with minimum survival advantage.
The benzyl-substituted unbridged titanocene bis-[(p-methoxybenzyl)cyclopentadienyl]
titanium(IV) dichloride (Titanocene Y) was
tested in vitro against the human prostate cancer
androgen-independent cell, PC-3, which demonstrated an IC50
value of 56 x 10-6 mol/L
compared to 5.6 x 10-6 mol/L
for cisplatin. Then Titanocene Y was given
at the maximum tolerable dose of 40 mg/kg/d on five consecutive
days to one cohort of eight PC3 tumor-bearing male NMRI:nu/nu
mice, while a second cohort was treated similarly with 3 mg/kg/d
of cisplatin. Both of these mouse cohorts showed a statistically
significant tumor growth reduction with respect to the third
solvent-treated control group, which led to T/C values of
42% for cisplatin and 52% for Titanocene Y
at the end of the experiment. This encouraging activity of
Titanocene Y against prostate tumors in
vivo, which is almost comparable with respect to cisplatin
hopefully leads to further development of Titanocene Y
in the future.
[Back to top]
Dopamine Receptors are Involved in the Control of Opioid
Antinociception in Mice
A. Capasso
The present investigation was focused on the effects induced
by haloperidol and apomorphine on the antinociception induced
by DAMGO (highly selective μ-agonist),
U50-488H (highly selective k-agonist) and deltorphin II (highly
selective δ-agonists).
Haloperidol (a dopamine receptor antagonist) and apomorphine
(a dopamine receptor agonist) (0.1-1.0-2.0 mg/kg/i.p.) per
se did not change the pain threshold of mice both in
the hot plate and in the tail flick test. The antinociception
effects of DAMGO (5 mg/kg/i.p.), U50-488H (5 mg/kg/i.p.) and
deltorphin II (10 ng/i.c.v./mouse) peaked by 15 min after
treatment and was antagonized by haloperidol in a dose dependent
manner. By contrast, the dopamine receptor agonist, apomorphine,
depending on the doses used, exhibited opposite effects on
opiate antinociception. Treatment of mice with low doses of
apomorphine (0.1-1.0 mg/kg/i.p.) reduces the antinociception
induced by μ,
k and δ
receptor agonists whereas a high dose (2 mg/kg/i.p.) potentiates
it.
Our results indicate that dopamine receptors are involved
in the control of antinociception at both the μ,
k and δ
receptor level.
[Back to top]
Propofol and Systemic Inflammatory Response in Abdominal Aortic
Surgery
J.M. Rodríguez-López and F.S. Lozano
Abdominal aortic surgery is relatively common associated
with considerable postoperative morbidity and mortality. The
aortic cross-clamping for the implantation of a vascular prosthetic
graft induces a systemic inflammatory response (SIR) because
of an ischemia-reperfusion (IR) injury. In our experimental
models we have reported that propofol anesthesia, compared
with sevoflurane, after IR modulates SIR and this effect might
result in renal protection.
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