| Medicinal
Chemistry
ISSN: 1573-4064
Medicinal Chemistry
Volume 1, Number 1, January 2005
Contents
Editorial Pp.1-1
Atta-ur-Rahman
Synthesis of A/B-Ring Partial Analogs of Bruceantin
as Potential Antimalarial Agents Pp. 3-11
Z. Guo, S. Vangapandu, A. Nimrod, L. A. Walker and R.
D. Sindelar
[Abstract]
A Novel Achiral seco-Amino-Cyclopropylindoline
(CI) Analog of CC-1065 and the Duocarmycins: Design, Synthesis
and Biological Studies Pp. 13-19
James L. Toth, John D. Trzupek, Lloyd V. Flores, Konstantinos
Kiakos, John A. Hartley,William T. Pennington,Moses Lee
[Abstract]
Novel Experimental Design for Steady-state Processes:
A Systematic Bayesian Approach for Enzymes, Drug Transport,
Receptor Binding, Continuous Culture and Cell Transport Kinetics
Pp. 21-29
M. James C. Crabbe, Emma F. Murphy and Steven G. Gilmour
[Abstract]
Influence of Trishomocubanes on Sigma Receptor
Binding of N-(1-Benzylpiperidin-4-yl)-4-[123I]iodobenzamide
In Vivo in the Rat Brain Pp. 31-38
Xiang Liu, Filomena Mattner, Andrew Katsifis, MacDonald
Christie and Michael Kassiou
[Abstract]
A New Nucleotide-composition Based Fingerprint
of SARS-CoV with Visualization Analysisa Pp.
39-47
Meng Wang, Jin-Song Yao, Zhen-De Huang, Zhi-Jie Xu, Guo-Ping
Liu, Hai-Yong Zhao, Xue-Yong Wang, Jie Yang, Yi-Sheng Zhu
and Kuo-Chen Chou
[Abstract]
Apoptosis Signaling Pathways in Lung Diseases
Pp. 49-56
K. Kuwano, M. Yoshimi, T. Maeyama, N. Hamada, M. Yamada
and Y. Nakanishi
[Abstract]
Full Length and Delta Lactoferrin Display Differential
Cell Localization Dynamics, but do not Act as Tumor Markers
or Significantly Affect the Expression of Other Genes Pp.
57-64
Gary S. Goldberg, Takehiko Kunimoto, David B.
Alexander, Kayoko Suenaga, Fumiyoshi shidate, Kazuaki Miyamoto,
Toshikazu Ushijima, Christina T. Teng, Jun Yokota, Tsutomu
Ohta and Hiroyuki Tsuda
[Abstract]
Cytotoxicity of an Ebulin l-Anti-Human CD105 Immunotoxin
on Mouse Fibroblasts (L929) and Rat Myoblasts (L6E9) Cells
Expressing Human CD105 Pp. 65-71
Jorge Benitez, J. Miguel Ferreras, Raquel Munoz, Yolanda
Arias, Rosario Iglesias, Manuel Cordoba-Diaz, Rosario del
Villar and Tomas Girbes
[Abstract]
Review Article
Protease Inhibitors in the Clinic Pp. 71-104
Giovanni Abbenante and David P. Fairlie
[Abstract]
Abstracts
[Back to top]
Editorial
Atta-ur-Rahman
The field of medicinal chemistry has continued to expand
rapidly, specially with the growing understanding of disease
processes at the molecular level. This first issue of “Medicinal
Chemistry” presents papers on recent advances in this
field written by eminent experts. The articles on novel anti-malarials,
anti-cancer agents, enzyme kinetics, sigma receptor binding
SARS-cov genome sequences, apoptosis, lactoferrin interactions,
immunotoxins and protease inhibitors should prove to be of
considerable interest to researchers as well as the general
community of medicinal chemists.
It is hoped that “Medicinal Chemistry” would
soon become an indispensable journal in this field.
[Back to top]
Synthesis of A/B-Ring Partial Analogs of Bruceantin
as Potential Antimalarial Agents
Z. Guo, S. Vangapandu, A. Nimrod, L. A. Walker
and R. D. Sindelar
Bruceantin (1), a classical quassinoid with the highest
reported antimalarial activity among the quassinoids examined
thus far, was selected as a natural product lead for the design
of a series of A/B-ring analogs. A viable strategy for the
synthesis of the series was developed. The functionalized
A-ring and the C-15 ester moiety in bruceantin are incorporated
in all designed compounds. The preliminary bioassay results
will be discussed in detail.
[Back to top]
A Novel Achiral seco-Amino-Cyclopropylindoline (CI)
Analog of CC-1065 and the Duocarmycins: Design, Synthesis
and Biological Studies
James L. Toth, John D. Trzupek, Lloyd V. Flores,
Konstantinos Kiakos, John A. Hartley,William T. Pennington,Moses
Lee
The design, synthesis and DNA binding properties of a
novel achiral and amino-containing seco-cyclopropylindoline
analog (seco-amino-CI-TMI, 1) of the duocarmycins
are described. Thermal induced DNA cleavage studies on pUC18
DNA revealed compound 1 to preferentially bind in the minor
groove and to covalently react with ATrich sequences, particularly
at the underlined adenine-N3 group of 5’-AAAAA(865)-3’.
This sequence specificity is similar to adozelesin and CC-1065.
Using a 4-day continuous exposure, compound 1 inhibited the
growth of K562 human chronic myeloid leukemia cells in culture.
Compound 1 has appreciable cytotoxicity (IC50 value
of 1.30 μM)
relative to compound 2 (0.15 μM),
the corresponding racemic and hydroxy-seco-CI-TMI
analog. These results indicate that the aminophenethyl chloride
group present in compound 1 has similar sequence specific
and cytotoxic properties to the hydroxy-containing seco-precursors
of CC-1065 and the duocarmycins. Moreover, the results suggest
that the chiral center present in the natural products is
not absolutely necessary for biological activity. The novel
aminophenethyl halide moiety is, therefore, a useful template
from which to develop future achiral analogs of CC-1065 and
the duocarmycins.
[Back to top]
Novel Experimental Design for Steady-state Processes:
A Systematic Bayesian Approach for Enzymes, Drug Transport,
Receptor Binding, Continuous Culture and Cell Transport Kinetics
M. James C. Crabbe, Emma F. Murphy and Steven
G. Gilmour
We demonstrate that a Bayesian approach (the use of prior
knowledge) to the design of steady-state experiments can produce
major gains quantifiable in terms of information, productivity
and accuracy of each experiment.
Developing the use of Bayesian utility functions, we have
used a systematic method to identify the optimum experimental
designs for a number of kinetic model data sets. This has
enabled the identification of trends between kinetic model
types, sets of design rules and the key conclusion that such
designs should be based on some prior knowledge of the kinetic
model.
We suggest an optimal and iterative method for selecting features
of the design such as the substrate range, number of measurements
and choice of intermediate points. The final design collects
data suitable for accurate modelling and analysis and minimises
the error in the parameters estimated. It is equally applicable
to enzymes, drug transport, receptor binding, microbial culture
and cell transport kinetics.
[Back to top]
Influence of Trishomocubanes on Sigma Receptor Binding of
N-(1-Benzylpiperidin-4-yl)-4-[123I]iodobenzamide
In Vivo in the Rat Brain
Xiang Liu, Filomena Mattner, Andrew Katsifis,
MacDonald Christie and Michael Kassiou
Three new trishomocubane analogues based on the 4 azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]
dodecane-3-ol skeleton have been synthesised and assessed
for their affinities at both sigma-1 and sigma-2 receptors.
The effect of various N-substitution on the polycyclic
moiety was examined. All synthesised compounds displayed high
affinity for sigma-1 receptors (9-10 nM) and good affinity
for sigma-2 receptors (230-310 nM), suggesting that substitution
at the nitrogen moiety of the trishomocubane is well tolerated
and represents a platform for the development of improved
higher affinity sigma receptor ligands. The interaction of
these functionalised trishomocubanes on the binding of the
known sigma receptor radioligand, 4-[123I]IBP,
was evaluated in the rat brain. Although 4-[123I]IBP
had been used for imaging sigma receptors in tumours, this
is the first examination of sigma receptor binding in the
rat brain and therefore the potential of 4-[123I]IBP
for imaging the brain was also evaluated. In vivo
specificity and selectivity of 4-[123I]IBP binding
was examined by studying the effects of preadministration
of sigma receptor binding drugs (+)-pentazocine and unlabelled
4-IBP. This resulted in a blockade of only 42% of 4-[123I]IBP
uptake in the brain indicating high degree of non-specific
binding suggesting that it may not be suitable for imaging
sigma receptors in the brain. The inhibition of 4-[123I]IBP
uptake using the two of the three trishomocubanes displayed
a consistent blockade of 48-30% in all brain structures. This
demonstrates for the first time the ability of functionalised
trishomocubanes to interact with sigma receptors in vivo.
[Back to top]
A New Nucleotide-composition Based Fingerprint of SARS-CoV
with Visualization Analysisa
Meng Wang, Jin-Song Yao, Zhen-De Huang, Zhi-Jie
Xu, Guo-Ping Liu, Hai-Yong Zhao, Xue-Yong Wang, Jie Yang,
Yi-Sheng Zhu and Kuo-Chen Chou
It has been observed by conducting an extensive analysis
of the two-dimensional cellular automata images of known SARS-CoV
genome sequences that the V-shaped cross-lines only exist
in some special locations, and hence can be used as a fingerprint
to identify the SARS sequences. Such a discovery can be used
to rapidly and reliably diagnose SARS coronavirus for both
basic research in laboratories and practical application in
clinics.
[Back to top]
Apoptosis Signaling Pathways in Lung Diseases
K. Kuwano, M. Yoshimi, T. Maeyama, N. Hamada,
M. Yamada and Y. Nakanishi
Evidence that apoptosis plays an important role in the
pathophysiology of lung diseases has been accumulated. Apoptosis
signaling is classically composed of two principle pathways.
One is a direct pathway from death receptor ligation to caspase
cascade activation and cell death. Death receptor ligation
triggers recruitment of the precursor form of caspase-8 to
a death-inducing complex, through the adaptor protein FADD,
which leads to caspase-8 activation. The other pathway triggered
by stimuli such as drugs, radiation, infectious agents and
reactive oxygen species is initiated in mitochondria. After
cytochrome c is released into the cytosol from the mitochondria,
it binds to Apaf1 and ATP, which then activate caspase-9.
Recently, endoplasmic reticulum has also been shown to be
the organelle to execute apoptosis. Further understanding
of molecular mechanisms of apoptosis and its regulation by
novel drugs may lead to the development of effective strategies
against lung diseases. We overview the signaling pathways
of apoptosis and discuss the involvement of apoptosis in the
pathophysiology of various lung diseases.
[Back to top]
Full Length and Delta Lactoferrin Display Differential
Cell Localization Dynamics, but do not Act as Tumor Markers
or Significantly Affect the Expression of Other Genes
Gary S. Goldberg, Takehiko Kunimoto, David B.
Alexander, Kayoko Suenaga, Fumiyoshi Ishidate, Kazuaki Miyamoto,
Toshikazu Ushijima, Christina T. Teng, Jun Yokota, Tsutomu
Ohta and Hiroyuki Tsuda
Lactoferrin is a secreted protein related to transferrin.
Lactoferrin indirectly protects host cells against foreign
insults by killing bacteria, scavenging free iron, and binding
to receptors required for viral invasion. However, lactoferrin
is also proposed to act directly on cells as a transcription
factor and tumor suppressor gene. In addition to full length
lactoferrin, a truncated form, called delta lactoferrin, can
also be produced by alternative splicing. We show here that
transformed and nontransformed cells are equally able to express
both full length and delta lactoferrin. Moreover, both forms
of lactoferrin failed to substantially modulate the expression
of other genes. Thus, lactoferrin does not seem to directly
control gene expression or inhibit tumor cell growth.
[Back to top]
Cytotoxicity of an Ebulin l-Anti-Human CD105 Immunotoxin
on Mouse Fibroblasts (L929) and Rat Myoblasts (L6E9) Cells
Expressing Human CD105
Jorge Benitez, J. Miguel Ferreras, Raquel Munoz,
Yolanda Arias, Rosario Iglesias, Manuel Cordoba-Diaz, Rosario
del Villar and Tomas Girbes
Tumour growth is characterised by the formation of a
fine vessel network or neovasculature which nourishes tumour
cells. Two kinds of novel anti-angiogenic therapies are based
on the prevention of vessels growth and on the destruction
of those vessels already formed. We report here on the design
and construction of a novel immunotoxin formed with the non-toxic
type II ribosome-inactivating protein ebulin l and the mouse
anti-human CD105 monoclonal antibody 44G4. The 44G4-ebulin
immunotoxin was formed by covalent linking of both proteins
with N-succinimidyl-3- (2-pyridyldithio)propionate
(SPDP) and was purified by chromatography on Superdex 200
HiLoad. The analysis of the anti-ribosomal effects in a cell-free
translation system indicated that conjugation does not affect
the activity of ebulin l. The immunotoxin displays cytotoxicity
with nanomolar IC50 values on human CD105+ cells like the
mouse fibroblasts L929 cells transfected with the short form
of human CD105 and the rat myoblasts L6E9 transfected with
the long form of human CD105. In contrast, cells lacking human
CD105 were 2-2.5 logs less sensitive to the immunotoxin. Free
ebulin displays IC50 values in the range 10-6
M. Since CD105 is being considered as a potential target for
the anti-vascular therapy of tumours, the present immunotoxin
could be a promising tool for the anticancer therapy, especially
due to the very low in vivo toxicity of ebulin l
as compared ricin and other toxins used for immunotoxins.
[Back to top]
Protease Inhibitors in the Clinic
Giovanni Abbenante and David P. Fairlie
This review describes the clinical status (based on available
information) of experimental drugs that inhibit enzymes called
proteases, or more precisely a sub-class of proteases called
peptidases that catalyse the hydrolysis of polypeptide main
chain amide bonds. These peptidases are classified by the
key catalytic residue in the active site of the enzyme that
effects hydrolysis, namely aspartic, serine, cysteine, metallo
or threonine proteases. In this review we show structures
for 108 inhibitors of these enzymes and update the clinical
disposition of over 100 inhibitors that have been considered
worthy enough by pharmaceutical, biotechnology or academic
researchers and their financial backers to be trialed in humans
as prospective medicines. We outline some of their chemical
and pharmacological characteristics and compare the current
status of protease inhibitors in the clinic with what was
observed about 5 years ago (Leung et al, J. Med. Chem. 2000,
43, 305-341). We assess the progress of protease inhibitors
into man, predict their futures, and outline some of the hurdles
that have been overcome and that still remain for this promising
class of new therapeutic agents.
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