Mini-Reviews in Medicinal Chemistry

ISSN: 1389-5575

Mini-Reviews in Medicinal Chemistry
Volume 7, Number 6, June 2007

Contents


Allosteric Enhancers for A₁ Adenosine Receptor Pp. 559-569
Pier Giovanni Baraldi, Maria Antonietta Iaconinoto, Allan R. Moorman, Maria Dora Carrion, Carlota Lopez Cara, Delia Preti, Olga Cruz López, Francesca Fruttarolo, Mojgan Aghazadeh Tabrizi and Romeo Romagnoli
[Abstract]


Natural Peroxy Anticancer Agents Pp. 571-589
Valery M. Dembitsky, Tatyana A. Gloriozova and Vladimir V. Poroikov
[Abstract]


New Perspectives in the Management of Secondary Hyperparathyroidism Pp. 591-598
Francesco Locatelli, Monica Limardo and Giuseppe Pontoriero
[Abstract]


Back to the Future: COX-2 Inhibitors for Chemoprevention and Cancer Therapy Pp. 599-608
Fazlul H. Sarkar, Shreelekha Adsule, Yiwei Li and Subhash Padhye
[Abstract]


A Search for Inhibitors of S100B, a Member of the S100 Family of Calcium-Binding Proteins Pp. 609-616
Joseph Markowitz, Alexander D. MacKerell Jr. and David J. Weber
[Abstract]


New Opportunities for Pregnane X Receptor (PXR) Targeting in Drug Development. Lessons from Enantio- and Species-Specific PXR Ligands Identified from A Discovery Library of Amino Acid Analogues Pp. 617-625
Peter Wipf, Haibiao Gong, Jelena M. Janjic, Song Li, Billy W. Day and Wen Xie
[Abstract]


DNA Intercalators in Cancer Therapy: Organic and Inorganic Drugs and Their Spectroscopic Tools of Analysis Pp. 627-648
Nial J. Wheate, Craig R. Brodie, J. Grant Collins, Sharon Kemp and Janice R. Aldrich-Wright
[Abstract]


Angiogenesis and Metastasis Inhibitors for the Treatment of Malignant Melanoma Pp. 649-661
Riichiro Abe, Yasuyuki Fujita and Sho-ichi Yamagishi
[Abstract]




Abstracts


[Back to top]
Allosteric Enhancers for A₁ Adenosine Receptor
Pier Giovanni Baraldi, Maria Antonietta Iaconinoto, Allan R. Moorman, Maria Dora Carrion, Carlota Lopez Cara, Delia Preti, Olga Cruz López, Francesca Fruttarolo, Mojgan Aghazadeh Tabrizi and Romeo Romagnoli

Allosteric enhancers at the adenosine A₁ receptor have received attention as anti-arrhythmic cardiac agents, and, more recently, as anti-lipolytic agents. In addition, allosteric modulators at the adenosine A₁ receptor have therapeutic potential as analgesics and neuroprotective agents. In particular, the compounds with improved potency as enhancers and reduced antagonist properties are mentioned.


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Natural Peroxy Anticancer Agents
Valery M. Dembitsky, Tatyana A. Gloriozova and Vladimir V. Poroikov

Present review describes research on novel natural anticancer agents isolated from terrestrial and marine sources. More than 120 cytotoxic anticancer compounds have shown confirmed activity in vitro tumor cell lines bioassay and are of current interest to Natural Cancer Institute for further in vivo evaluation. Intensive searches for new classes of pharmacologically potent agents produced by terrestrial and marine organisms have resulted in the discovery of dozens of compounds possessing high cytotoxic activities. However, only a limited number of them have been tested in pre-clinical and clinical trials. One of the reasons is a limited supply of the active ingradients from the natural sources. However, the pre-clinical and clinical development of many terrestrial and/or marine-derived natural products into pharmaceuticals is often hampered by a limited supply from the natural source. Total synthesis is of vital importance in these situations, allowing for the production of useful quantities of the target compound for further biological evaluation. With computer program PASS some additional biological activities are also predicted, which point toward new possible applications of these compounds. This review emphasizes the role of terrestrial and marine peroxides as an important source of leads for drug discovery.


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New Perspectives in the Management of Secondary Hyperparathyroidism
Francesco Locatelli, Monica Limardo and Giuseppe Pontoriero

The traditional treatment of secondary hyperparathyroidism, which affects many patients with chronic kidney disease and is associated with an increased risk of morbidity and mortality, is not very effective. Recent approaches to its management include the use of vitamin D analogues, non-calcium non-aluminium containing phosphate binders, and calcimimetics.


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Back to the Future: COX-2 Inhibitors for Chemoprevention and Cancer Therapy
Fazlul H. Sarkar, Shreelekha Adsule, Yiwei Li and Subhash Padhye

For more than a century, inhibition of prostaglandin biosynthesis via inhibition of the fatty acid cyclooxygenase (COX) has been achieved by non-steroidal anti-inflammatory drugs (NSAIDs), which targets both COX-1 and COX-2 and as such could be responsible for causing gastrointestinal (GI) toxicity. COX-2 is an inducible enzyme produced by many cell types in response to multiple stimuli. Recently, COX-2 over-expression has been found in several types of human cancers such as colon, breast, prostate and pancreas and appears to control many cellular processes. Because of its role in carcinogenesis, apoptosis, and angiogenesis, it is an excellent target for developing new drugs with selectivity for prevention and/or treatment of human cancers. Development of selective COX-2 inhibitors has been successfully documented and as such showed less toxicity to GI tract as compared to conventional NSAIDs. However, the long term use of COX-2 selective inhibitors showed cardiovascular toxicity, and thus their utilization for cancer prevention and therapy is currently questionable, suggesting that further development of novel COX-2 selective agents are needed. Among many solid tumors, pancreatic cancer has the worst prognosis, and inflammation has been identified as a significant factor in the development of pancreatic malignancy. Several cytokines, reactive oxygen species (ROS) and mediators of inflammatory pathway such as activation of nuclear factor-kappaB (NF-κB) and COX-2 leads to an increase in cell proliferation, survival, and inhibition of pro-apoptotic pathway, ultimately resulting in tumor angiogenesis, invasion and metastasis. In this brief review, we summarize the role of COX-2 and discuss some of the experimental data linking inflammation with the development of pancreatic cancer. In addition, we provide further evidence regarding the state of our knowledge toward the development of novel COX-2 targeting agents for the prevention and/or treatment of human cancers especially pancreatic cancer.


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A Search for Inhibitors of S100B, a Member of the S100 Family of Calcium-Binding Proteins
Joseph Markowitz, Alexander D. MacKerell Jr. and David J. Weber

Typically, malignant melanoma has wild-type p53, and yet this cancer proliferates. S100B, which binds p53 and is up-regulated in melanoma, down-regulates wild-type p53 tumor suppressor function. Inhibitors of the S100B-p53 interaction were identified using computer aided drug design (CADD) combined with NMR methodologies and represent potentially new chemotherapeutics for melanoma.


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New Opportunities for Pregnane X Receptor (PXR) Targeting in Drug Development. Lessons from Enantio- and Species-Specific PXR Ligands Identified from A Discovery Library of Amino Acid Analogues
Peter Wipf, Haibiao Gong, Jelena M. Janjic, Song Li, Billy W. Day and Wen Xie

Nuclear hormone receptors (NHRs) are transcription factors that bind to lipophilic signaling molecules (ligands), and subsequently regulate the expression of target genes. Since NHR ligands have potential as therapeutic agents, one of the most active research areas in the NHR field is the synthesis and identification of small molecule ligands for NHRs. Wipf et al. have recently reported the creation of a discovery library using a new method for the synthesis of homoallylic amides, allylic amides and C-cyclopropylalkylamides. This article is intended to review the use of this discovery library to screen for activators for the pregnane X receptor (PXR), a master xenobiotic receptor that regulates the expression of Phase I and Phase II enzymes as well as drug transporters. Our screening of the discovery library identified potent PXR activators whose carbon scaffolds are distinct from the chemical structures of known PXR agonists. Moreover, we found that enantiomers of the same compound show a species-specific activation of PXR. The development of the discovery library and the implications of enantiospecificity of PXR ligand design represent the primary focus of this account.


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DNA Intercalators in Cancer Therapy: Organic and Inorganic Drugs and Their Spectroscopic Tools of Analysis
Nial J. Wheate, Craig R. Brodie, J. Grant Collins, Sharon Kemp and Janice R. Aldrich-Wright

Since the discovery of the DNA intercalation process by Lerman in 1961 thousands of organic, inorganic octahedral (particularly ruthenium(II) and rhodium(III)) and square-planar (particularly platinum(II)) compounds have been developed as potential anticancer agents and diagnostic agents. The design and synthesis of new drugs is focused on bis-intercalators which have two intercalating groups linked via a variety of ligands, and synergistic drugs, which combine the anticancer properties of intercalation with other functionalities, such as covalent binding or boron-cages (for radiation therapy). Advances in spectroscopic techniques mean that the process of DNA intercalation can be examined in far greater detail than ever before, yielding important information on structure-activity relationships. In this review we examine the history and development of DNA intercalators as anticancer agents and advances in the analysis of DNA-drug interactions.


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Angiogenesis and Metastasis Inhibitors for the Treatment of Malignant Melanoma
Riichiro Abe, Yasuyuki Fujita and Sho-ichi Yamagishi

Malignant melanoma is one of the most highly invasive and metastatic tumors. Melanoma is an increasingly common malignancy as well, and its mortality rates have been rapidly increasing above those of any other cancer in recent years. Surgical resection and systemic chemotherapy are the main therapeutic strategies for the treatment of malignant melanoma. However, these approaches are insufficiently effective and may be associated with significant adverse effects. Angiogenesis, a process by which new vascular networks are formed from pre-existing capillaries, is required for tumors to grow, invade and metastasize. Tumor vessels are genetically stable, and less likely to accumulate mutations that allow them to develop drug resistance in a rapid manner. Therefore, targeting vasculatures that support tumor growth, rather than cancer cells, is considered the most promising approach to malignant melanoma therapy. Now, novel anti-angiogenic agents with tolerable side effects is actually desired for the treatment of patients with malignant melanoma. In this paper, we review the current understanding of anti-angiogenic therapy for malignant melanoma, especially focusing on pigment epithelium-derived factor (PEDF), which was recently identified as the most potent endogenous inhibitor of angiogenesis in the mammalian eye. We also discuss here the involvement of a receptor for advanced glycation end products (RAGE) in angiogenesis, melanoma growth and metastasis, and the therapeutic implications of the blockers of RAGE in this devastating disorder.