Mini-Reviews in Medicinal Chemistry, Volume 1, No. 3, 2001
N-Oxides as
Hypoxia Selective Cytotoxins
Pp. 219-231
Recent Advances in the Design of Iron Chelators Against Oxidative Damage Pp. 233-242
J.-B. Galey
Synthesis and
Structure-Activity Relationships of 2,3-Benzodiazepines as AMPA Receptor
Antagonists Pp. 243-253
M. Zappalŕ, S. Grasso, N. Micale, S. Polimeni and C. De Micheli
Towards
Improved Acetylcholinesterase Inhibitors: A Structural and Computational
Approach Pp. 255-266
X. Barril, M. Orozco
and F. J. Luque
Peripheral and
Dual Binding Site Acetylcholinesterase Inhibitors: Implications in treatment of
Alzheimer's Disease Pp.
267-272
Ana Castro and Ana
Martinez
Designing
Peptide Mimetics for the Treatment of Multiple Sclerosis Pp. 273-282
J. Matsoukas, V.
Apostolopoulos and T. Mavromoustakos
Viral Protein
Functions Study by Affinity Modification Pp. 283-291
O.V. Morozova and
I.V. Safronov
Aerobic
Nitroreduction by Flavoproteins: Enzyme Structure, Mechanisms and Role in
Cancer Chemotherapy Pp.
293-306
Jane V. Skelly, Richard J. Knox and Terence
C. Jenkins
Targeting "Hydrolytic" Activity of the S-Adenosyl-L-
Homocysteine Hydrolase Pp.
307-316
S. F. Wnuk
[Back to top] N-Oxides
as Hypoxia Selective Cytotoxins
Hugo Cerecetto and Mercedes González
N-Oxide-containing
compounds have been developed as prodrugs that are selectively bioactivated in
the hypoxic cells in tumors. This selectivity is based on the net reduction of
the N-oxide moiety in the absence of
oxygen, in a one or two-electron process, by reductive enzymes. A wide range of
N-oxides have been studied and some
of them are currently in clinical use. This review covers the principal
families of compounds under study and in clinical trials.
[Back to top] Recent Advances in the Design of Iron Chelators Against Oxidative Damage
J.-B. Galey
Iron imbalance plays a pivotal role in oxidative damages associated with a wide range of pathological conditions. However, owing to the essential role of iron in biological processes, the beneficial effects of iron chelation therapy against oxidative damage have to be balanced against potential toxicity. The present review briefly introduces iron redox biochemistry and oxidative-stress associated pathologies, surveys recent advances in iron chelating strategies and summarizes some of our recent findings in this field, with a special emphasis on the chemical design constraints one must satisfy in order to synthesize iron chelators which could be beneficial against oxidative stress without inducing iron depletion of the body. The concept of oxidative stress activatable iron chelators is presented as a new paradigm for safe and efficient treatment of oxidative-stress associated conditions.
[Back to top]
Synthesis and Structure-Activity
Relationships of 2,3-Benzodiazepines as AMPA Receptor Antagonists
M. Zappalŕ, S.
Grasso, N. Micale, S. Polimeni and C. De Micheli
There is increasing evidence of the potential therapeutic utility of glutamate receptor antagonists in the treatment of several neurodegenerative disorders, including stroke and epilepsy. In the last few years noncompetitive AMPA receptor antagonists have received considerable attention due to their therapeutic potentiality. The discovery of GYKI 52466, the prototype of noncompetitive AMPA receptor antagonists endowed with anticonvulsant and neuroprotective properties, induced growing interest on 2,3-benzodiazepine derivatives. This review covers the chemistry and pharmacology of this important class of AMPA receptor antagonists.
[Back to top] Towards Improved Acetylcholinesterase
Inhibitors: A Structural and Computational Approach
X. Barril, M. Orozco
and F. J. Luque
During the last years, solving the X-ray crystallographic structure of both the unliganded acetylcholinesterase (AChE) and AChE complexes with various inhibitors has provided valuable knowledge of the interactions that mediate inhibitor binding. This structural information allows us to rationalize differences in binding affinities for related analogues, and more importantly opens new strategies to design compounds with improved pharmacological properties. This is illustrated in the case of the recently reported huprines, which are a new class of very potent and selective acetylcholinesterase inhibitors.
[Back to top] Peripheral and Dual Binding Site
Acetylcholinesterase Inhibitors: Implications in treatment of Alzheimer's
Disease
Ana Castro and Ana
Martinez
Recently advances in understanding the molecular basis of Alzheimer's disease have led to the consideration of the relationship between cholinergic inhibitors and amyloid deposition as a new hypothesis for the future rational design of effective anti-Alzheimer drugs. In the present review, the non-cholinergic functions of acetylcholinesterase (AChE) and the therapeutic potential of peripheral and dual binding site AChE inhibitors in delaying the neurodegenerative process will be discussed.
[Back to top] Designing Peptide Mimetics for the Treatment
of Multiple Sclerosis
J. Matsoukas, V.
Apostolopoulos and T. Mavromoustakos
Multiple sclerosis is a chronic inflammatory disease of the central nervous system. While the molecular basis of the disease is still unknown, research effort is currently under progress to prevent or ameliorate its effects. There are two major approaches currently in the pursuing of improved therapeutics for the treatment of multiple sclerosis. The first approach focuses on peptide or mimetic therapy and the second on immunotherapy by preventing or controlling disease through the release of appropriate cytokines.
[Back to top] Viral Protein Functions Study by Affinity
Modification
O.V. Morozova and
I.V. Safronov
The knowledge of virus reproduction is necessary to design
new safe drugs for inhibition of infections. Ultra-violet irradiation of virus
proteins with labeled virus genome fragments permits to identify specific
nucleic acid binding proteins. Affinity modification of enzymes with nucleotide
derivatives could help to determine NTP-binding proteins and those involved in
viral genome replication. Photoreactive analogues of nucleic acids are among
the tools used to detect elongation subunits of replicative complexes. Affinity
modification approach has already resulted in successful treatment of virus
diseases.
[Back to top] Aerobic Nitroreduction by Flavoproteins:
Enzyme Structure, Mechanisms and Role in Cancer Chemotherapy
Jane V. Skelly,
Richard J. Knox and Terence C. Jenkins
NQO1 (DT-diaphorase) and its truncated isoenzyme, the metalloenzyme NQO2, can reduce quinone substrates by two-electron transfer. While NQO1 is a known detoxification enzyme, the function of NQO2 is less well understood. Both rat NQO1 and human NQO2 reductively bioactivate the dinitroarene CB 1954 to a cytotoxic product that behaves as a difunctional DNA-crosslinking species with potent anti-tumour activity, although human NQO1 is much less effective. A FMN-dependent nitroreductase from E. coli B also reduces quinones and reductively bioactivates CB 1954. However, this enzyme reduces CB 1954 to the 2- and 4‑hydroxylamines in equivalent yield, whereas NQO1 and NQO2 generate only the 4-isomer.
The reduction profile is a key factor in the development of anti-tumour prodrugs, where distinct delivery strategies are being evaluated: prodrug therapy, antibody-, macromolecule- and gene-directed enzyme prodrug therapy (ADEPT, MDEPT or GDEPT). The flavoprotein enzymes are explored in terms of structure and bioreduction mechanism, particularly for use in the design of novel prodrugs with potential application as chemotherapeutic agents.
[Back to
top] Targeting
"Hydrolytic" Activity of the S-Adenosyl-L- Homocysteine Hydrolase
S. F. Wnuk
Substrates that are specific for the "hydrolytic" activities of AdoHcy hydrolase have been recently identified. Upon interaction with the AdoHcy hydrolase such substrates generate the "active" electrophiles which then react with the enzyme nucleophiles to produce covalent inhibition. Dihalohomovinyl and haloacetylene analogues derived from adenosine as well 5'-S-allenyl-5'-thioadenosine derivative have been characterized as the first type II mechanism-based inhibitors of AdoHcy hydrolase that rely only on the "hydrolytic" activity. Design and synthesis of the novel adenine nucleosides as well their interaction with AdoHcy hydrolase are discussed in this review