Current Medicinal Chemistry

ISSN: 0929-8673

Current Medicinal Chemistry
Volume 13, Number 17, 2006

Contents


Soluble Receptor for Advanced Glycation End Products: From Disease Marker to Potential Therapeutic Target Pp. 1971-1978
Diego Geroldi, Colomba Falcone and Enzo Emanuele
[Abstract]


Catecholamines: Physiological Immunomodulators During Health and Illness Pp. 1979-1989
Reiner Oberbeck
[Abstract]

Development of Ligands for the Peripheral Benzodiazepine Receptor Pp. 1991-2001
Michelle L. James, Silvia Selleri and Michael Kassiou
[Abstract]

Antiviral Drug Discovery Against SARS-CoV Pp. 2003-2020
Yu-Shan Wu, Wen-Hsing Lin, John T.-A. Hsu and Hsing-Pang Hsieh
[Abstract]

Review Camptothecin: Current Perspectives Pp. 2021-2039
Qing-Yong Li, Yuan-Gang Zu, Rong-Zhen Shi and Li-Ping Yao
[Abstract]

Secondary Metabolites from the South China Sea Invertebrates: Chemistry and Biological Activity Pp. 2041-2090
Wen Zhang, Yue-Wei Guo and Yucheng Gu
[Abstract]




Abstracts


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Soluble Receptor for Advanced Glycation End Products: From Disease Marker to Potential Therapeutic Target
Diego Geroldi, Colomba Falcone and Enzo Emanuele

The receptor for advanced glycation end products (RAGE) is a cell-bound receptor of the immunoglobulin superfamily which may be activated by a variety of proinflammatory ligands including advanced glycoxidation end products, S100/calgranulins, high mobility group box 1, and amyloid β -peptide. RAGE has a secretory splice isoform, soluble RAGE (sRAGE), that lacks the transmembrane domain and therefore circulates in plasma. By competing with cell-surface RAGE for ligand binding, sRAGE may contribute to the removal/neutralization of circulating ligands thus functioning as a decoy. Clinical studies have recently shown that higher plasma levels of sRAGE are associated with a reduced risk of coronary artery disease, hypertension, the metabolic syndrome, arthritis and Alzheimer’s disease. Increasing the production of plasma sRAGE is therefore considered to be a promising therapeutic target that has the potential to prevent vascular damage and neurodegeneration. This review presents the state of the art in the use of sRAGE as a disease marker and discusses the therapeutic potential of targeting sRAGE for the treatment of inflammation-related diseases such as atherosclerosis, arthritis and Alzheimer’s disease.


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Catecholamines: Physiological Immunomodulators During Health and Illness
Reiner Oberbeck

The existence of an immune-endocrine interaction has been reported and the modulatory effects of the natural occurring catecholamines epinephrine, norepinephrine and dopamine as well as of pharmaceutically generated catecholamines like dopexamine on a wide variety of immune functions were demonstrated. Furthermore, it was noticed that these effects are mediated by specific adrenergic and dopaminergic receptors expressed on the surface of immunological target cells.

At first, the adrenergic immunomodulation was predominantly investigated in healthy volunteers and profound immunomodulatory effects were reported for endogenously released and exogenously administered catecholamines. To further elucidate the physiological significance of these interactions, investigators tried to reveal the importance of the catecholaminergic modulation of the immune system under pathological conditions like hemorrhagic shock and systemic inflammation, since catecholamines and adrenergic antagonists are frequently used drugs in the treatment of the critically ill. Furthermore, the interaction between catecholamines and the immune system is supposed to be an important factor in the development of autoimmune diseases and may influence their progress.

In addition to the effects of peripheral circulating catecholamines, it was demonstrated that catecholamines that are released within the central nervous system may profoundly influence the activity of the peripheral immune system.

Starting with a short historical overview over the immunomodulatory effects of blood catecholamines under good health conditions during critical illness and during autoimmune disease will be reviewed and the immunomodulatory effects of centrally released catecholamines will be discussed.


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Development of Ligands for the Peripheral Benzodiazepine Receptor
Michelle L. James, Silvia Selleri and Michael Kassiou

The peripheral benzodiazepine receptor (PBR) initially characterised as a high affinity binding site for diazepam, is densely distributed in most peripheral organs whilst only moderately expressed in the healthy brain. The predominant cell type expressing the PBR at regions of central nervous system (CNS) pathology are activated microglial cells. Under neuroinflammatory conditions there is an over-expression of PBR binding sites indicating that measurements of PBR density can act as a useful index of brain disease activity. The PBR is now considered a significant therapeutic and diagnostic target which has provided the impetus for PBR ligand development. There are several classes of PBR ligands available including benzodiazepines (Ro5-4864), isoquinoline carboxamides (PK 11195), indoleacetamides (FGIN-1-27), phenoxyphenyl-acetamides (DAA1106) and pyrazolopyrimidines (DPA-713). Subsequent conformationally restrained isoquinoline and indoleacetamide analogues have been synthesised in an attempt to yield PBR ligands with superior affinity and brain kinetics. Even though the PBR has been linked to a number of biochemical processes, including cell proliferation, apoptosis, steroidogenesis, porphyrin transport and immunomodulation, its exact physiological role is yet to be deciphered. Selective PBR ligands with favourable in vivo binding properties and kinetics is required to gain a more complete understanding on the normal functioning of the PBR and the chemical pathways underlying several pathological conditions. Novel PBR ligands with unique binding properties and functional activity may also generate information on the localisation of the PBR and the possibility of PBR subtypes. This review highlights the main classes of PBR ligands to date. In addition the biological activity and therapeutic potential of certain PBR ligands is discussed.


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Antiviral Drug Discovery Against SARS-CoV
Yu-Shan Wu, Wen-Hsing Lin, John T.-A. Hsu and Hsing-Pang Hsieh

Severe Acute Respiratory Syndrome (SARS) is a life-threatening infectious disease caused by SARS-CoV. In the 2003 outbreak, it infected more than 8,000 people worldwide and claimed the lives of more than 900 victims. The high mortality rate resulted, at least in part, from the absence of definitive treatment protocols or therapeutic agents. Although the virus spreading has been contained, due preparedness and planning, including the successful development of antiviral drugs against SARS-CoV, is necessary for possible reappearance of SARS. In this review, we have discussed currently available strategies for antiviral drug discovery and how these technologies have been utilized to identify potential antiviral agents for the inhibition of SARS-CoV replication. Moreover, progress in the drug development based on different molecular targets is also summarized, including 1) Compounds that block the S protein-ACE2-mediated viral entry; 2) Compounds targeting SARS-CoV M^pro; 3) Compounds targeting papain-like protease 2 (PLP2); 4) Compounds targeting SARS-CoV RdRp; 5) Compounds targeting SARS-CoV helicase; 6) Active compounds with unspecified targets; and 7) Research on siRNA. This review aims to provide a comprehensive account of drug discovery on SARS. The experiences with the SARS outbreak and drug discovery would certainly be an important lesson for the drug development for any new viral outbreaks that may emerge in the future.


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Review Camptothecin: Current Perspectives
Qing-Yong Li, Yuan-Gang Zu, Rong-Zhen Shi and Li-Ping Yao

The review provides a detailed discussion of recent advances in the medicinal chemistry of camptothecin, a potent antitumor agent that targets topoisomerase I. Thousands of CPT derivatives have been synthesized. Two of them, Topotecan and Irinotecan, are commercially approved for use in clinic as antitumor agents while more are still in clinic trials. This review summarizes the current status of the modern synthetic approaches to CPT, the mechanism of action of CPT, the structure-activity relationship(SAR), a number of novel CPT analogs and their biologic activity. There is a systematic evaluation of A-, B- and E-ring- modified camptothecins reported recently.


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Secondary Metabolites from the South China Sea Invertebrates: Chemistry and Biological Activity
Wen Zhang, Yue-Wei Guo and Yucheng Gu

The increasing demand for new lead compounds in the pharmaceutical and agrochemical industries has driven scientists to search for new sources of bioactive natural products. Marine invertebrates are a rich source of novel, bioactive secondary metabolites and they have attracted a great deal of attention from scientists in the fields of chemistry, pharmacology, ecology, and molecular biology. During the past 25 years, many complex and structurally unique secondary metabolites have been isolated from the invertebrates inhabiting the South China Sea. These metabolites are responsible for various bioactivities such as anti-tumor, anti-inflammation and antioxidant activities, and/or they act on the cardiovascular system. This review will focus on the marine natural product chemistry of invertebrates from the South China Sea, aiming to give the reader a brief view of the compounds isolated from these invertebrates, as well as their biological activities. The article covers the literature published during the period from the beginning of 1980 to the end of 2005, with 340 citations and 811 compounds from invertebrates from the South China Sea, including sponges, coelenterates, molluscs and echinoderms.