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Letters in Drug Design & Discovery, Volume 1, No. 1, 2004
Contents
Discovery of Potent, Non-Steroidal
and Highly Selective Glucocorticoid Receptor Antagonists with Anti-Obesity
Activity Pp.1-5
Bradley P. Morgan, Kevin K.-C. Liu, Deepak K. Dalvie,
Andrew G. Swick, Diane M. Hargrove, Theresa C. Wilson, Janet A. LaFlamme,
Melinda S. Moynihan, Margaret A. Rushing, Graeme F. Woodworth, Jisong Li,
Richard V. Trilles, Xiaojing Yang, Kenneth W. Harper, Richard S. Carroll, Kelly
A. Martin, Nancy A. Nardone, John P. O’Donnell, Michael B. Faletto,
Chandravathi Vage and Victor Soliman
Probing Proteinase Active Sites
Using Oriented Peptide Mixture Libraries – ADAM-10 Pp.6-13
John L. Krstenansky, Jihong Wang, Gregg R. Chenail, Matthew
R. Tiffany, Geoffrey M. Kuesters, Barbara C. Natke and John J. Nestor, Jr.
Structure-Function Study of
Quinazolinone-Based Vitronectin Receptor (αVβ3) Antagonists:
Computer-Assisted Analysis of Ligand-Receptor Interactions Pp.14-18
Edward C. Lawson, William A. Kinney, Michael J. Costanzo,
William J. Hoekstra, Jack A. Kauffman, Diane K. Luci, Rosemary Santulli, Brett A. Tounge, Stephen C. Yabut, Patricia Andrade-Gordon
and Bruce E. Maryanoff
SAR and Molecular Modeling of
N-Benzyl-N-hydroxy-3-(cyclopentyloxy)-4- methoxybenzene Carboxamide Analogues
as Potent Phosphodiesterase-4 Inhibitors Pp.19-23
Jeewoo Lee, Su Yeon Kim, Hye Ra Lee and Je Hak Kim
Fungal Metabolites as Potent
Protein Kinase Inhibitors: Identification of a Novel Metabolite and Novel
Activities of Known Metabolites
Pp.24-29
Masayoshi Oyama, Zhihong Xu, Kuo-Hsiung Lee, Timothy D. Spitzer, Peter Kitrinos, Octerloney B. McDonald, Rosie R.J. Jones and Edward P. Garvey
Molecular Modeling, Synthesis And
Biological Evaluation of Heterocyclic Hydroxamic Acids Designed as Helicobacter
Pylori Urease Inhibitors Pp.30-34
E.M.F. Muri, H. Mishra, S.M. Stein and J.S. Williamson
Structure-Activity Relationship
Determination Study of a Series of Novel Compounds as Potential Inhibitors of
the Enzyme Estrone Sulfatase (ES) Pp.35-44
Chirag K. Patel, Caroline P. Owen, Kwabina Aidoo-Gyamfi and Sabbir Ahmed
Thymidine Phosphorylase
Over-Expression in Oral Squamous Carcinoma Tissue as a Potential Target of
Capecitabine Pp.45-49
G. Ranieri, R. Patruno, G. Fiore, G. Saponaro, A. Paradiso and L. Grammatica
Preclinical Evaluation of
no-Carrier-Added [131I]Meta-Iodobenzyl Guanidine, for the Treatment of Tumours
Transfected with the Noradrenaline Transporter Gene Pp.50-57
M. Boyd, S. Ross, J. Owens, D. Hunter, J. Babich, M.R. Zalutsky, T.G. Hamilton, S. Bell and R.J. Mairs
Structure Activity Relationships
for Nicotinamide in the Treatment of Stroke Pp.58-65
Jun Yang and James D. Adams Jr.
Suppressive Components in Salvia
miltiorrhiza Against Trp-P-1 and Activated Trp-P-1-Induced SOS Response Using
Salmonella typhimurium TA1535/pSK1002 Umu Test Pp.66-68
Yoshiharu Okuno and Mitsuo Miyazawa
Synthesis and Cytotoxicity of
Enediyne Prodrugs with 3-Hydroxy-4- (arylmethylidene)cyclodeca-1,5-diyne
Scaffolds Pp.69-72
Wei-Min Dai, Yukihiro Tachi, Sei-ichi Nishimoto, Xiaofen Zhong and Zhihong Guo
Expression of Peptide
Transporters on the Rabbit Retina: A Strategy to Improve Retinal Delivery of
Ganciclovir Pp.73-77
Soumyajit Majumdar, Sreeraj Macha, Yasser Nashed and Ashim K. Mitra
Two Identical Twin Nitrogen
Mustard Agents that Express Rapid Alkylation Activity at Physiological pH 7.4
and 37oC Pp.78-83
Ronald Bartzatt and Laura Donigan
Somatostatin Receptor Subtype 4
(sst4) Ligands: Synthesis and Evaluation of Indol-3-yl- and 2-Pyridyl-Thioureas Pp.84-87
A.M. Crider, S. Liu, T. Li, S. Mahajan, M. Ankersen and
C.E. Stidsen
Polycations. 15. Polyammonium
Surfaces - A New Approach to Antifungal Activity Pp.88-90
J.I. Cohen, T. Abel1, D. Burkett, R. Engel, J. Escalera, M. Filshtinskaya, T. Hatchett, M. Leto, Y. Melgar and K. Melkonian
Abstracts
[Back to top] Discovery of Potent,
Non-Steroidal and Highly Selective Glucocorticoid Receptor Antagonists with
Anti-Obesity Activity
Bradley P. Morgan, Kevin K.-C. Liu, Deepak K. Dalvie,
Andrew G. Swick, Diane M. Hargrove, Theresa C. Wilson, Janet A. LaFlamme,
Melinda S. Moynihan, Margaret A. Rushing, Graeme F. Woodworth, Jisong Li,
Richard V. Trilles, Xiaojing Yang, Kenneth W. Harper, Richard S. Carroll, Kelly
A. Martin, Nancy A. Nardone, John P. O’Donnell, Michael B. Faletto,
Chandravathi Vage and Victor Soliman
To thwart phase II metabolism, Structure-Activity-Relationship (SAR)
studies around the phenol of the potent glucocorticoid receptor (GR)
antagonists CP-394531 and CP-409069 were examined. The discovery of the potent,
selective, nonsteroidal GR antagonist (CP-472555) with anti-GR and anti-obesity
activity in animal models is described.
[Back to top] Probing Proteinase Active Sites
Using Oriented Peptide Mixture Libraries – ADAM-10
John L. Krstenansky, Jihong Wang, Gregg R. Chenail, Matthew
R. Tiffany, Geoffrey M. Kuesters, Barbara C. Natke and John J. Nestor, Jr.
Oriented Peptide Mixture Libraries can provide a full matrix of
preferred and disfavored amino acids at each subsite of an optimal substrate
for a new proteinase. This approach is rapid and convenient, requiring only two
mixture libraries to complete the analysis. In this paper we demonstrate an
extension of this type of analysis, using a focused library employing unnatural
amino acids to probe the depth of the S1 position in the catalytic site of the
alpha secretase ADAM-10. This analysis indicates that ADAM-10 will accept amino
acids with substantial length and hydrophobicity (e.g. 2-naphthylalanine), but
suggests that the S1 site has limitations in the apparent “width” of substituents being presented (e.g.
1-naphthylalanine; gamma branching). A highly selective and efficient substrate
for ADAM-10, with a selectivity factor of 380,000 M-1 s-1, was derived from the
predicted consensus substrate. This detailed analysis provides a starting point
for the design of inhibitors of this interesting proteinase.
[Back to top] Structure-Function Study of
Quinazolinone-Based Vitronectin Receptor (αVβ3) Antagonists:
Computer-Assisted Analysis of Ligand-Receptor Interactions
Edward C. Lawson, William A. Kinney, Michael J. Costanzo,
William J. Hoekstra, Jack A. Kauffman, Diane K. Luci, Rosemary Santulli, Brett
A. Tounge, Stephen C. Yabut, Patricia Andrade-Gordon and Bruce E. Maryanoff
Modification of the pendant functionalities on a quinazolinone scaffold
led to potent antagonist
activity for integrin
V3 with
selectivity over integrin
IIb3. Various guanidine mimetics, linkers, and
arylsulfonamides were investigated to optimize the series. A molecular model
was constructed based on a published X-ray structure and used to analyze
ligand-receptor interactions. We identified key interactions for the
quinazolinone and arylsulfonamide groups that may explain the changes in
potency in the structure-function study.
[Back to top] SAR and Molecular Modeling of
N-Benzyl-N-hydroxy-3-(cyclopentyloxy)-4- methoxybenzene Carboxamide Analogues
as Potent Phosphodiesterase-4 Inhibitors
Jeewoo Lee, Su Yeon Kim, Hye Ra
Lee and Je Hak Kim
A series of N-benzyl-N-hydroxy-3-(cyclopentyloxy)-4-methoxybenzene
carboxamide analogues have been investigated as PDE4 inhibitors. Two compounds,
3-carboxylic (12b) and 3-hydroxamic acid (13b) derivatives, have shown potent
inhibition toward PDE4, with IC50s of 0.114 and 0.047 M, respectively.
Docking of the compound 13b into the binding pocket of the PDE4 catalytic
domain revealed interactions corresponding to those of the cAMP substrate.
[Back to top] Fungal Metabolites as Potent
Protein Kinase Inhibitors: Identification of a Novel Metabolite and Novel
Activities of Known Metabolites
Masayoshi Oyama, Zhihong Xu,
Kuo-Hsiung Lee, Timothy D. Spitzer, Peter Kitrinos, Octerloney B. McDonald,
Rosie R.J. Jones and Edward P. Garvey
A novel undecylresorcinol dimer (1) was isolated from Coleophoma sp.
and inhibited cFMS receptor tyrosine kinase (IC50 of 0.4 M), with
greater than 10-fold selectivity versus
nine other protein kinases. The
known fungal metabolites
balanol and altenusin inhibited
cFMS kinase and pp60c-Src kinase, respectively, even more potently and
selectively. Altenusin inhibited pp60c-Src with an IC50 of 20 nM and a
selectivity of at least 400-fold versus nine other protein kinases. Balanol
inhibited cFMS receptor kinase with an IC50 of 1 nM and selectivities of
14-75-fold versus pp60c-Src and VEGF receptor kinases and greater than
10,000-fold versus seven other kinases.
[Back to top] Molecular Modeling, Synthesis And
Biological Evaluation of Heterocyclic Hydroxamic Acids Designed as Helicobacter
Pylori Urease Inhibitors
E.M.F. Muri, H. Mishra, S.M.
Stein and J.S. Williamson
A computer-generated homology model of the antimicrobial target
Helicobacter pylori urease was derived, using the x-ray crystal structure of
Klebsiella aerogenes as a template, in order to design novel urease inhibitors.
Based on these computational studies, several heterocyclic hydroxamic acid
derivatives have been designed, synthesized, and examined for their ability to
inhibit urease activity.
[Back to top] Structure-Activity Relationship Determination Study of a
Series of Novel Compounds as Potential Inhibitors of the Enzyme Estrone Sulfatase (ES)
Chirag K. Patel, Caroline P.
Owen, Kwabina Aidoo-Gyamfi and Sabbir Ahmed
The synthesis and biochemical evaluation of a series of esters of 4-
sulfamoylated cinnamic acid as potential inhibitors of the enzyme estrone
sulfatase (ES) is reported. The results of the study show that the esters of
trans 4-sulfamoylated cinnamic acid are weaker irreversible inhibitors of ES in
comparison to 4- methylcoumarin-7-O-sulfamate (COUMATE) and its tricyclic
derivatives such as 667- COUMATE, as well as the steroidal inhibitor
estrone-3-O-sulfamate (EMATE). Structureactivity relationship determination
indicates that the flexible nature of the cinnamic acid backbone results in
these compounds possessing greatly reduced inhibitory activity compared to the
corresponding coumarin derivative. Furthermore, from the superimpositioning of
the synthesised compounds onto the substrate, we propose that steric hindrance
is an important factor which results in a marked decrease in the inhibitory
activity within the large alkyl chain containing compounds.
[Back to top] Thymidine Phosphorylase Over-Expression in Oral Squamous
Carcinoma Tissue as a Potential Target of Capecitabine
G. Ranieri, R. Patruno, G.
Fiore, G. Saponaro, A. Paradiso and L. Grammatica
Advanced oral squamous carcinoma (OSC) is typically treated with 5-
Fluorouracil (5-FU) based regimens. Capecitabine (CAP) is a thymidine phosphorylase
(TP) activated oral fluoropyrimidine, rationally designed to generate 5-FU
preferentially within tumours. The high activity of CAP in intestinal and
breast cancer suggests that CAP may have a role in the therapy of OSC. This
tumour selectively is achieved through exploitation of the significantly higher
activity of TP in tumour compared with healthy tissue. In the present study,
the epithelial and macrophages TP expression were significantly higher in OSC
than in non-dysplastic oral leukoplakia (NDOLP) (p=0.004, p=0.005;
respectively). Because OSC is sensitive to 5-FU, and TP expression is
significantly higher in OSC than in NDOLP, TP-activated CAP could be a
promising therapy worthy of clinical investigation.
[Back to top] Preclinical Evaluation of no-Carrier-Added
[131I]Meta-Iodobenzyl Guanidine, for the Treatment of Tumours Transfected with
the Noradrenaline Transporter Gene
M. Boyd, S. Ross, J. Owens, D.
Hunter, J. Babich, M.R. Zalutsky, T.G. Hamilton, S. Bell and R.J. Mairs
Meta-[131I]iodobenzylguanidine ([131I]MIBG), used for neuroblastoma
treatment, binds to the noradrenaline transporter (NAT). After NAT gene
transfection, other tumour types might be treatable with [131I]MIBG. At 14 MBq,
carrier-added [131I]MIBG (1110 MBq/mg) delayed tumour regrowth in NAT
gene-transfected xenografts by 39-days, while no-carrier-added [131I]MIBG
(>104 GBq/mg) cured 100% of tumours.
[Back to top] Structure Activity Relationships for Nicotinamide in the
Treatment of Stroke
Jun Yang and James D. Adams Jr.
Oxidative stress is the main pathophysiological mechanism involved in
the development of stroke. Severe DNA damage induced by oxidative stress or
apoptotic stimuli activates poly (ADP-ribose) polymerase (PARP), causing a
rapid depletion of nuclear NAD pools, cellular energy, and thiols. The
biochemical activity of nicotinamide in the body is based on its conversion
into NAD. Nicotinamide and its structural analogues possess a weak inhibitory
effect on PARP. Nicotinamide exerts its neuroprotective effects by increasing
NAD synthesis and ATP production indirectly and inhibiting PARP directly. By
inhibiting PARP, membrane phosphatidylserine exposure and DNA fragmentation,
nicotinamide can prevent brain necrosis and apoptosis effectively.
Administration of nicotinamide at an early stage of stroke provides a new means
to rescue the still viable but injured nerve cells within the ischemic and
limit areas.
[Back to top] Suppressive Components in Salvia miltiorrhiza Against
Trp-P-1 and Activated Trp-P-1-Induced SOS Response Using Salmonella typhimurium
TA1535/pSK1002 Umu Test
Yoshiharu Okuno and Mitsuo
Miyazawa
The methanol extract from Salvia miltiorrhiza Bungee showed a suppressive
effect on umu gene expression of the SOS response in Salmonella typhimurium
TA1535/pSK1002 against the mutagen, Trp-P-1, which requires liver metabolizing
enzyme. The methanol extract was successively re-extracted with
dichloromethane, butanol, and water. Three suppressive compounds were isolated
by SiO2 column chromatography from dichloromethane fraction and identified as
tanshinone IIA (1), tanshinone I (2) and Cryptotanshinone (3) by GC, GC-MS, 1H-
and 13C-NMR spectroscopy.
Compounds 1, 2 and 3 inhibited the SOS-inducing activity of Trp-P-1 in
the umu test. Gene expression was suppressed by 76%, 96% and 81% at less than
0.18 µmol/mL, 9 respectively. The ID50 (50% inhibition dose) values were 0.03
µmol/mL 0.008 µmol/mL and 0.010 µmol/mol, respectively. These compounds were
assayed with activated Trp-P-1. Compound 2 showed suppressive effect of
SOS-inducing activity of activated Trp-P-1 but compounds 1 and 3 did not.
[Back to top] Synthesis and Cytotoxicity of Enediyne Prodrugs with
3-Hydroxy-4- (arylmethylidene)cyclodeca-1,5-diyne Scaffolds
Wei-Min Dai, Yukihiro Tachi,
Sei-ichi Nishimoto, Xiaofen Zhong and
Zhihong Guo
A series of enediyne prodrugs with (E)- or
(Z)-3-hydroxy-4-(arylmethylidene)cyclodeca-1,5- diyne scaffolds have been
synthesized via an intramolecular Nozaki–Hiyama–Kishi reaction as the key step.
Cytotoxicity in micro molar range against P388 cancer cell line was observed
for selected compounds and a structure-activity relationship is discussed.
[Back to top] Expression of Peptide Transporters on the Rabbit Retina: A
Strategy to Improve Retinal Delivery of Ganciclovir
Soumyajit Majumdar, Sreeraj
Macha, Yasser Nashed and Ashim K. Mitra
The objective of this study was to investigate functional expression of
peptide transporters on the rabbit retina. In vivo and ex vivo retina/choroidal
uptake studies were carried out with New Zealand albino rabbits. [3H]Gly-Sar
was used as the model peptide transporter substrate. [3H]Gly-Sar solutions, in
the presence and absence of specific inhibitors, were added to the vitreal side
of the retina. Results indicate that retinal uptake of [3H]Gly-Sar was
significantly inhibited in the presence of other known peptide transporter
substrates, such as Gly-Pro and cephalexin. Importantly, valganciclovir, a
peptidomimetic prodrug of ganciclovir, also inhibited uptake of [3H]Gly-Sar.
These studies therefore, indicate that peptide transporters are functionally
expressed on the rabbit retina and retinal concentrations of GCV may be
enhanced by targeting these transporters through prodrug derivatization.
[Back to top] Two Identical Twin Nitrogen Mustard Agents that Express
Rapid Alkylation Activity at Physiological pH 7.4 and 37oC
Ronald Bartzatt and Laura Donigan
Two nitrogen mustard (N-mustard ) agents were synthesized utilizing
ethylene diamine and hexane diamine as the parent compounds. These N-mustard
agents were solids at 25o C and stable while stored dry at -10o C. The two
N-mustards assumed the configuration of identical twin drugs which when placed
in aqueous solution were highly reactive. Both N-mustards were soluble in
aqueous NaHCO3 buffer and expressed alkylation activity directed towards a
nucleophilic primary amine target (4-chloroaniline) at blood pH 7.4 and 37o C.
Utilizing the fluorescent probe fluorescamine, which is highly specific for
primary amines, the quantity of unreacted nucleophilic 4-chloroaniline
remaining after a known time period was determined. This enabled the
calculation of rate constants and the determination of rate equation for
alkylation to be first-order for
N,N,N’,N’-tetrakis(2-chloroethyl)ethane-1,2-diamine and zero-order for
N,N,N’,N’- tetrakis(2-chloroethyl)hexane-1,6-diamine. Molecular property
descriptors such as Log P, parachor, molar volume, molar refractivity, dipole,
molecular volume & area, and polar surface area were calculated for
comparison. Zero violations of the Rule of 5 indicates these two mustard agents
will have good bioavailability and good bioactivity.
[Back to top] Somatostatin Receptor Subtype 4 (sst4) Ligands: Synthesis
and Evaluation of Indol-3-yl- and 2-Pyridyl-Thioureas
A.M. Crider, S. Liu, T. Li, S.
Mahajan, M. Ankersen and C.E. Stidsen
Thiourea analogues of NNC 26-9100 (2) were prepared as somatostatin
receptor subtype 4 (sst4) ligands. The indole 9 exhibited high affinity (Ki =
23 nM) and about a 100-fold selectivity at sst4 compared to sst2 receptors. The
(imidazol-4-yl) propyl group appears to play a major role in the affinity and
selectivity of these thioureas at sst4.
[Back to top] Polycations. 15. Polyammonium Surfaces - A New Approach to
Antifungal Activity
J.I. Cohen, T. Abel1, D.
Burkett, R. Engel, J. Escalera, M. Filshtinskaya, T. Hatchett, M. Leto, Y.
Melgar and K. Melkonian
Several types of porous surfaces, including cotton cloth, paper, wood,
silk, and wool, have been modified chemically by the attachment of polycationic
adjuncts to provide them with antifungal characteristics. Structure/activity
relationships for the antifungal adjuncts have been determined in this
investigation for the effect on a series of fungi.