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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 13, Number 1, 2006
Contents
Naturally Occurring and Synthetic Imidazoles:
Their Chemistry and Their Biological Activities
Pp. 1-23
Lidia De Luca
[Abstract]
Recent Developments in the Design of Orally Bioavailable
β3-Adrenergic Receptor Agonists Pp.
25-37
Masaaki Sawa and Hiroshi Harada
[Abstract]
Bacterial Symbionts: Prospects for the Sustainable
Production of Invertebrate-Derived Pharmaceuticals
Pp. 39-50
J. Piel
[Abstract]
Heptahelical and Other G-Protein-Coupled Receptors
(GPCRs) Signaling Pp. 51-63
Y. Landry, N. Niederhoffer, E. Sick and J.P. Gies
[Abstract]
Privileged Structures as Leads in Medicinal Chemistry
Pp. 65-85
Luca Costantino and Daniela Barlocco
[Abstract]
Comparative Studies of the Antioxidant Effects of
Cis- and Trans-Resveratrol Pp.
87-98
F. Orallo
[Abstract]
Sol-gel Chemistry in Medicinal Science Pp.
99-108
Thibaud Coradin, Michel BoissirRe and Jacques Livage
[Abstract]
Voglibose (Basen¨, AO-128), One of the Most
Important α-Glucosidase Inhibitors Pp. 109-116
Xiaolong Chen, Yuguo Zheng and Yinchu Shen
[Abstract]
Abstracts
[Back to top]
Naturally Occurring and Synthetic
Imidazoles: Their Chemistry and Their Biological Activities
Lidia De Luca
Imidazoles are an important class of heterocycles and include
many substances of both biological and chemical interest.
They are part of a large number of highly significant biomolecules
such as the essential amino acid histidine and related compounds,
biotin, and the imidazole alkaloids. Insertion of the imidazole
nucleus is an important synthetic strategy in drug discovery.
Imidazole drugs have broad applications in many areas of clinical
medicine. The imidazoles are a class of antifungal azole derivatives
and have a broad spectrum of activities both in vitro
and in vivo. The imidazole moiety is also contained
in many histaminergic ligands for histamine H1,
H2, and H3 receptors. These are currently
used as tools in pharmacological studies. The important therapeutic
properties of imidazole related drugs have encouraged the
medicinal chemists to synthesize and test a large number of
novel molecules. Some of these have chemotherapeutic properties,
such as for example several FTase inhibitors with an imidazole
moiety. Imidazole derivatives have also been shown to have
antibacterial activity and recently several P38 MAP Kinase
inhibitors and 5-Lipoxygenase inhibitors containing the imidazole
moiety have been synthesized. This review reports current
progress in the area of new biologically active imidazoles
and recently discovered naturally occurring imidazole.
[Back to top]
Recent Developments in the Design of Orally Bioavailable
β3-Adrenergic Receptor Agonists
Masaaki Sawa and Hiroshi Harada
The ß3-adrenergic receptor (ß3-AR)
has been shown to mediate various pharmacological and physiological
effects such as lipolysis, thermogenesis, and relaxation of
the urinary bladder. Activation of the ß3-AR
is thought to be a possible approach for the treatment of
obesity, type 2 diabetes mellitus, and frequenturination.
Therefore, the ß3-AR is recognized as an
attractive target for drug discovery. On the other hand, activation
of the ß1- or ß2-AR can
cause undesirable side effects such as increased heart rate
or muscle tremors. Consequently, a number of recent efforts
in this field have been directed toward the design of selective
agonists for the ß3-AR. This review summarizes
recent advances in ß3-AR agonists with an
emphasis on recent attempts to create potent, selective and
orally bioavailable small-molecule agonists.
[Back to top]
Bacterial Symbionts: Prospects for the Sustainable
Production of Invertebrate-Derived Pharmaceuticals
J. Piel
Invertebrate animals, such as sponges, tunicates and bryozoans,
are among the most important sources of biomedically relevant
natural products. However, as these animals generally contain
only low quantities of the compounds, further pharmacological
development is in most cases difficult. There is increasing
evidence that many metabolites, in particular polyketides
and nonribosomally synthesized peptides, are not produced
by the animals themselves but by associated bacterial symbionts.
This symbiont hypothesis currently attracts considerable interest,
since it implicates that animal-independent production systems
based on bacterial fermentation processes could be created.
This review gives an overview about recent developments in
the research on natural product symbiosis. Different techniques
will be discussed that have been employed to pinpoint the
actual producer. Since bacterial symbionts are highly fastidious
and have been generally resistant to cultivation attempts,
emphasis will be laid on culture-independent strategies, such
as cell separation approaches and the cloning of biosynthetic
genes. These strategies have provided insights into possible
sources of several natural products, e.g. the bryostatins,
pederin, the onnamides, swinholide A and theopalauamide. Finally,
potential techniques for the generation of renewable supplies
of symbiont-derived drug candidates will be discussed. Cultivation
approaches and the heterologous expression of cloned biosynthesis
genes from uncultured symbionts could in future provide access
to several important marine drug candidates, including bryostatin
1, halichondrin or ET-743.
[Back to top]
Heptahelical and Other G-Protein-Coupled Receptors
(GPCRs) Signaling
Y. Landry, N. Niederhoffer, E. Sick and J.P. Gies
Heptahelical receptors are coupled to heterotrimeric GTP-binding
proteins (G-proteins) which transduce most signals through
their α
and ßγ
subunits to effectors, enzymes and ion channels. Of the 367
heptahelical receptors for endogenous ligands, about 330 are
potential targets for drug discovery with agonist, antagonist
or inverse agonist properties. The term G-protein-coupled
receptors (GPCRs) is a broader functional definition rather
than a structural one referring to heptahelical receptors
specifically. Non-heptahelical putative GPCRs include some
transmembrane receptors with tyrosine-kinase activity on their
cytosolic endings (EGF, insulin and IGF-1 receptors), other
transmembrane receptors (mannose-6-phosphate/IGF-2 receptor
and integrin-associated protein IAP or CD47), and some receptors
belonging to the class of glycosylphosphatidylinositol (GPI)-anchored
proteins and located on the outer face of the plasma membrane.
Also, activators of G-protein signaling (AGS) proteins that
regulate vesicular trafficking activate heterotrimeric G-proteins
in the Golgi independently of receptor activation. Main effectors
activated through their direct interactions with α
subunits or ßγ
dimers of heterotrimeric G-proteins include adenylylcyclases,
cGMPphosphodiesterase, phospholipases Cß, phosphoinositide
3-kinase γ,
CaV2 calcium channels, GIRK/Kir3 potassium channels, and guanine
nucleotide exchange factors RasGEF and RhoGEF leading to small
G-proteins and MAP-kinases activation. Current signaling cascades
leading to final cell responses are depicted.
[Back to top]
Privileged Structures as Leads in Medicinal Chemistry
Luca Costantino and Daniela Barlocco
Among the strategies that can lead to the discovery of new
drugs, the identification and use of privileged structures,
molecular fragments that are able to interact with more than
one target, gained particular attention, in an attempt to
find new drugs in a shorter time with respect to other strategies.
These structures, that have been identified mainly by empirical
observations, can target only a given protein family, or can
be able to interact with more, unrelated targets. This review
deals with structures not covered in recent papers on this
topic, and emphasizes the importance of understanding the
structure-target relationships, that confer the privileged
status.
[Back to top]
Comparative Studies of the Antioxidant Effects of
Cis- and Trans-Resveratrol
F. Orallo
Resveratrol (3,4',5 trihydroxystilbene, RESV) is a natural
phenolic compound that exists as cis and trans
isomers [c RESV or (Z)-RESV and t RESV or
(E)-RESV, respectively]. t-RESV is a natural component
of Vitis vinifera L. (Vitaceae), abundant in the
skin of grapes (but not in the flesh) and in the leaf epidermis,
and present in wines, especially red wines. In in vitro,
ex vivo and in vivo experiments t-RESV
exhibits a number of biological activities, including anti
inflammatory and anticarcinogenic properties. RESV also exists
in wines as a cis isomer, which (unlike t-RESV)
is not currently available commercially; as a result, little
is known about this isomer’s pharmacological activity.
In this review, I will focus on the few comparative studies
of the antioxidant effects of the two RESV isomers in different
experimental models.
[Back to top]
Sol-gel Chemistry in Medicinal Science
Thibaud Coradin, Michel BoissirRe and Jacques Livage
The sol-gel process is an inorganic polymerization process
taking place in mild conditions, allowing the association
of mineral phases with organic or biological systems. The
possibility to immobilize drugs, enzymes, antibodies and even
whole cells without loss of their biological activity led
to the development of diagnostic tools, drug delivery carriers
as well as new hosts for artificial organ design. These systems
take profit from the wide variety of chemical compositions,
dimensions and forms that can be achieved via sol-gel
chemistry. Recent advances involve multi-functional “smart”
devices combining biocompatibility, biological activity and
stimuli-responsive materials. The design of such novel devices
with significant added value when compared to current products
is probably a key factor when foreseeing industrial developments
of sol-gel materials in medicinal science.
[Back to top]
Voglibose (Basen¨, AO-128), One of the Most Important
α-Glucosidase Inhibitors
Xiaolong Chen, Yuguo Zheng and Yinchu Shen
The number of people with diabetes is expected to rise from
the current estimated 150 million to 220 million in 2010 and
300 million in 2025, and 90% is Type 2 diabetes or non-insulin
dependant diabetes mellitus (NIDDM). Voglibose, one of the
most important α-glucosidase
inhibitors, delays the digestion and absorption of carbohydrates,
thereby inhibiting postprandial hyperglycemia and hyperinsulinemia,
and is the aid in the treatment of diabetes. In this paper,
properties and the preparation of voglibose are reviewed.
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