| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 16, Number 28, 2009
Contents
The Role of Cellular Plasticity in Cancer Development Pp.
3676-3685
C. Vicente-Dueñas, J. Gutiérrez
de Diego, F.D. Rodríguez, R. Jiménez and
C. Cobaleda
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Methionine-Derived Metabolites in Apoptosis:
Therapeutic Opportunities for Inhibitors of their Metabolism
in Chemoresistant Cancer Cells Pp. 3686-3700
G. Quash, and G. Fournet
[Abstract] [Purchase
Article]
Losartan Chemistry and Its Effects via
AT1 Mechanisms in the Kidney Pp. 3701-3715
Feichao Xu, Caiping Mao, Yujuan Liu, Lei
Wu, Zhice Xu and Lubo Zhang
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Article]
Potential Targets and Their Relevant
Inhibitors in Anti-influenza Fields Pp. 3716-3739
Jianzhi Gong, Hao Fang, Minyong Li, Yu Liu,
Kanghui Yang, Yingzi Liu and Wenfang Xu
[Abstract] [Purchase
Article]
β-Lactamase
Inhibitors: The Story so Far Pp. 3740-3765
Francisco José Pérez-Llarena
and Germán Bou
[Abstract] [Purchase
Article]
Functional Variants of the Interleukin-23 Receptor
Gene in Non-Gastrointestinal Autoimmune Diseases Pp.
3766-3774
E. Safrany and B. Melegh
[Abstract] [Purchase
Article]
Caged Garcinia Xanthones: Development
Since 1937 Pp. 3775-3796
Q.-B. Han and H.-X. Xu
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Article]
Abstracts
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The Role of Cellular Plasticity in Cancer Development
C. Vicente-Dueñas, J. Gutiérrez
de Diego, F.D. Rodríguez, R. Jiménez and
C. Cobaleda
It has traditionally been accepted that, in the process
of cellular differentiation, developmental options are progressively
restricted until commitment to a specific fate is established
and then only terminal differentiation along this lineage
is possible. Although this is usually the case in normal physiological
development, the latest experimental evidences indicate that
the differentiated state of mature cells is not always as
stable and durable as it was thought to be. In fact, recently,
a hidden plasticity has been revealed in differentiated cells
which allows them to deviate to other cell types that might
be, functionally, very far away in other developmental pathways.
This plasticity has biological significance since it is necessary
for normal development to occur, but it also makes possible
the emergence of aberrant lineages when interferences with
the normal transcriptional and epigenetic mechanisms in charge
of maintaining cellular identity do appear. Cancer is one
of the possible outcomes of this aberrant reprogramming. The
plasticity of the initial cell suffering the first oncogenic
alteration plays an essential role in cancer development,
since only if this cell possesses enough plasticity a tumoral
reprogramming will be possible and a full-blown tumor will
develop. Also, plasticity makes it possible for differentiated
cells to acquire cancer stem cell properties in the presence
of the appropriate oncogenic insults. In this review we discuss
the role of cellular plasticity in the normal development
of adult tissues and how cellular susceptibility to reprogramming
plays an essential part in cancer development.
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Methionine-Derived Metabolites in Apoptosis: Therapeutic Opportunities
for Inhibitors of their Metabolism in Chemoresistant Cancer
Cells
G. Quash and G. Fournet
Methionine, in addition to its role in protein synthesis,
participates in 3 important cellular functions: as AdoMet
in transmethylation; as decarboxylated-AdoMet in aminopropylation;
as homocysteine its demethylated form, in transsulphuration.
Here we provide evidence from the literature and from our
own work for a fourth role for its oxoacid: 4- methylthio-2-oxo-butanoate
(MTOB) in apoptosis [28,29]. MTOB enters 2 pathways: (a) transamination
by glutaminetransaminase K to methionine[13,14].(b)oxidative
decarboxylation by the mitochondrial Branched-Chain-Oxo-Acid-Dehydrogenase-Complex
to methional and finally to methylthiopropanoyl CoA (MTPCoA)
[26,27]. Some of the methional formed after MTOB decarboxylation
leaks into the cytoplasm as free methional [29]. Exogenous
methional induces apoptosis in normal and cancer cells in
culture [28, 29] but not in those overexpressing the antiapoptotic
gene bcl2 [30]. In physiologically-induced apoptosis e.g.
trophic factor (IL3) withdrawal, methional leakage is decreased
[29] suggesting that MTPCoA is also involved in apoptosis.
Both methional and MTPCoA give rise to metabolites that may
act as cross-linking agents. In the case of methional, the
CH3-S moiety is lost and malondialdehyde (MDA) is formed when
methional is subjected to •OH
attack [29]. MDA generated in situ from 1,3-propanediol, induces
DNA-protein cross-linking [41].With regard to MTPCoA, it is
metabolized to malonic semialdehyde CoA (MASACoA) with loss
of the CH3-S moiety [48,49 ]. The capacity of MASACoA to form
cross-links has not yet been established experimentally, but
it could be a substrate for one of the histone acyl transferases
[50, 51] and so form amides via the CoA at one end
and imines by its CHO group at the other, with amino groups
on proteins. Chromatin cross-linking/condensation is one of
the hall-marks of apoptosis [40]. Methional, MDA and other
apoptogenic aldehydes like 4-hydroxy-2-nonenal are oxidized
by ALDHs to non-apoptogenic carboxylic acids [29, 44, 45,
68] but retain their apoptotic activity when the ALDHs are
inhibited [98, 110]. MASACoA would also lose its cross-linking
capacity if its CoA moiety were putatively hydrolysed by ALDHs
and/or acylCoA thioesterases [56, 58, 88, 89]. ALDH inhibitors
that control cellular MDA and possibly MASACoA homeostasis
are cited as examples of targeted therapeutic approaches in
chemoresistant cancers [62, 84, 97, 98, 110].
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Losartan Chemistry and Its Effects via AT1 Mechanisms
in the Kidney
Feichao Xu, Caiping Mao, Yujuan Liu, Lei
Wu, Zhice Xu and Lubo Zhang
Besides the importance of the renin-angiotensin system
(RAS) in the circulation and other organs, the local RAS in
the kidney has attracted a great attention in research in
last decades. The renal RAS plays an important role in the
body fluid homeostasis and long-term cardiovascular regulation.
All major components and key enzymes for the establishment
of a local RAS as well as two important angiotensin II (Ang
II) receptor subtypes, AT1 and AT2 receptors, have been confirmed
in the kidney. In addition to renal contribution to the systemic
RAS, the intrarenal RAS plays a critical role in the regulation
of renal function as well as in the development of kidney
disease. Notably, kidney AT1 receptors located at different
cells and compartments inside the kidney are important for
normal renal physiological functions and abnormal pathophysiological
processes. This mini-review focuses on: 1) the local renal
RAS and its receptors, particularly the AT1 receptor and its
mechanisms in physiological and pathophysiological processes,
and 2) the chemistry of the selective AT1 receptor blocker,
losartan, and the potential mechanisms for its actions in
the renal RAS-mediated disease.
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Potential Targets and Their Relevant Inhibitors in Anti-influenza
Fields
Jianzhi Gong, Hao Fang, Minyong Li, Yu Liu,
Kanghui Yang, Yingzi Liu and Wenfang Xu
Influenza is a disease for deeply affecting millions
of people every year. Recently, there has been considerable
concern regarding the highly pathogenic H5N1 avian influenza
virus, and its human pandemic potential. With developments
in viral biology, there are more novel antiviral strategies
targeting these viruses. In this review, we will discuss several
proven and potential anti-influenza targets, including viral
factors (such as hemagglutinin (HA), M2 ion channel protein,
RNA-dependent RNA polymerase (RdRp), nucleoprotein (NP), non-structural
protein (NS) and neuraminidase (NA)) and host factors (such
as v-ATPase, protease, inosine monophosphate dehydrogenase
(IMPDH) and intracellular signalling cascades), and their
relevant inhibitors.
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β-Lactamase
Inhibitors: The Story so Far
Francisco José Pérez-Llarena
and Germán Bou
Antimicrobial resistance constitutes one of the major threats
regarding pathogenic microorganisms. Gram-negative pathogens,
such as Enterobacteriaceae (specially those producing
extended-spectrum β-lactamases),
Pseudomonas aeruginosa, and Acinetobacter baumannii,
have acquired an important role in hospital infections, which
is of particular concern because of the associated broad spectrum
of antibiotic resistance.
β-Lactam
antibiotics are considered the most successful antimicrobial
agents since the beginning of the antibiotic era. Soon after
the introduction of penicillin, microorganisms able to destroy
this β-lactam
antibiotic were reported, thus, emphasizing the facility of
pathogenic microorganisms to develop β-lactam
resistance. In Gram-negative pathogens, β-lactamase
production is the main mechanism involved in acquired β-lactam
resistance. Four classes of β-lactamases
have been described: A, B, C, and D. Classes A, C, and D are
enzymes with a serine moiety in the active centre that catalyzes
hydrolysis of the β
-lactam ring through an acyl-intermediate of serine, whereas
the class B enzymes require a metal cofactor (e.g. zinc in
the natural form) to function, and for this reason, they are
also referred to as metallo-β-lactamases
(MBLs).
To overcome β-lactamase-mediated
resistance, a combination of β-lactam
and a β-lactamase
inhibitor, which protects the β-lactam
antibiotic from the activity of the β-lactamase,
has been widely used in the treatment of human infections.
Although there are some very successful combinations of β-lactams
and β-lactamase
inhibitors, most of the inhibitors act against class A β-lactamases
and remain ineffective against class B, C, and D β-lactamases.
This review constitutes an update of the current status and
knowledge regarding class A to D β-lactamase
inhibitors, as well as a summary of the drug discovery strategy
currently used to identify new β-lactamase
inhibitors, mainly based on the knowledge of crystal structure
of β-lactamase
enzymes.
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Functional Variants of the Interleukin-23 Receptor Gene in
Non-Gastrointestinal Autoimmune Diseases
E. Safrany and B. Melegh
Variants of the gene of the interleukin-23 receptor (IL23R)
were first identified as susceptibility factors in association
with inflammatory bowel diseases. Since then it became clear
that different variants of the gene play role also in a number
of other autoimmune diseases like psoriasis, rheumatoid arthritis,
ankylosing spondylitis and multiple sclerosis while in others,
like systemic sclerosis, systemic lupus erythematosus or Sjögren
syndrome the same effect could not be seen. However, the results
are very controversial both in terms of the various polymorphisms
and also in population specificity. The aim of the current
paper is to overview all available reports on IL23R
gene polymorphisms in various autoimmune and inflammatory
diseases and to try to give an explanation on the possible
effect of the examined variants.
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Caged Garcinia Xanthones: Development Since 1937
Q.-B. Han and H.-X. Xu
Covering: 1937 to Mar 2008.
Caged xanthones, characterized by a unique 4-oxa-tricyclo[4.3.1.03,7]dec-2-one
scaffold, are a special class of bioactive components mainly
derived from the Garcinia genus(Guttiferae family).
Around 100 compounds from this family have been reported to
date and most of them have potent antitumor activity, with
gambogic acid being the best representative. During the past
decades, inspired by the unusual caged skeleton and remarkable
bioactivity, scientists from various fields have shown increasing
interest on these promising natural products. In this review,
the plant resources, structural characteristics, total synthesis,
biological activity and mechanisms of action, structure activity
relationship, and anticancer drug development of these caged
xanthones are described.
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