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Combinatorial Chemistry &
High Throughput Screening
ISSN: 1386-2073
Combinatorial Chemistry &
High Throughput Screening
Volume 9, Number 3, March 2006
Contents
GHRH Analogs and Cancer
Guest Editor: Hippokratis Kiaris
Editorial Pp. 161
Antagonists of Growth Hormone-Releasing
Hormone in Oncology Pp. 163-170
Andrew V. Schally and Jozsef L. Varga
[Abstract]
Growth Hormone-Releasing Factor: Structural Modification or
Protection for More Potent Analogs Pp. 171-174
Pascal Dubreuil and Cyril Désévaux
[Abstract]
Growth Hormone Secretagogues Pp. 175-180
Maria Luisa Isidro and Fernando Cordido
[Abstract]
Plasmid-Based Expression Technology Using Growth
Hormone Releasing Hormone: A Novel Method for Physiologically
Stimulating Long-Term Growth Hormone Secretion Pp.
181-185
Ruxandra Draghia-Akli, Melissa A. Pope, Patricia A. Brown
and Amir S. Khan
[Abstract]
Synthesis and Pharmacological Profile of an Orally-Active
Growth Hormone Secretagogue, SM-130686 Pp. 187-196
Jun Nagamine, Tetsuya Kawamura, Teruhisa Tokunaga, W.
Ewan Hume,Ryu Nagata, Tsutomu Nakagawa and Mutsuo Taiji
[Abstract]
A Novel hGHRH Analog and its Comparative Activity
Pp. 197-202
Song-Shan Tang, Ming-Hua Du, Xiao-Wen Zhang, Juan-Hui
Zhang, Jie Wu, Esam Mahanmad and Jing-Jing Liu
[Abstract]
General Articles
Microarray: A Versatile Platform for High-Throughput Functional
Proteomics Pp. 203-212
Yi Hu, Mahesh Uttamchandani and Shao Q. Yao
[Abstract]
Computational Methods in Developing Quantitative Structure-Activity
Relationships (QSAR): A Review Pp. 213-228
Arkadiusz Z. Dudek, Tomasz Arodz and Jorge Gálvez
[Abstract]
Functionalized Ionic Liquids as New Supports for Peptide
Coupling and Traceless Catalyzed Carbon-Carbon Coupling Reactions
Pp. 229-232
Fabien Bonnette, Zoia Mincheva and Olivier Lavastre
[Abstract]
Meet the Guest Editor
Pp. 233
Abstracts
[Back to top]
Editorial
Although discovered a few decades ago, growth hormone –
releasing hormone (GHRH) was thought until recently to have
only a single function, namely the regulation of growth hormone
release from the pituitary. However, new evidence has provided
strong support to the notion that additional physiological
and patho-physiological processes, and including carcinogenesis,
might be regulated by GHRH. Recently, interest in this small
neuropeptide has been increasing steadily and has resulted
in the development of GHRH analogs that modulate its activity
and potentially might be used as agents that permit clinical
intervention.
In this special issue of Combinatorial Chemistry &
High Throughput Screening an attempt was made to provide
the state of the art with respect to information in this field.
Contributions include both review and original research papers
related to chemical and biological synthesis of GHRH analogs,
as well as the biological consequenses of such compounds.
Articles on GH secretagogues were also included in this effort
considering that the complexity of growth hormone regulation
has only recently begun to unravel. It is the contributors’
and the special editor’s hope that this attempt will
stimulate further interest regarding the role and use of GH
regulatory agents in health and disease.
Hippokratis Kiaris
Department of Biological Chemistry
University of Athens Medical School
M. Asias 75
115 27 Athens
Greece
E-mail: hkiaris@med.uoa.gr
[Back to top]
Antagonists of Growth Hormone-Releasing Hormone in
Oncology
Andrew V. Schally and Jozsef L. Varga
The development of antagonists of growth hormone (GH) -
releasing hormone (GH-RH) is reviewed. GH-RH antagonists bind
with a high affinity to pituitary receptors for GH-RH and
inhibit the release of GH in vitro and in vivo.
The main applications of GH-RH antagonists would be for tumor
therapy. The antitumor effects of GH-RH antagonists are exerted
in part indirectly through the inhibition of the secretion
of pituitary GH and the reduction in the levels of hepatic
insulin like growth factor (IGF-I). However, principal effects
of the GH-RH antagonists are exerted directly on tumors. Antagonists
of GH-RH inhibit the proliferation of various cancer cell
lines in vitro and suppress in vivo the
levels and the expression of mRNA for IGF-I and IGF-II in
tumors. In many human cancers, the effects of GH-RH antagonists
appear to be due to the blockade of the action of tumoral
GH-RH. GH-RH ligand is present in various human cancers indicating
that it may be an autocrine/paracrine growth factor. Splice
variants (SVs) of GH-RH receptors and pituitary type of GH-RH
receptors that might mediate effects of tumoral GH-RH and
of GH-RH antagonists were demonstrated in many human cancers.
This suggests the presence of a stimulatory loop based on
GH-RH and SVs or pituitary type of GH-RH receptors in diverse
tumors. It was shown that GH-RH antagonists inhibited the
growth of various human cancer lines xenografted into nude
mice including mammary, ovarian, endometrial and prostate
cancers, small cell lung carcinomas (SCLC) and non-SCLC, renal,
pancreatic, gastric and colorectal carcinomas, malignant gliomas,
osteosarcomas and Non-Hodgkin’s lymphomas. Further development
of GH-RH antagonists should lead to potential therapeutic
agents for various cancers.
[Back to top]
Growth Hormone-Releasing Factor: Structural Modification
or Protection for More Potent Analogs
Pascal Dubreuil and Cyril Désévaux
Growth hormone-releasing factor was discovered in 1982 by
Guillemin and has been subjected to intense investigations
because of its huge potential applications. The major concerns
encountered with the native molecules were their short half-lives
in vivo in many species including man, precluding
the practical use of these peptides for medical or production
purposes. Many efforts to produce analogs of shorter length,
more resistant to degradation and having higher affinity to
the receptors have been made during the last decades. The
present paper presents a quick review of the work done to
produce such analogs.
[Back to top]
Growth Hormone Secretagogues
Maria Luisa Isidro and Fernando Cordido
Growth hormone secretagogues (GHSs) are synthetic molecules
that stimulate and amplify pulsatile pituitary growth hormone
release, via a separate pathway distinct from GH
releasing hormone/somatostatin. The activity of GHSs is not
fully specific for GH secretion; some GHSs also have slight
releasing activity on other pituitary hormones and mediate
GH independent biological activities. The first GHSs were
discovered in 1977. Since then, an intensive research to synthesize
a potent oral GHSs has been undertaken. Although the potential
applications of GHSs are numerous, long term trials are needed
to evaluate the clinical efficacy and safety of these substances.
In the present article we review the historic background
of GHSs, their potential clinical uses, the types and the
main GHSs that have been synthesized hitherto.
[Back to top]
Plasmid-Based Expression Technology Using Growth Hormone
Releasing Hormone: A Novel Method for Physiologically Stimulating
Long-Term Growth Hormone Secretion
Ruxandra Draghia-Akli, Melissa A. Pope, Patricia A. Brown
and Amir S. Khan
Novel DNA-based technologies were recently introduced for
various purposes, such as screening of targets identified
from genomic projects, shuffled molecules for vaccination,
or to direct the in vivo production of hormones and
other peptides for therapeutic or preventative applications.
We have used a plasmid-based technology to deliver growth
hormone releasing hormone (GHRH) to various animal species
for screening, toxicology and therapy. A single intramuscular
injection of a low dose of plasmid followed by electroporation
can ensure that the target species will produce physiological
levels of GHRH for extended periods of time, which would replace
costly, frequent injections of the recombinant hormone and
improve the quality of life and compliance of patients. This
therapeutic modality is of particular importance in circumstances
requiring long-term administration of small molecules with
naturally short half-life (e.g. treatment of anemia
and cachexia associated with renal failure, cancer or other
chronic disability). A similar technique was used to create,
test and validate protease-resistant analogs of GHRH with
significantly longer half-life. Analysis of the characteristics
of each of the plasmid components and tissue-specific transcription
factors and the choice of target tissue is imperative when
designing plasmids for therapeutic applications. Using the
species-specific sequences of GHRH or other molecule along
with the appropriate choice of plasmid backbone and expression
cassette components can result in long and steady expression
of the transgene product.
[Back to top]
Synthesis and Pharmacological Profile of an Orally-Active
Growth Hormone Secretagogue, SM-130686
Jun Nagamine, Tetsuya Kawamura, Teruhisa Tokunaga, W.
Ewan Hume,Ryu Nagata, Tsutomu Nakagawa and Mutsuo Taiji
Hypothalamic hormones physiologically regulate pulsatile
release of growth hormone (GH) from the anterior pituitary
gland. Since the discovery of these hormones in the 1970s,
several new chemically synthesized peptidyl and non-peptidyl
derivatives have been proved to stimulate and amplify GH secretion,
and this series of molecules has been named the growth hormone
secretagogues (GHSs). One of these compounds led to the discovery
of a GPCR-type receptor for GHSs (GHS-R), and subsequently
the endogenous ligand for the receptor has been identified,
and is referred to as ghrelin. The identification of GHSs
as physiological regulators of GH secretion encouraged us
to examine our GHSs pharmacologically. We previously reported
that novel oxindole derivatives have been identified as GHS-R
agonists from our internal chemical library. Among these derivatives,
(+)-6-carbamoyl-3-(2-chlorophenyl)-(2-diethylaminoethyl)-4-trifluoromethyloxindole
(SM-130686, 37S) was found to have potent activity in
vitro with a good pharmacokinetic profile in rats (bioavailability
of 28%). In this article, we review the synthesis and pharmacological
evaluation of SM-130686. SM-130686 binds specifically to GHS-R
and increases the Ca2+ concentration in Chinese
hamster ovary cells expressing recombinant GHS-R. Maximal
enhancement of the intracellular Ca2+ concentration
induced by SM-130686 treatment was approximately 55% that
induced by ghrelin, suggesting that SM-130686 may be a partial
GHS-R agonist. Also, in in vivo studies, oral administration
of SM-130686 increased body length and fat-free mass gain.
We compare the pharmacological profile of SM-130686 with other
GHSs, including GHRH and ghrelin, and discuss the therapeutic
usefulness of GHSs against several disorders, as well as for
treatment of GH deficiency.
[Back to top]
A Novel hGHRH Analog and its Comparative Activity
Song-Shan Tang, Ming-Hua Du, Xiao-Wen Zhang, Juan-Hui
Zhang, Jie Wu, Esam Mahanmad and Jing-Jing Liu
Growth hormone releasing hormone is one of the hormones secreted
from the hypothalamus. Because of its potential applications
in agriculture and medicine, its short half-life and its expensive
chemical synthesis, an analog with high GHRH activity and
prolonged half-life was sought after. The fusion partner gene
with 127 amino acid residues of the C-terminus from L-asparaginase
was recombined with asp-pro-hGHRH(1-44) gene synthesized
by PCR method to form one kind of fusion protein with unique
acid labile linker Asp-Pro. The Pro-hGHRH(1-44) peptide was
purified to homogeneity by means of cell disruption, washing,
ethanol precipitation, acid hydrolysis, SP-Sephadex C-25,
and Sephadex G-10 column chromatography. The peptide’s
molecular weight of 5,139 Da as measured by EIS-MS was coincident
with the actual values. In the study of the activity, the
doses of peptide were 0.1, 1.0, and 10 µg/ml for rat
pituitary and 5 µg/ml for human pituitary. The peptide
increased GH releases from rat pituitary in a concentration-dependent
manner (P<0.05; P<0.01). At 1.0 µg/ml,
there was a significant difference between Pro-Pro-hGHRH(1-44)-Gly-Gly-Cys
and Pro-hGHRH(1-44) or Pro-Pro-hGHRH(1-44) (P<0.05),
whereas the standard hGHRH(1-40) showed no measured rGH release.
For human fetal pituitary, the Pro-hGHRH(1-44) peptides showed
good GH-releasing activity, but there were no significant
differences between them. The structure-activity relationship
showed that for both rat and human fetal pituitary, the net
GH-releasing activity of the Pro-hGHRH(1-44) analog was more
than that of Pro-Pro-hGHRH(1-44). The results of the other
hormones from human pituitary showed that the analog had good
function-selectivity and species specificity.
[Back to top]
Microarray: A Versatile Platform for High-Throughput
Functional Proteomics
Yi Hu, Mahesh Uttamchandani and Shao Q. Yao
The advent of microarray technologies has dramatically accelerated
the functional study of proteins, including enzymes (catalomics)
in a proteome. Herein, we review recent advances and exciting
new developments of microarrays in high-throughput functional
proteomics.
[Back to top]
Computational Methods in Developing Quantitative Structure-Activity
Relationships (QSAR): A Review
Arkadiusz Z. Dudek, Tomasz Arodz and Jorge Gálvez
Virtual filtering and screening of combinatorial libraries
have recently gained attention as methods complementing the
high-throughput screening and combinatorial chemistry. These
chemoinformatic techniques rely heavily on quantitative structure-activity
relationship (QSAR) analysis, a field with established methodology
and successful history. In this review, we discuss the computational
methods for building QSAR models. We start with outlining
their usefulness in high-throughput screening and identifying
the general scheme of a QSAR model. Following, we focus on
the methodologies in constructing three main components of
QSAR model, namely the methods for describing the molecular
structure of compounds, for selection of informative descriptors
and for activity prediction. We present both the well-established
methods as well as techniques recently introduced into the
QSAR domain.
[Back to top]
Functionalized Ionic Liquids as New Supports for Peptide
Coupling and Traceless Catalyzed Carbon-Carbon Coupling Reactions
Fabien Bonnette, Zoia Mincheva and Olivier Lavastre
A new strategy to obtain pure ionic liquid support with a
high loading (3 mmol/g) of primary amino groups is reported.
The compatibility of the imidazolium unit was demonstrated
with DIC or DCC coupling reactions of protected amino acids
and with classical cleavage of BOC or Fmoc protecting groups.
In addition, this is the first report of a traceless ionic
liquid support based on a silicon linker with a high loading
(3 mmol/g) of aryl bromide reactive groups used in a palladium-catalyzed
carbon-carbon coupling reaction.
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