Current Medicinal Chemistry

ISSN: 0929-8673

Current Medicinal Chemistry
Volume 12, Number 24, 2005

Contents


Advances in DNA-Ligands with Groove Binding, Intercalating and/or Alkylating Activity: Chemistry, DNA-Binding and Biology Pp. 2805-2847
Ulf Pindur, Michaela Jansen and Thomas Lemster
[Abstract]


Based on HLA-DRβ1* Allele Binding Specificities, Striking Differences in Distance and TCR Contacting Residue Orientation can be Observed in Modified Protection-Inducing Malarial Synthetic Peptides Pp. 2849-2865
M.E. Patarroyo, G. Cifuentes, L.M. Salazar, F. Espejo, M.P. Alba and A. Bermœdez
[Abstract]


Non-hydroxamate Histone Deacetylase Inhibitors Pp. 2867-2880
Takayoshi Suzuki and Naoki Miyata
[Abstract]


The IGF-I/IGF-I Receptor Pathway: Implications in the Pathophysiology of Thyroid Cancer Pp. 2881-2891
A. Ciampolillo, C. De Tullio and F. Giorgino
[Abstract]


Quinone Methide Derivatives: Important Intermediates to DNA Alkylating and DNA Cross-linking Actions Pp. 2893-2913
Ping Wang, Yang Song, Lixia Zhang, Hanping He and Xiang Zhou
[Abstract]


On the Physiological Relevance of Muscarinic Acetylcholine Receptors in Alzheimer's Disease Pp. 2915-2921
H.J. Koch, S. Haas and T. JŸrgens
[Abstract]




Abstracts

[Back to top]
Advances in DNA-Ligands with Groove Binding, Intercalating and/or Alkylating Activity: Chemistry, DNA-Binding and Biology
Ulf Pindur, Michaela Jansen and Thomas Lemster

It is known that DNA is a well-characterized intracellular target but its size and sequential characteristics make it an elusive target for selective drug action. Binding of low molecular weight ligands to DNA causes a variety of significant biological responses. In this context the main consideration is given to recent developments in DNA sequence selective binding agents bearing conjugated effectors because of their potential application in treatment of cancers, in diagnosis as well as in molecular biology. In the present review recent results about analogues of netropsins, distamycin A and of some lexitropsins and combilexins or related hybrid molecules with sequence reading, intercalating or alkylating activity are described and evaluated for prospective applications. Furthermore there exists DNA minor groove binder with different basic structures which does not possess the typical polyamide chain, including dimeric intercalating chromophores. Finally new results about peptide nucleic acids and related nucleic acid bases linked with polyamides are reported. In pronounced examples the structural chemistry, synthesis, DNA binding with several biophysical methods, molecular aspects, structure activity relationship, topoisomerase inhibition, antitumour and antibacterial effects are discussed in detail.


[Back to top]
Based on HLA-DRβ1* Allele Binding Specificities, Striking Differences in Distance and TCR Contacting Residue Orientation can be Observed in Modified Protection-Inducing Malarial Synthetic Peptides
M.E. Patarroyo, G. Cifuentes, L.M. Salazar, F. Espejo, M.P. Alba and A. Bermœdez

An anti-malarial vaccine is urgently needed, especially against P. falciparum which causes 2 to 3 million deaths each year, mostly in Sub-Saharan African children. This vaccine should contain molecules from the parasite’s different developmental stages due to the parasite’s remarkable complexity and genetic variability. The first approach using synthetic peptides from different parasite stage molecules (the SPf66 malaria vaccine) conferred limited protective efficacy in Aotus monkeys and in large field-trials carried out in different parts of the world

SPf66 contains red blood cell (RBC) binding merozoite peptides for which immune responses against them are genetically controlled by HLA-DR region. Therefore, a systematic search of conserved high activity binding peptides (HABP) was undertaken aimed at using them as immunogens. However, these peptides were poorly immunogenic and had poor protection-inducing capacity against experimental challenge with a P. falciparum strain highly infective for Aotus monkeys an experimental model with an immune system quite similar to humans. Modifications were thus made to key residues to render them immunogenic and protection-inducing.

These native and modified HABPs’ three-dimensional structure was determined by ¹H-NMR studies and their ability in forming stable Major Histocompatibility Class II - peptide (MHCII-peptide) complexes was correlated with their ability to bind in vitro to purified HLA-DRβ1* molecules.

Our experimental data suggests a correlation between modified HABPs’ three-dimensional structure, HLA-DRβ1* binding preferences and their protection-inducing capacity in monkeys.

Furthermore, the data presented here indicates that a synthetic peptide vaccine’s three-dimensional structural features dictate both HLA-DRβ1* allele binding preference (imposing genetic restriction on the immune response) and on these vaccines’ protection-inducing value. Basic knowledge of a parasite’s functionally active peptides, their 3D structure and their interaction for forming the MHC II- peptide-TCR complex will thus contribute towards designing fully effective multi-component, multi-stage subunit-based malarial vaccines.


[Back to top]
Non-hydroxamate Histone Deacetylase Inhibitors
Takayoshi Suzuki and Naoki Miyata

A number of histone deacetylase (HDAC) inhibitors have been developed as anticancer agents and most of them are hydroxamic acid derivatives, typified by suberoylanilide hydroxamic acid (SAHA), Trichostatin A (TSA) and NVP-LAQ824. However, hydroxamic acids have been associated with poor pharmacokinetics and severe toxicity. In addition, although isozyme-selective HDAC inhibitors are considered useful not only as tools for probing the biology of an enzyme but as drugs with low toxicity, many of the hydroxamate HDAC inhibitors do not distinguish well among the HDAC isozymes. Thus, there has been considerable interest in developing non-hydroxamate HDAC inhibitors. To date, small fatty acids, o-aminoanilides, electrophilic ketones, N-formyl hydroxylamines, thiols and mercaptoamides have been reported as non-hydroxamate HDAC inhibitors, and some of them show antiproliferative activity comparable to hydroxamates. Interestingly, hydroxamate HDAC inhibitors such as SAHA and TSA do not discriminate well among the HDAC isozymes whereas many non-hydroxamate HDAC inhibitors have shown selectivity. These non-hydroxamate HDAC inhibitors should pave the way for the development of tools for biological research and new medicines with few side effects. In this review, we introduce non-hydroxamate HDAC inhibitors describing their design, enzyme inhibition, cancer cell growth inhibition and isozyme selectivity.


[Back to top]
The IGF-I/IGF-I Receptor Pathway: Implications in the Pathophysiology of Thyroid Cancer
A. Ciampolillo, C. De Tullio and F. Giorgino

The biological actions of the insulin-like growth factor(IGF)-I are mediated by its activation of the IGF-I receptor (IGF-I R), a transmembrane tyrosine kinase linked to the Akt and ras-raf-MAPK cascades. A functional IGF-I R is required for the cell to progress through the cell cycle. Most importantly, cells lacking this receptor cannot be transformed by any of a number of dominant oncogenes, a finding that proves that the presence of the IGF-I R is important for the development of a malignant phenotype.

Consistent with this role, it has been well established that IGF-I can protect cells from apoptosis under a variety of circumstances. For example, IGF-I prevents apoptosis induced by overexpression of c-myc in fibroblasts, by interleukin-3 withdrawal in interleukin-3-dependent hemopoietic cells, etoposide, a topoisomerase I inhibitor, anti-cancer drugs, UV-B irradiations, and serum deprivation.

While the anti-apoptotic effect of IGF-I has been clearly demonstrated, the molecular mechanisms by which IGF-I inhibits apoptosis induced by these various stimuli remain unknown.

We have previously documented increased IGF-I and IGF-I R immunoreactivity in human thyroid carcinomas with a corresponding up-regulation of IGF-I mRNA. Immunoreactivity for IGF-I and IGF-I R positively correlated with tumor diameter, but not with the occurrence of lymph node metastases. Several recent studies have identified new signaling pathways emanating from the IGF-I R that affect cancer cell proliferation, adhesion, migration and apoptosis, which represent critical functions for cancer cell survival and metastasizing capacity. In this review, various aspects of the IGF-I/IGF-I R pathway and its relationship to thyroid cancer are discussed.


[Back to top]
Quinone Methide Derivatives: Important Intermediates to DNA Alkylating and DNA Cross-linking Actions
Ping Wang, Yang Song, Lixia Zhang, Hanping He and Xiang Zhou

Induced DNA interstrand cross-links by chemical agents or photoactivation play very important roles for cancer therapy. Several important clinical drugs (e.g. cisplatin, psoralens, and mitomycin C) are known to induce DNA ISC formation, which can disrupt cell maintenance and replication. Among these anti-tumor agents, one mechanism was involved in quinone methide intermediate. Quinone methide derivative has played important roles in organic syntheses as well as in chemical and biological processes. This review is concerned with current efforts of quinone methide derivatives to DNA alkylation and DNA cross-links. The latest advances in this field will be reviewed in this article. The chemical and physical properties of quinone methide derivatives, the interactions between nucleobases and quinone methide derivatives, the reactions with phosphodiester, DNA alkylation and cross-link via quinone methide intermediate action will be discussed.


[Back to top]
On the Physiological Relevance of Muscarinic Acetylcholine Receptors in Alzheimer’s Disease
H.J. Koch, S. Haas and T. Jürgens

The loss of cholinergic neurons, particularly in the forebrain, plays an important role in the pathophysiology of Alzheimer’s disease (DAT). This concept has lead to the effective treatment of DAT by means of acetylcholine (Ach) esterase inhibitors. G-protein-coupled muscarinic acetylcholine receptors (mAchR) are classified in 5 subtypes, the M1 receptor stimulation and M2 inhibition being especially associated with cognitive skills. Modified cerebral muscarinic receptor profiles in patients with Alzheimer´s disease in addition to loss of Ach releasing neurons help us to understand the pathophysiology of dementia and offer potential therapeutic approaches. Specific agonists and antagonists of muscarinic receptors are discussed as possible treatment options in DAT. Experimental results postulate a positive long lasting modulation of the pathological neuronal protein pattern in addition to their cholinomimetic effect.