Mini-Reviews in Medicinal Chemistry

ISSN: 1389-5575

Mini-Reviews in Medicinal Chemistry
Volume 6, Number 10, October 2006

Contents

Human Beta-Defensin-3: A Promising Antimicrobial Peptide Pp. 1063-1073
G. Batoni, G. Maisetta, S. Esin and M. Campa
[Abstract]


Intracellular Amyloid β-Protein and Its Associated Molecules in the Pathogenesis of Alzheimer’s Disease Pp. 1075-1080
Yasumasa Ohyagi and Takeshi Tabira
[Abstract]


Preservation Solutions for Solid Organ Transplantation Pp. 1081-1090
C.H. Wilson, N.R. Brook and D. Talbot
[Abstract]


Receptors and Enzymes for Medical Sensing of L-Glutamate Pp. 1091-1100
Ayumi Hirano and Masao Sugawara
[Abstract]


Small Molecule Inhibitors of Protein Kinases in Cancer- How to Overcome Resistance Pp. 1101-1110
R. Griffith, M.N. Brown, A. McCluskey and L.K. Ashman
[Abstract]


Recombinant Factor VIIA, its Clinical Properties, and the Tissue Factor Pathway of Coagulation Pp. 1111-1117
Timothy J. Bosinski and Ali A. El Solh
[Abstract]


The Urocortins: Mechanisms of Cardioprotection and Therapeutic Potential Pp. 1119-1126
K.M. Lawrence and D.S. Latchman
[Abstract]


Synthesis and Biological Activity of Akt/PI3K Inhibitors Pp. 1127-1136
C. Redaelli, F. Granucci, L. De Gioia and L. Cipolla
[Abstract]


Effectiveness of Hsp90 Inhibitors as Anti-Cancer Drugs Pp. 1137-1143
Li Xiao, Xiangyi Lu and Douglas M. Ruden
[Abstract]


New Anti-Mitotic Drugs with Distinct Anti-Calmodulin Activity Pp. 1145-1157
F. Orosz, I. Horváth and J.Ovádi
[Abstract]


Virtual Screening: Are We There Yet? Pp. 1159-1167
Mehran Jalaie and Veerabahu Shanmugasundaram
[Abstract]


Silicon Switches of Marketed Drugs Pp. 1116-1177
P.K. Pooni and G.A. Showell
[Abstract]




Abstracts

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Human Beta-Defensin-3: A Promising Antimicrobial Peptide
G. Batoni, G. Maisetta, S. Esin and M. Campa

The field of naturally occurring antimicrobial peptides is a research area rapidly expanding due to the high potential of such molecules as new antimicrobial drugs. In this regard, the human beta-defensin-3 is particularly attractive because of its strong antibacterial activity, relative salt-insensitiveness and low toxicity for host cells.


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Intracellular Amyloid β-Protein and Its Associated Molecules in the Pathogenesis of Alzheimer’s Disease
Yasumasa Ohyagi and Takeshi Tabira

Amyloid β-protein (Aβ) plays a pivotal role in Alzheimer’s disease (AD). Therapeutic strategies inhibiting Aβ aggregation and promoting extracellular Aβ removal are currently advocated. Here, we review recent literature on intracellular Aβ, especially intranuclear Aβ, and its associated molecules. We also discuss alternative therapeutic strategies to inhibit intracellular Aβ-related pathogenesis.


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Preservation Solutions for Solid Organ Transplantation
C.H. Wilson, N.R. Brook and D. Talbot

Solid organ transplantation was one of the greatest medical advances of the 20^th century. Current preservation technology falls short of maintaining organs ex vivo in perpetuity. This review examines the biochemical basis of organ degradation in response to ischaemia, preservation solution composition and potential future organ preservation technology.


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Receptors and Enzymes for Medical Sensing of L-Glutamate
Ayumi Hirano and Masao Sugawara

Medical sensing systems using isolated or intact glutamate receptor (GluR) ion channels and glutamate oxidase (GluOx) are discussed for L-glutamate, one of the principal neurotransmitter in the central nervous systems of mammalian brain, and related agonists. The GluR-based sensing system used for the evaluation of signal transduction ability of GluR channels demonstrate that the agonist selectivity based on the signal transduction ability is not parallel to that of the binding assay. On the other hand, the appropriate design of the enzyme system, namely glutamate oxidase (GluOx), in combination with horseradish peroxidase (HRP), enables to real-time monitoring of L-glutamate in vivo and in vitro and also to visualize its release in submerged, acute mouse hippocampal slices.


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Small Molecule Inhibitors of Protein Kinases in Cancer- How to Overcome Resistance
R. Griffith, M.N. Brown, A. McCluskey and L.K. Ashman

Small molecule protein kinase inhibitors show great promise as anti-cancer agents, however, de novo and acquired resistance present problems. These are reviewed and illustrated using the receptor tyrosine kinase, KIT, as an example. Emerging solutions are presented, such as targeting active kinase conformations.


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Recombinant Factor VIIA, its Clinical Properties, and the Tissue Factor Pathway of Coagulation
Timothy J. Bosinski and Ali A. El Solh

Recombinant factor VIIa (rFVIIa) is a synthetic coagulation protease that is structurally similar to human-derived plasma FVIIa. Pharmacologic doses of rFVIIa have been shown to enhance thrombin generation and assist in forming stable fibrin plugs at the site of injury. Recombinant factor VIIa appears to emerge as a valuable treatment alternative for the treatment of bleeding episodes and for achieving hemostasis post surgery in those with bleeding disorders.


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The Urocortins: Mechanisms of Cardioprotection and Therapeutic Potential
K.M. Lawrence and D.S. Latchman

The study of the Urocortin family of peptides is becoming increasingly important clinically, as new discoveries have revealed that their roles in the body are extremely diverse. They range from being involved in the aetiology of affective disorders, boosting the immune system, to cardioprotection during ischaemia and reperfusion injury. Therefore, it is important to understand how these peptides become activated, how they activate different cell types and finally their intracellular signalling pathways. Such studies may enable scientists to develop clinical therapies based on their mechanism of action, which may be used to alleviate a diverse range of pathologies.


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Synthesis and Biological Activity of Akt/PI3K Inhibitors
C. Redaelli, F. Granucci, L. De Gioia and L. Cipolla

Phosphatidylinositol 3-kinase (PI3K) and serine/threonine protein kinase B (PKB or Akt) pathways regulate important cellular processes and are related to a number of human pathologies, such as cancer. The development of kinase inhibitors, with particular attention to small molecule analogues of natural phosphoinositides for pathway interruption and therapeutic applications will be reviewed.


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Effectiveness of Hsp90 Inhibitors as Anti-Cancer Drugs
Li Xiao, Xiangyi Lu and Douglas M. Ruden

Hsp90 is a chaperone with over 100 identified client proteins. What makes Hsp90 especially promising as a target for anti-cancer drugs is that many of its client proteins are in signaling and chromatin-remodeling pathways, and these pathways are often disrupted in many types of cancers. Recently, it was determined that Hsp90 bound to a client protein in a co-chaperone complex has a higher ATPase activity and binds to the geldanamycin inhibitor with over 100-fold higher affinity than the low-ATPase form. Consequently, despite Hsp90 being an abundant protein in most cell types, Hsp90 inhibitors accumulate at high levels primarily in tumor cells because tumor cells are “oncogene addicted” and require especially high levels of the high-ATPase form of Hsp90. Numerous classes of Hsp90 inhibitors have recently been developed, such as the anasamysin geldanamycin and derivatives 17-AAG and 17-DMAG; the macrolide radicicol and derivatives; purine-scaffold derivatives; pyrazoles; and shepherdins that bind to the N-terminal high-affinity ATP-binding domain of Hsp90. Other inhibitors have recently been shown to bind to the C-terminal dimerization domain of Hsp90, such as cisplatin and novobiocin, or modify Hsp90 postranslationally, such as histone deacetylase or proteasome inhibitors. In this mini-review, we present hypothetical mechanisms for Hsp90 inhibitors in treating cancers, preliminary studies in early clinical trials, and potential tumor-killing and tumor-promoting activities of Hsp90 inhibitors.


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New Anti-Mitotic Drugs with Distinct Anti-Calmodulin Activity
F. Orosz, I. Horváth and J.Ovádi

Bisindole Vinca alkaloids target microtubule system causing anti-mitotic activity. The problem of their clinical application is the lack of selectivity resulting in toxic side effects. In this paper we review the late history of new bisindole derivatives focusing on KARs recognized as potent anti-cancer drugs with low side effect. KARs, just as other bisindoles, impede microtubule assembly of mitotic spindle, however, they display no anti-calmodulin activity. This new drug family appears to be less potent than vinblastine in vitro systems, but it shows high antitumor efficacy with considerably higher doses being well tolerated in the animal tumor models. 3D data of calmodulin complexed with KAR-2 explain the specificity and unique pharmacology of KAR derivatives.


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Virtual Screening: Are We There Yet?
Mehran Jalaie and Veerabahu Shanmugasundaram

The cost of pharmaceutical development has increased dramatically in recent years, and many assorted approaches have been developed to decrease both the time and costs associated with bringing a drug to the market. Among these methods is the use of in silico screening of compound databases for potential new lead compounds, commonly referred to as virtual screening (VS). Virtual screening has become an integral part of the early discovery process in pharmaceutical development, readily observed by the large number of methodologies that have been published to date. Other reviews have been published detailing the various types of virtual screening methods in use. This work will review some of the virtual screening approaches and strategies that have been attempted to identify compounds to launch medicinal chemistry campaigns. Understanding trends and drivers in VS should help to set expectations about how and when VS could be used and what it can and cannot deliver and how it can be integrated in a successful screening campaign and used in a complementary fashion to HTS.


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Silicon Switches of Marketed Drugs
P.K. Pooni and G.A. Showell

The application of organosilicon chemistry is a strategy to develop best in class drugs applied to targets that have been validated as tractable and drug-able. Silicon switches of known drugs have been synthesised and evaluated in biological assay systems then compared to their marketed all-carbon counterparts. Recent examples include the silicon switches of drugs haloperidol, fexofenadine, bexarotene and venlafaxine.