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Letters in
Drug Design & Discovery
ISSN: 1570-1808
Letters in Drug Design &
Discovery
Volume 2, Number 4, June 2005
Contents
Graphical Abstracts
Cytostatic and Cytotoxic Activity of Synthetic Diterpene
Derivatives Obtained from (-)-Kaur-9(11), 16-Dien-19-Oic Acid
Against Human Cancer Cell Lines Pp. 255-259
Randolph Alonso, Heidi Gomis, Antonieta Taddei and Cristina
Sajo
[Abstract]
Synthesis and Properties of Two Antineoplastic Methanesulfonate
Agents Utilizing Folic Acid and Triethanolamine Pp. 260-265
R.L. Bartzatt
[Abstract]
Prostate-Apoptosis-Response-Gene-4: Biological Properties
and their Potential Therapeutic Exploitation in Hematological
Malignancies Pp. 266-273
Simone Boehrer, Daniel Nowak, Dieter Hoelzer, Paris S.
Mitrou and Kai Uwe Chow
[Abstract]
Targeting the G2/M Transition for Antitumor Therapy Pp.
274-281
J. Yuan and K. Strebhardt
[Abstract]
Computational Studies of 1-Hydrazinophthalazine (Hydralazine)
as Antineoplasic Agent. Docking Studies on Methyltransferase
Pp. 282-286
Enrique Angeles, Víctor HugoVazquez-Valadez, Oscar
Vazquez-Valadez, Ana Maria Velazquez-Sanchez, Alberto Ramirez,
Luisa Martinez, Sandra Diaz-Barriga, Andres Romero-Rojas,
Gustavo Cabrera, Rafael Lopez-Castanares and Alfonso Duenas-Gonzalez
[Abstract]
A Quantitative Structure-Activity Relationship Study on
Some Na+ and K+ Channel Blockers: Role
of Molecular Connectivity Index Pp. 287-290
S.P. Gupta, Anitha Paleti, S.B. Mekapati, A.N. Nagappa
and S. Kumaran
[Abstract]
Synthesis of a Spiro D-Proline Analogue Bearing D-Fructose
Pp. 291-293
Laura Cipolla, Cristina Redaelli and Francesco Nicotra
[Abstract]
Novel Benzo[1,2-c]1,2,5-Oxadiazole N-Oxide Derivatives
as Antichagasic Agents: Chemical and Biological Studies
Pp. 294-301
Claudio Olea-Azar, Carolina Rigol, Fernando Mendizabal,
Hugo Cerecetto, Rossanna Di Maio, Mercedes Gonzalez, Williams
Porcal, Antonio Morello, Yolanda Repetto and Juan Diego Maya
[Abstract]
Development of Polyfluorophenyltropanes: Potential Probes
for 19F Magnetic Resonance Imaging (MRI) and Spectroscopy
(MRS) Assessments of the Dopamine Transporter Pp. 302-306
Ao Zhang, Nora S. Kula, Kehong Zhang, Ross J. Baldessarini,
Marc J. Kaufman, Perry F. Renshaw and John L. Neumeyer
[Abstract]
Synthesis of Azetidin-2-One Derivatives as Inhibitor of
Secretory Phospholipase A2 with Anti-Inflammatory Activity
Pp. 307-310
Mayur C. Yerigeri, Satish Kumar Murari, Salahuddin Mohammed,
Shanta Kumar Sugur Math, Kuntebommanahalli N. Thimmaiah and
Bannikuppe Sannanaik Vishwanath
[Abstract]
Pituitary Adenylate Cyclase Activating Polypeptide in Animal
Models of Neurodegenerative Disorders - Implications for Huntington
and Parkinson`s Diseases Pp. 311-315
D. Reglodi, A. Tamas, A. Somogyvari-Vigh
[Abstract]
Cytoprotection by Melatonin, Precursors and Metabolites
in an In Vitro Model of Neurotoxicity Induced by Okadaic Acid
Pp. 316-321
I. Tunez, R. Drucker-Colin, M.C. Munoz and P. Montilla
[Abstract]
Computational Characterization of a Series of Eicosanoids
Pp. 322-328
A.S.A. Gracon, S.J. Pernecky, M.C. Milletti, J.-A Park,
Y.Yuan and H. Kim
[Abstract]
Synthesis and Cyclooxygenase-2 (COX-2) Inhibiting Properties
of 1,5- Diarylpyrazoles Possessing N-Substitution on the Sulfonamide
(–SO2NH2) Moiety Pp. 329-340
Manojit Pal, Venugopal Rao Veeramaneni, Sanjeev Kumar,
Akhila Vangoori, Ramesh Mullangi, Parimal Misra, Shaikh Abdul
Rajjak, Vidya B. Lohray, Seshagiri Rao Casturi and Koteswar
Rao Yeleswarapu
[Abstract]
Abstracts
[Back to top]
Cytostatic and Cytotoxic Activity of Synthetic Diterpene
Derivatives Obtained from (-)-Kaur-9(11), 16-Dien-19-Oic Acid
Against Human Cancer Cell Lines
Randolph Alonso, Heidi Gomis, Antonieta Taddei and Cristina
Sajo
These diterpenes (1) and (2) were synthesized via epoxidation
and rearrangements of (-)-Kaur-9(11), 16-dien-19-oate (7)
isolated from Venezuelan species of espeletia (frailejón),
and their antimicrobial and antitumoral activity were evaluated.
Compound (1) showed GI50 values of 51.6 nM against CNS SF-539,
LC50 = 100 mM, log10 GI50 = -7.29; compound (2) showed GI50
at 4.17 mM against breast cancer T47D, LC50 = 39 mM and Log10
GI50 = -5.38. Our results suggest that these compounds are
highly cytotoxic and cytostatic against human cancer cell
lines.
[Back to top]
Synthesis and Properties of Two Antineoplastic Methanesulfonate
Agents Utilizing Folic Acid and Triethanolamine
R.L. Bartzatt
The synthesis of two antineoplastic compounds is accomplished
by placing threemethanesulfonate groups on folic acid (I)
and triethanolamine (II). Methane-sulfonate agents (I) and
(II), alkylate an aqueous nucleophilic primary amine group
at physiological pH 7.4 and 37 oC. Compound (I) utilizes folic
acid as a drug carrier for highly specific delivery into tumor
cells that have increased folic acid receptors.
There are three reactive sites within (I) and (II) for alkylation
of nucleophilic targets within tumor cells. Alkylation activity
of compounds (I) and (II) showed first-order and second-order
reaction kinetics, respectively. Molecular properties such
as Log P,molar refractivity, aqueous solubility, polar surface
area, halflife of reaction, and Log BB are determined.
[Back to top]
Prostate-Apoptosis-Response-Gene-4: Biological Properties
and their Potential Therapeutic Exploitation in Hematological
Malignancies
Simone Boehrer, Daniel Nowak, Dieter Hoelzer, Paris S.
Mitrou and Kai Uwe Chow
Primary or secondary resistance towards conventional chemotherapeutic
agents presents the major clinical obstacle in the induction
of remission and definite cure of hematological malignancies.
Definition of the underlying molecular mechanisms determining
response or resistance not only enables the clinician to define
prognostic markers, but moreover, facilitates the design of
molecularly targeted therapies aiming to reverse the causative
lesion and/or the therapeutic resistance. Prostate-apoptosis-response-gene-4
(par-4), which is expressed in a broad spectrum of normal
and neoplastic tissues, was originally described in prostate
cancer cells forced to undergo apoptosis. In particular, the
observation that overexpression of par-4 potentiates apoptosis
in malignant cells while sparing normal tissues, renders the
assessment of its biological properties and their potential
therapeutic exploitation worthwhile. This article focuses
on the functional properties of par- 4 in hematopoietic cells,
describing their pro-apoptotic and anti-transforming role,
and provides an outlook on the potential therapeutical employment
of this knowledge.
[Back to top]
Targeting the G2/M Transition for Antitumor Therapy
J. Yuan and K. Strebhardt
The deregulated cell cycle is a prominent hallmark of oncogenesis.
In addition to the genetic alterations in G1 and S phase,
emerging data demonstrate that the loss of checkpoint control
at the G2/M transition is also closely involved in neoplastic
transformation. Among many modulators of the G2/M transition,
the defective regulation of cyclin B1, the regulatory subunit
of cyclin dependent kinase 1 (Cdk1), and of Polo-like kinase
1 (Plk1) is attracting increasing attention as both of them
are overexpressed in a wide spectrum of human tumors. Cyclin
B1 and Plk1 serve as negative prognostic markers for patients
with various tumors. In this review, we focus on these two
molecules and highlight their roles in normal cell cycle,
the involvement in oncogenesis and their potential as intervention
targets for antitumor therapy.
[Back to top]
Computational Studies of 1-Hydrazinophthalazine (Hydralazine)
as Antineoplasic Agent. Docking Studies on Methyltransferase
Enrique Angeles, Víctor HugoVazquez-Valadez, Oscar
Vazquez-Valadez, Ana Maria Velazquez-Sanchez, Alberto Ramirez,
Luisa Martinez, Sandra Diaz-Barriga, Andres Romero-Rojas,
Gustavo Cabrera, Rafael Lopez-Castanares and Alfonso Duenas-Gonzalez
Hydralazine is a drug used as anti-hypertensive, and recently
reported to be a DNA methylation inhibitor able to demethylate
and reactivate the expression of tumor suppressor genes in
cancer. The aim of the present study was to explore the potential
mechanism by which hydralazine inhibits DNA methylation. For
this purpose, we assessed the structural and electronic properties
between 1-hydrazinophthalazine (hydralazine) and a putative
ligand methyltransferase.
[Back to top]
A Quantitative Structure-Activity Relationship Study on
Some Na+ and K+ Channel Blockers: Role of Molecular Connectivity
Index
S.P. Gupta, Anitha Paleti, S.B. Mekapati, A.N. Nagappa
and S. Kumaran
A quantitative structure-activity relationship (QSAR) study
is made on a series of Na+ channel blockers (diphenylacetamide
derivatives) and on a series of K+ channel blockers (blockers
of cardiac delayed rectifier potassium current IKs) (benzodiazepine
derivatives). In both the cases, the blocking activity is
found to be significantly correlated with Kier’s first-order
valence molecular connectivity index.
[Back to top]
Synthesis of a Spiro D-Proline Analogue Bearing D-Fructose
Laura Cipolla, Cristina Redaelli and Francesco Nicotra
A bicyclic spiro analogue of D-proline was synthesized from
perbenzylated methyl D-fructoside. The synthetic steps required
first a three carbon chain elongation at the anomeric position
by C-glycosylation, secondly the introduction of the amino
function at C-1, and finally the cyclization to the pyrrolidine
ring and introduction of the carboxylic group.
[Back to top]
Novel Benzo[1,2-c]1,2,5-Oxadiazole N-Oxide Derivatives
as Antichagasic Agents: Chemical and Biological Studies
Claudio Olea-Azar, Carolina Rigol, Fernando Mendizabal,
Hugo Cerecetto, Rossanna Di Maio, Mercedes Gonzalez, Williams
Porcal, Antonio Morello, Yolanda Repetto and Juan Diego Maya
In order to gain inside the mechanism of action of a series
of benzo[1,2-c]1,2,5-oxadiazole N-oxide derivatives with in
vitro anti-trypanosomal activity, electrochemical and biological
studies were performed. Cyclic voltammetry and electron spin
resonance spectroscopy were used to predict the bio-reduction
processes. Effects on the parasitic respiration were studied.
[Back to top]
Development of Polyfluorophenyltropanes: Potential Probes
for 19F Magnetic Resonance Imaging (MRI) and Spectroscopy
(MRS) Assessments of the Dopamine Transporter
Ao Zhang, Nora S. Kula, Kehong Zhang, Ross J. Baldessarini,
Marc J. Kaufman, Perry F. Renshaw and John L. Neumeyer
A novel series of nonradiolabeled, polyfluorinated phenyltropanes
were developed containing three or more 19 F atoms/molecule
in a magnetic resonance (MR) equivalent chemical environment
to increase coherent MR signal characteristics. Competitive
radioreceptor affinity assays of such compounds yielded nM
affinity at dopamine (DAT) and serotonin (SERT) transporters
in rat brain tissue. Compound 3b (MCL-314) at 50 µM
gave a clear magnetic resonance spectroscopy signal, and 9
(MCL-319) yielded very high DAT potency and improved selectivity
over SERT. Such compounds might potentially serve as MRI-
or MRS-detectable index ligands for the dopamine transporter
proteins, and preliminary observations call for further study
of additional polyfluorinated phenyltropanes.
[Back to top]
Synthesis of Azetidin-2-One Derivatives as Inhibitor of
Secretory Phospholipase A2 with Anti-Inflammatory Activity
Mayur C. Yerigeri, Satish Kumar Murari, Salahuddin Mohammed,
Shanta Kumar Sugur Math, Kuntebommanahalli N. Thimmaiah and
Bannikuppe Sannanaik Vishwanath
The title compounds have been synthesized and tested for
structure activity relationship for Phospholipase A2 (PLA2)
[E.C. 3.1.1.4] enzyme inhibition. The in vitro PLA2 enzyme
inhibitory activity of azetidin-2-one derivatives and in vivo
anti-inflammatory activity studies using mice are highlighted.
The results show that some azetidin-2-one derivatives are
very good PLA2 inhibitors and can also be used as antiinflammatory
drugs.
[Back to top]
Pituitary Adenylate Cyclase Activating Polypeptide in Animal
Models of Neurodegenerative Disorders - Implications for Huntington
and Parkinson`s Diseases
D. Reglodi, A. Tamas, A. Somogyvari-Vigh
The present study summarizes results obtained with PACAP
treatment in models of neurodegenerative diseases. The data
show that PACAP protected a significant number of neurons
in quinolinic acid- and 6-hydoxydopamine-induced lesions,
which correlated with the less severe behavioral symptoms.
These effects may have clinical implications in Huntington
and Parkinson`s diseases.
[Back to top]
Cytoprotection by Melatonin, Precursors and Metabolites
in an In Vitro Model of Neurotoxicity Induced by Okadaic Acid
I. Tunez, R. Drucker-Colin, M.C. Munoz and P. Montilla
Recently, it has been emphasized that oxidative stress could
play a synergistic role with tau phosphorylation, cell shape
changes, cytoskeletal disruption and cell death in Alzheimer’s
disease. Okadaic acid induces oxidative damage, cell shape
alterations, tau hyperphosphorylation and cytoskeletal disorganization
similar to Alzheimer’s disease. In this sense, different
evidence suggests that indolamines may be useful for protection
against oxidative stress and cellular disorganization. In
this study, we looked at the effects of melatonin, 5-hydroxytryptophan
(5OHTrp), 5-hydroxytryptamine (5HT), N-acetyl-5- hydroxytryptamine
(NA5OHT) or 6-hydroxymelatonin (6OHMEL) (10-5 M) on the oxidative
changes and cell shape alterations produced by okadaic acid
(50 nM) in N1E-115 neuroblastoma cells. The effects of okadaic
acid were evaluated as changes in the quantity of lipid peroxidation
products, reduced glutathione (GSH) content, activity of anti-oxidative
enzymes and major length axes (as an index of cell shape changes).
Okadaic acid gives rise to lipid peroxidation products (P<
0.001), GSH consumption (P< 0.001), major length axis (P<
0.001) and a reduction in the activity of GSH-transferase,
GSH-reductase and catalase between 43.33 – 55.17%. These
changes were completely prevented by melatonin, whereas 5OHTrp,
5HT, NA5OHT and 6OHMEL partially blocked the alterations induced
by okadaic acid. In conclusion, our data indicates: (i) The
importance of oxidative stress in both this experimental model
and in the development and course of neurodegenerative diseases,
especially Alzheimer’s. (ii) The protective effects of
indolamines (iii) and that melatonin is much more efficient
than its precursors and metabolites in reducing the extent
of oxidative stress and cell shape changes induced by okadaic
acid.
[Back to top]
Computational Characterization of a Series of Eicosanoids
A.S.A. Gracon, S.J. Pernecky, M.C. Milletti, J.-A Park,
Y.Yuan and H. Kim
Ab initio molecular orbital calculations are employed to
elucidate structural and electronic characteristics of a series
of eicosanoids, which have been used to examine the specificity
of a 14,15-DHET ELISA. The results of the calculations show
that activity is correlated to two combined factors: molecular
volume and energy of the HOMO.
[Back to top]
Synthesis and Cyclooxygenase-2 (COX-2) Inhibiting Properties
of 1,5- Diarylpyrazoles Possessing N-Substitution on the Sulfonamide
(–SO2NH2) Moiety
Manojit Pal, Venugopal Rao Veeramaneni, Sanjeev Kumar,
Akhila Vangoori, Ramesh Mullangi, Parimal Misra, Shaikh Abdul
Rajjak, Vidya B. Lohray, Seshagiri Rao Casturi and Koteswar
Rao Yeleswarapu
A number of novel 1,5-diarylpyrazoles possessing N-substitution
on the sulfonamide (–SO2NH2) moiety were synthesized
and tested for COX-1/COX-2 inhibition in vitro. Many of these
1,1-dioxo-2,3- dihydrobenzo[d]isothiazolyl substituted 1,5-diarylpyrazoles,
where the SO2NH2 group was a part of the fused ring, showed
COX inhibitory activity. Few of them were identified as selective
COX-2 inhibitors. Structure Activity Relationship study within
the series are discussed.
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