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Medicinal Chemistry Reviews
- Online
Volume 2, Number 6, November 2005
Contents
Development
of Cancer Vaccine Targeting WT1 Product which is Expressed in Various Kinds
of Malignant Neoplasms Pp. 447-454
Y. Oka, A. Tsuboi, O. A. Elisseeva, H. Nakajima, Y. Oji and H. Sugiyama
[Abstract]
Neuronal
Nicotinic Receptors and Neuroprotection: Newer Ligands May Help us Understand
their Role in Neurodegeneration Pp. 455-471
M.J. O’Neill, P. Astles, C.P. Dell, M. Keenan, T.K. Murray, V. Lakics,
N.P. Visanji and S. Duty
[Abstract]
Cognition-Enhancing
Drugs in Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD): An
Update [1] Pp. 471-487
Fulvio Gualtieri, Luca Guandalini, Dina Manetti, Elisabetta Martini and
Maria Novella Romanelli
[Abstract]
Novel
Agents in Anticancer Drug Therapy I (Antiangiogenic Agents, Egfr Inhibitors)
Pp. 489-494
Sándor Eckhardt
[Abstract]
Proteinases
of Trypanosoma cruzi: Potential Targets for the Chemotherapy of Chagas
Disease Pp. 495-504
Juan José Cazzulo
[Abstract]
Biological
Characteristics and Role of Histamine in Case of Allergic Rhinitis
Pp. 505-510
Md. Tanveer Raza and De-Yun Wang
[Abstract]
Macrolide
Resistance in Mycobacteria Pp. 511-523
F. Doucet-Populaire, K. Buriánková, J. Weiser and J.-L.
Pernodet
[Abstract]
Abstracts
[Back to top] Development
of Cancer Vaccine Targeting WT1 Product which is Expressed in Various Kinds
of Malignant Neoplasms
Y. Oka, A. Tsuboi, O. A. Elisseeva, H. Nakajima, Y. Oji and H. Sugiyama
The Wilms’ tumor
gene WT1 is highly expressed not only in hematopoietic malignancies,
including leukemia and myelodysplastic syndromes (MDS), but also in various
kinds of solid tumors, including lung, breast, and colorectal cancer. Human
cytotoxic T lymphocytes (CTLs) which could specifically lyse WT1-expressing
tumor cells with HLA-A*0201 or HLA-A*2402 restriction were generated in
vitro. We have also demonstrated that mice immunized with the WT1 peptide
rejected challenges by WT1-expressing tumor cells and survived with
no signs of auto-aggression to nor-mal organs which physiologically expressed
WT1 both in prophylactic and therapeutic models. Furthermore, we
and oth-ers recently detected IgM and IgG WT1 antibodies in the patients with
hematopoietic malignancies, indicating that WT1 protein was highly
immunogenic, and that WT1-specific cellular immune responses that induce immunoglobulin
class-switch of WT1 antibodies were elicited in the patients. These results
provided us with the rationale for elicitation of CTL responses targeting
the WT1 product for cancer immunotherapy. On the basis of the findings mentioned
above, we performed a phase I clinical trial of WT1 peptide cancer vaccine
for the patients with malignant neoplasms. It was dem-onstrated that WT1 peptide
cancer vaccine had efficacy in the clinical setting, because reduction of
leukemic blast cells, decrease of tumor markers, or regression of tumor masses
was observed after the WT1 vaccination in patients with he-matopoietic malignancies
or solid cancers.
[Back to top] Neuronal
Nicotinic Receptors and Neuroprotection: Newer Ligands May Help us Understand
their Role in Neurodegeneration
M.J. O’Neill, P. Astles, C.P. Dell, M. Keenan, T.K. Murray, V. Lakics,
N.P. Visanji and S. Duty
In the last
five-six years there has been a rapid increase in publications reporting that
neuronal nicotinic acetylcholine receptors (nAChR) play a role in neurodegenerative
disorders. Furthermore, there is a well-established loss in nAChR in post-mortem
brains from patients with Alzheimer’s disease, Parkinson’s disease and a range
of other disorders. In the present review we discuss (1) the new pharmacological
ligands for studying neuronal nicotinic receptors and (2) evidence that nicotine
and subtype selective nAChR ligands can provide neuroprotection in vitro
in cell culture systems and in vivo using animal models of such disorders.
This review is an up-dated and revised version of an earlier review published
in Current Drug Targets – CNS and Neurological Disorders 4, 399-411, 2002.
In terms of developing new drugs for nicotinic receptors, researchers at Abbott
Laboratories have discovered a series of pyridyl ether analogues that are
potent, full agonists of the α4β2
receptor. Sanofi Synthelabo reported that SSR 591813 is a novel and selective
partial α4β2_agonist,
while Targacept have extensively evaluated the SAR of nicotine and met-anicotine
in their laboratories and developed a novel ligand, TC-2559. The α4β2
partial agonist profile of cytisine has led researchers at Pfizer to
explore the potential of cytisine analogues in the treatment of addiction,
in particular smok-ing cessation. These efforts have led to the discovery
of CP-526555 (7,8,9,10 tetrahydro-6,10-methano-6H-pyrazino[2,3-h]
[3]benzazepine (2R,3R)-2,3-dihydroxybutanedioate, varenicline). There
has also been a huge increase in the patent literature on ?7 selective ligands.
In the present review we summarise work from Astra, Pharmacia, Sanofi-Synthelabo
and Bayer.
Whilst in
vitro data pertaining to a protective effect of nicotine against nigral
neurotoxins like MPTP is less robust, most studies agree that nicotine is
protective against glutamate and β-amyloid
toxicity in various culture systems. This effect appears to be mediated by
α7 subtype
nAChR since the protection is blocked by α-bungarotoxin
and is mimicked by α7
selective agonists.
In vivo studies indicate that α7
receptors play a critical role in protection from cholinergic lesions and
enhancing cogni-tive function. The exact subtype involved in the neuroprotectant
effects seen in animal models of Parkinson’s disease is not clear, but in
general broad spectrum nAChR agonists appear to provide protection, while
α4β2
receptor agonists ap-pear to provide symptomatic improvements. Evidence
favouring a protectant effect of nicotine against acute degenera-tive conditions
is less strong, though some protection has been observed with nicotine pre-treatment
in global ischaemia models. A variety of cellular mechanisms ranging from
the production of growth factors through to inactivation of toxins and antioxidant
actions of nicotine have been proposed to underlie the nAChR-mediated neuroprotection
in vitro and in vivo.
In summary,
although until recently the lack of subtype selective ligands has hampered
progress, it is clear that in the future neuronal nAChR agonists could provide
functional improvements and slow or halt the progress of several crip-pling
degenerative diseases.
[Back to top] Cognition-Enhancing
Drugs in Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD): An
Update [1]
Fulvio Gualtieri, Luca Guandalini, Dina Manetti, Elisabetta Martini and
Maria Novella Romanelli
Cognition enhancers
are drugs able to facilitate attentional abilities and acquisition, storage
and retrieval of information, and to attenuate the impairment of cognitive
functions associated with head traumas, stroke, age and age-related pathologies
such as MCI and AD. Development of cognition enhancers is still a difficult
task because of the complexity of the brain functions, poor predictivity of
animal tests and lengthy and expensive clinical trials. Current research is
based on several working hypotheses, derived from the progress of knowledge
in the neuro-bio-pathology of cognitive processes.
Approaches followed to develop cognition enhancing drugs, the results obtained
in the past few years (since 2000) and the most promising molecules under
study are reviewed.
[Back to top] Novel Agents in Anticancer Drug Therapy
I (Antiangiogenic Agents, Egfr Inhibitors)
Sándor Eckhardt
This report
is the first part of an updated review of a previous survey published in this
journal (2002, 2, 419-439). Since the discovery of the Human Genome Project
dramatically increased our knowledge in regard of the mutated cancer cell,
it is worthy to follow up those findings, that have brought progress in the
therapy of malignant diseases. The molecular targeted drug therapy with transtuzumab
or imatinib produced great initial success and several other candidate agents
are now available for cancer treatment.
This review summarises the antitumour effect of compounds under clinical testing.
In the extracellular space, antiangio-genic molecules inhibit the metastasis
production. Anti-MMP-s currently investigated are listed, followed by drugs
de-signed to block endothelial proliferation. Membrane receptor blockers,
signal transduction inhibitors, DNA replication inactivators, revertants and
apoptosis inducers act in the intracellular space. Amongst these, proteasome
inhibitors are of particular interest.
This part of the review deals only with antiangiogenic products and the membrane
receptor inhibitors. All other agents will be reviewed in the next part of
this publication.
[Back to top] Proteinases
of Trypanosoma cruzi: Potential Targets for the Chemotherapy of Chagas
Disease
Juan José Cazzulo
Trypanosoma
cruzi, the agent of the American Trypanosomiasis, Chagas Disease, contains
cysteine, serine, threonine and metallo proteinases. Aspartic proteinases
have not been found so far. The most abundant among these enzymes is cruzipain,
a cysteine proteinase expressed as a complex mixture of isoforms by the major
developmental stages of the parasite, including some membrane-bound isoforms.
The enzyme is an immunodominant antigen in human chronic Chagas disease and
seems to be important in the host/parasite relationship. Inhibitors of cruzipain
kill the parasite and cure infected mice, thus making the enzyme a very promising
target for the development of new drugs against Chagas disease. In addition,
30 kDa cathepsin B-like enzymes have been described. Serine peptidases described
in the parasite include oligopeptidase B, a member of the prolyl oligopeptidase
family involved in Ca2+-signaling during mammalian cell invasion;
a prolyl endopeptidase (Tc80), against which inhibitors are being developed,
and a serine car-boxypeptidase, belonging to the S10 family. Metalloproteinases
homologous to the gp63 of Leishmania spp. are also present. The proteasome
has properties similar to those of other eukaryotes, and its inhibition by
lactacystin, blocks some differentiation steps in the life cycle of the parasite.
[Back to top] Biological
Characteristics and Role of Histamine in Case of Allergic Rhinitis
Md. Tanveer Raza and De-Yun Wang
Histamine exerts its biological effect an humans through
interaction with four histamine receptors (H1R, H2R, H3R and H4R). Histamine
is a major mediator of allergic rhinitis (AR) that produces classical symptoms
(sneezing, itching, rhinorrhea and congestion) both in adults and children.
Nasal itch, sneezes, and rhinorrhoea are predominantly neural, while congestion
is predominantly vascular. Antagonism of H1 receptors reduces majority of
AR symptoms, which act primarily by the reversible and competitive inhibition
of histamine action at H1R. To date, antihistamines are among the most commonly
used pharmacological treatments in AR. This paper reviews the characteristic
of histamine and histamine receptors in humans and the implication of antihistamine
on AR
[Back to top] Macrolide
Resistance in Mycobacteria
F. Doucet-Populaire, K. Buriánková, J. Weiser and J.-L.
Pernodet
The genus Mycobacterium
contains two of the most important human pathogens, Mycobacterium tuberculosis
and Mycobacterium leprae, the etiological agents of tuberculosis
and leprosy, respectively. Other mycobacteria are mostly saprophytic organisms,
living in soil and water, but some of them can cause opportunistic infections.
The increasing incidence of tuberculosis as well as infections with non-tuberculous
mycobacteria (NTM) in immuno-compromised patients has renewed interest in
molecular mechanisms of drug resistance in these pathogens. Mycobacteria show
a high degree of intrinsic resistance to most common antibiotics. For instance,
species from the M. tuberculosis complex (MTC) are intrinsically
resistant to macrolides. Nevertheless, some semi-synthetic macrolides as clarithromycin,
azithromycin and most recently the ketolides, are active against NTM and widely
used for infection treatment. However, shortly after the introduction of these
new drugs, resistant strains appeared due to mutations affecting the macrolide
tar-get, the ribosome. The mycobacterial cell wall is considered to be a major
factor in promoting the natural resistance of mycobacteria to various antibiotics.
However, recent data show that specific macrolide resistance determinants
(erm genes) are present in some species.
This mini-review summarizes the current knowledge on the natural and acquired
macrolide resistance in mycobacteria, gives an overview of potential mechanisms
implicated in the intrinsic resistance and of macrolide resistance determi-nants
in mycobacteria.