Mini-Reviews in Medicinal Chemistry

ISSN: 1389-5575

Mini-Reviews in Medicinal Chemistry
Volume 7, Number 10, October 2007

Contents


Sphingolipid Signaling Pathways as Potential Therapeutic Targets in Gliomas Pp. 984-990
James R. Van Brocklyn
[Abstract]


Recent Advances Towards New Anti-Infective Agents that Inhibit Cell Surface Protein Anchoring in Staphylococcus aureus and Other Gram-Positive Pathogens Pp. 991-1000
N. Suree, M.E. Jung and R.T. Clubb
[Abstract]


The Toxic Conformation of the 42-residue Amyloid β Peptide and Its Relevance to Oxidative Stress in Alzheimer’s Disease Pp. 1001-1008
K. Irie, K. Murakami, Y. Masuda, A. Morimoto, H. Ohigashi, H. Hara, R. Ohashi, K. Takegoshi, H. Fukuda, M. Nagao, T. Shimizu and T. Shirasawa
[Abstract]


High-Speed Screening and Quantitative SAR Analysis of Human ABC Transporter ABCG2 for Molecular Modeling of Anticancer Drugs to Circumvent Multidrug Resistance Pp. 1009-1018
H. Saito, H. Hirano and T. Ishikawa
[Abstract]


Cell-Based Biosensors in Clinical Chemistry Pp. 1019-1026
Spiridon E. Kintzios
[Abstract]


α -Fluorinated Ethers as "Exotic" Entity in Medicinal Chemistry Pp. 1027-1034
Peter Jeschke, Eckhard Baston and Frédéric R. Leroux
[Abstract]


Mechanisms of Action of DNA-Damaging Anticancer Drugs in Treatment of Carcinomas: Is Acute Apoptosis an “Off-Target” Effect? Pp. 1035-1039
Aleksandra Mandic Havelka, Maria Berndtsson, Maria Hägg Olofsson, Maria C. Shoshan and Stig Linder
[Abstract]


Michael Acceptors as Cysteine Protease Inhibitors Pp. 1040-1050
Maria M.M. Santos and Rui Moreira
[Abstract]


Symptom and Structure Modifying Properties of Chondroitin Sulfate in Osteoarthritis Pp. 1051-1061
Jean-Yves Reginster, Florence Heraud, Brigitte Zegels and Olivier Bruyere
[Abstract]


Depsipeptide (FK228) as a Novel Histone Deacetylase Inhibitor: Mechanism of Action and Anticancer Activity Pp. 1062-1069
Ewa Lech-Maranda, Ewa Robak, Anna Korycka and Tadeusz Robak
[Abstract]


Cyclin-Dependent Kinase 5 (Cdk5): A Potential Therapeutic Target for the Treatment of Neurodegenerative Diseases and Diabetes Mellitus Pp. 1070-1074
Fan-Yan Wei and Kazuhito Tomizawa
[Abstract]


Synthesis of Compounds as Melatonin Agonists and Antagonists Pp. 1075-1088
Peter J. Garratt and Andrew Tsotinis
[Abstract]




Abstracts


[Back to top]
Sphingolipid Signaling Pathways as Potential Therapeutic Targets in Gliomas
James R. Van Brocklyn

Glioblastoma multiforme (GBM) is a highly malignant brain tumor. The interconvertible bioactive sphingolipids sphingosine-1-phosphate (S1P) and ceramide have profound effects on GBM cells, with ceramide causing cell death and S1P leading to cell survival, proliferation and invasion. This review will examine the effects of ceramide and S1P on glioma cells and the therapeutic potential of these pathways.


[Back to top]
Recent Advances Towards New Anti-Infective Agents that Inhibit Cell Surface Protein Anchoring in Staphylococcus aureus and Other Gram-Positive Pathogens
N. Suree, M.E. Jung and R.T. Clubb

Sortase enzymes are attractive targets for the development of new anti-infective agents against Gram-positive pathogens because they covalently anchor virulence factors to the cell wall. Here we review what is known about the mechanism of sortase mediated protein anchoring and discuss recently identified inhibitors of this new important enzyme family.


[Back to top]
The Toxic Conformation of the 42-residue Amyloid β Peptide and Its Relevance to Oxidative Stress in Alzheimer’s Disease
K. Irie, K. Murakami, Y. Masuda, A. Morimoto, H. Ohigashi, H. Hara, R. Ohashi, K. Takegoshi, H. Fukuda, M. Nagao, T. Shimizu and T. Shirasawa

Senile plaques in the brain of patients with Alzheimer’s disease mainly consist of aggregates of amyloid β peptides (Aβ42, Aβ40). Aβ42 is more neurotoxic than Aβ40. This review describes recent findings from a structural analysis of Aβ42 aggregates and discusses their relevance to neurotoxicity through the formation of radicals.


[Back to top]
High-Speed Screening and Quantitative SAR Analysis of Human ABC Transporter ABCG2 for Molecular Modeling of Anticancer Drugs to Circumvent Multidrug Resistance
H. Saito, H. Hirano and T. Ishikawa

The transport mechanism-based molecular design strategy would provide an effective tool for rationalized chemotherapy against tumors. To develop a platform for molecular modeling to circumvent multidrug resistance, we established new methods of high-speed screening for human ABCG2-drug interactions, quantitative structure-activity relationship (QSAR) analysis, and quantum chemical calculation for lead optimization.


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Cell-Based Biosensors in Clinical Chemistry
Spiridon E. Kintzios

Cell-based biosensors represent the next revolution in medical diagnostics, offering a number of significant advantages, such as high speed, portability and low cost. The present review focuses on the most successful technologies used for the detection of ultra-low concentrations of bioactive analytes (such as metabolic markers and pathogens) in clinical samples.


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α -Fluorinated Ethers as "Exotic" Entity in Medicinal Chemistry
Peter Jeschke, Eckhard Baston and Frédéric R. Leroux

After nitrogen, fluorine occupies the position of second favorite heteroelement in life science-oriented research. In contrast, the trifluoromethoxy group is still perhaps the least well understood fluorine substituent, although its occurrence has significantly increased in the recent years.

Today, significant application areas for trifluoromethoxy substituted pharmaceuticals are in the field of analgesics, anesthetics, cardiovascular drugs, respiratory drugs, psychopharmacologic drugs, neurological drugs, gastrointestinal drugs and anti-infective therapeutics.

The present review will give an overlook of its use in medicinal chemistry.


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Mechanisms of Action of DNA-Damaging Anticancer Drugs in Treatment of Carcinomas: Is Acute Apoptosis an “Off-Target” Effect?
Aleksandra Mandic Havelka, Maria Berndtsson, Maria Hägg Olofsson, Maria C. Shoshan and Stig Linder

DNA damage induces apoptosis of cells of hematological origin. Apoptosis is also widely believed to be the major antiproliferative mechanism of DNA damaging anticancer drugs in other cell types, and a large number of laboratories have studied drug-induced acute apoptosis (within 24 hours) of carcinoma cells. It is, however, often overlooked that induction of apoptosis of carcinoma cells generally requires drug concentrations that are at least one order of magnitude higher than those required for loss of clonogenicity. This is true for different DNA damaging drugs such as cisplatin, doxorubicin and camptothecin. We here discuss apoptosis induction by DNA damaging agents using cisplatin as an ex-ample. Recent studies have shown that cisplatin induces caspase activation in enucleated cells (cytoplasts lacking a cell nucleus). Cisplatin-induced apoptosis in both cells and cytoplasts is associated with rapid induction of cellular reactive oxygen species and increases in [Ca²⁺]_i. Cisplatin has also been reported to induce clustering of Fas/CD95 in the plasma membrane. Available data suggest that the primary responses to cisplatin-induced DNA damage are induction of long-term growth arrest (“premature cell senescence”) and mitotic catastrophe, whereas acute apoptosis may be due to “off-target effects” not necessarily involving DNA damage.


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Michael Acceptors as Cysteine Protease Inhibitors
Maria M.M. Santos and Rui Moreira

Cysteine proteases selectively catalyze the hydrolysis of peptide bonds. Uncontrolled, unregulated, or undesired proteolysis can lead to many disease states including emphysema, stroke, viral infections, cancer, Alzheimer’s disease, inflammation, and arthritis. Cysteine proteases inhibitors thus have considerable potential utility for therapeutic intervention in a variety of disease states.

This review emphasizes on the new developments from literature reports on Michael acceptors as potential cysteine protease inhibitors, namely vinyl sulfones, α,β-unsaturated carbonyl derivatives and aza-peptides. These compounds irreversibly alkylate the active site cysteine residue via conjugate addition. Examples of Michael acceptors inhibitors that have already progressed to clinical testing are also presented.


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Symptom and Structure Modifying Properties of Chondroitin Sulfate in Osteoarthritis
Jean-Yves Reginster, Florence Heraud, Brigitte Zegels and Olivier Bruyere

Chondroitin sulfate (CS) is a complex carbohydrate polymer with variable sulfation which impacts function. CS exhibits a wide range of biological activities. Many experimental and clinical data are available, affirming that CS represents an effective and safe symptomatic treatment of osteoarthritis (OA) with delayed and sustained effects.


[Back to top]
Depsipeptide (FK228) as a Novel Histone Deacetylase Inhibitor: Mechanism of Action and Anticancer Activity
Ewa Lech-Maranda, Ewa Robak, Anna Korycka and Tadeusz Robak

Depsipeptide (FK228), a new histone deacetylase inhibitor, has been recently introduced into clinical trials. This agent shows interesting metabolic properties, novel mechanism of action, and is undergoing phase I-II clinical studies in hematopoietic malignancies and solid tumors. Mechanism of action, pharmacokinetics and anticancer activity of depsipeptide is the subject of this review.


[Back to top]
Cyclin-Dependent Kinase 5 (Cdk5): A Potential Therapeutic Target for the Treatment of Neurodegenerative Diseases and Diabetes Mellitus
Fan-Yan Wei and Kazuhito Tomizawa

Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine protein kinase, which forms active complexes with p35 or p39 expressed predominantly in neurons. Cdk5 is indispensable for the development of the central nervous system through regulation of neuronal migration. In mature neurons, Cdk5 has been implicated in various signaling transduction pathways, which contribute to functional neuronal activity. It has been widely accepted that aberrant Cdk5 activity induced by the conversion of p35 to p25 plays roles in the pathogenesis of neurodegenerative diseases. Cdk5 also contributes to adaptive changes in the brain related to drug addiction. Moreover, recent studies suggest that Cdk5 plays crucial roles in physiological functions in non-neuronal cells such as glucose-stimulated insulin secretion in pancreatic -cells. The present evidence indicates that Cdk5 might be a potential drug target for the treatment of neurodegenerative diseases, drug abuse and diabetes mellitus. This review focuses on the implication of Cdk5 in the signaling pathways of both neurodegenerative diseases and drug abuse, and the mechanism of Cdk5 involvement in insulin secretion. This review also discusses the possibility of using Cdk5 inhibitors as therapeutic drugs.


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Synthesis of Compounds as Melatonin Agonists and Antagonists
Peter J. Garratt and Andrew Tsotinis

The functions of melatonin, the hormone of the pineal gland, are of considerable current interest. Synthetic melatonin analogues as agonists and antagonists have been explored in some detail and the molecule can be considered as consisting of an indole core, acting mainly as a spacer, and the 5-methoxyl and 3-amidoethyl side chains acting as the functional components, as originally proposed by Heward and Hadley. This review focuses on the synthetic routes to these melatonin analogues, first of the core, then of the substituents that have been attached to the core, and finally those compounds with restricted conformations and those that are chiral. The importance of the various factors involved in the activity of the compounds as agonist or antagonists is indicated, as is the difference in activity of enantiomers.