Mini-Reviews in Medicinal Chemistry

ISSN: 1389-5575

Mini-Reviews in Medicinal Chemistry
Volume 7, Number 9, September 2007

Contents


The Potential of Peroxisome Proliferator-Activated Receptor γ (PPARγ) Ligands in the Treatment of Hematological Malignancies Pp. 877-887
C. Ulivieri and C.T. Baldari
[Abstract]


Recent Progress in the Pharmacology of Imidazo[1,2-α]pyridines Pp. 888-899
Cécile Enguehard-Gueiffier and Alain Gueiffier
[Abstract]


Recent Advances in Antifungal Agents Pp. 900-911
Tamás Lóránd and Béla Kocsis
[Abstract]


Drugs Made of RNA: Development and Application of Engineered RNAs for Gene Therapy Pp. 912-931
I. Drude, V. Dombos, S. Vauléon and S. Müller
[Abstract]


Novel Phospholipase-Resistant Lipid/Peptide Synthetic Lung Surfactants Pp. 932-944
Robert H. Notter, Adrian L. Schwan, Zhengdong Wang and Alan J. Waring
[Abstract]


5-HT₇ Receptor Ligands: Recent Developments and Potential Therapeutic Applications Pp. 945-960
Valeria Pittalà, Loredana Salerno, Maria Modica, Maria Angela Siracusa and Giuseppe Romeo
[Abstract]


Contribution of Analytical Microscopies to Human Neurodegenerative Diseases Research (PSP and AD) Pp. 961-975
Carmen Quintana
[Abstract]


Forodesine (BCX-1777, Immucillin H) – A New Purine Nucleoside Analogue: Mechanism of Action and Potential Clinical Application Pp. 976-983
Anna Korycka, Jerzy Z. Blonski and Tadeusz Robak
[Abstract]




Abstracts


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The Potential of Peroxisome Proliferator-Activated Receptor γ (PPARγ) Ligands in the Treatment of Hematological Malignancies
C. Ulivieri and C.T. Baldari

PPARγ has emerged as a key regulator of cell growth and survival, whose activity is modulated by a number of synthetic and natural ligands. Here we shall review the activities of PPARγ ligands in the control of immune cell proliferation, differentiation and apoptosis and their potential therapeutic applications to hematological malignancies.


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Recent Progress in the Pharmacology of Imidazo[1,2-α]pyridines
Cécile Enguehard-Gueiffier and Alain Gueiffier

Imidazo[1,2-α]pyridine is a bicyclic system with a bridgehead nitrogen atom, of growing interest in medicinal chemistry. The paper deals with the recent progress realised in the comprehension of the pharmacological properties of this scaffold. From the many imidazo[1,2-α]pyridine analogues described in the literature, those discussed herein will be presented in three parts concerning first the enzyme inhibitors, then the receptor ligands and finally the anti-infectious agents.


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Recent Advances in Antifungal Agents
Tamás Lóránd and Béla Kocsis

New antifungals are needed in the medicine because of more aggressive and invasive diagnostic and therapeutic methods used, rapid emergence of resistant and new opportunistic fungi, increasing number of patients suffering from immunosuppressive situations e.g., AIDS, transplantation, cancer, etc. Several classes of new antifungal agents are discussed here including some new members of known families. Voriconazole, posaconazole and ravuconazole, are novel triazoles that inhibit the ergosterol synthesis. These drugs overcome problems associated with the ineffectivity of fluconazole against some Aspergillus spp. or the variable bioavailability of itraconazole. Echinocandins (caspofungin, anidula-fungin and micafungin) represent a new family of antifungal agents that inhibit 1,3-β-glucan synthase. Nikkomycins targeting the chitin synthase, show activity against Histoplasma capsulatum and Blastomyces dermatitidis. Sordarin derivatives that block the fungal protein synthesis can be considered as a promising new class of antifungal agents for the treatment of Candida and Pneumocystis infections.


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Drugs Made of RNA: Development and Application of Engineered RNAs for Gene Therapy
I. Drude, V. Dombos, S. Vauléon and S. Müller

During the past decade, RNA has become a focus of investigation into new therapeutic schemes: antisense RNA, interfering RNA and trans-cleaving ribozymes are used to silence undesired gene expression. As an additional option with its own therapeutic potential, ribozymes may be employed to specifically alter the sequence of RNA. Among these RNA based strategies the mode of action varies: while antisense and interfering RNAs are capable of making specific contacts to other RNA molecules with the result of employing the cellular machinery for degradation of the RNA target, trans-cleaving ribozymes fold into specific three-dimensional structures to form catalytic centres and to specifically cleave a chosen RNA target. Beyond this, trans-splicing ribozymes have been engineered to first cleave a RNA target followed by ligation of a new RNA fragment delivered with the ribozyme. The latter strategy potentially extends the application of ribozymes from inhibition of gene expression to RNA repair, i. e. correction of genetic disorders at the level of RNA, and has already shown promising results in cell culture experiments. On the other side, advances in RNA synthesis, ribozyme engineering, delivery methods and expression systems have greatly enhanced the prospects of ribozymes, antisense and interfering RNAs in gene therapy.

This review provides an overview of existing strategies for potential RNA based gene therapy. It is focussed on the engineering of ribozymes and functional RNAs to be used as drugs and on the basic molecular principles of their action.


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Novel Phospholipase-Resistant Lipid/Peptide Synthetic Lung Surfactants
Robert H. Notter, Adrian L. Schwan, Zhengdong Wang and Alan J. Waring

Animal-derived drugs are currently widely-used to treat clinical lung surfactant deficiency, but synthetic surfactants have significant advantages as pharmaceutical agents. This article examines exogenous surfactants containing novel synthetic phospholipase-resistant lipids of extremely high surface activity. Mixtures of these lipid analogs with purified native surfactant apoproteins are detailed as a proof of concept for related fully-synthetic surfactants containing laboratory-produced peptides. The chemistry and biophysics of relevant lipid analogs and peptides are reviewed in the context of developing new synthetic drugs of utility for patients with surfactant deficiency or lung injury-related surfactant dysfunction.


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5-HT₇ Receptor Ligands: Recent Developments and Potential Therapeutic Applications
Valeria Pittalà, Loredana Salerno, Maria Modica, Maria Angela Siracusa and Giuseppe Romeo

The 5-HT₇ receptors (5-HT₇Rs) are the most recent classified members of the serotonin family. Characterized in 1993, they belong to the G protein-coupled receptor family. Since their discovery, they have been the subject of intense research due to their widespread distribution in the brain, suggestive of multiple central roles. The focus of this review is to discuss the literature concerning recent advances on 5-HT₇Rs and their ligands.


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Contribution of Analytical Microscopies to Human Neurodegenerative Diseases Research (PSP and AD)
Carmen Quintana

Using analytical microscopies we have observed an increase of Fe²⁺ iron-induced oxidative stress inside pathological ferritin (Ft). This finding, together with the presence of Ft in myelinated axons associated with oligodendrocyte processes and myelin sheet fraying, suggests that a dysfunction of ferritin (a ferritinopathy) may be the non-specific aging-dependent pathogenic event responsible for neurodegenerative disease.


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Forodesine (BCX-1777, Immucillin H) – A New Purine Nucleoside Analogue: Mechanism of Action and Potential Clinical Application
Anna Korycka, Jerzy Z. Blonski and Tadeusz Robak

Recently a few new purine nucleoside analogues (PNA) have been synthesized and introduced into preclinical and clinical trials. The transition-state theory has led to the design of 9-deazanucleotide analogues that are purine nucleoside phosphorylase (PNP) inhibitors, termed immucillins. Among them the most promising results have been obtained with forodesine. Forodesine (BCX-1777, Immucillin H, 1-(9-deazahypoxanthin)-1,4-dideoxy-1,4-imino-D-ribitol) has carbon-carbon linkage between a cyclic amine moiety that replaces ribose and 9-deaza-hypixanthine. The drug is a novel T-cell selective immunosuppressive agent which in the presence of 2’-deoxyguanosine (dGuo) inhibits human lymphocyte proliferation activated by various agents such as interleukin-2 (IL-2), mixed lymphocyte reaction and phytohemagglutinin. In the mechanism of forodesine action two enzymes are involved: PNP and deoxycytidine kinase (dCK). PNP catalyzes the phosphorolysis of dGuo to guanine (Gu) and 2’-deoxyribose-1-phosphate, whereas dCK converts dGuo to deoxyguanosino-5’-monophosphate (dGMP) and finally to deoxyguanosino-5’-triphosphate (dGTP). The affinity of dGuo is higher for PNP than for dCK. Nevertheless, if PNP is blocked by forodesine, plasma dGuo is not cleaved to Gu, but instead it is intracellularly converted to dGTP by high dCK activity, which leads to inhibition of ribonucleotide reductase (RR), an enzyme required for DNA synthesis and cell replication, which eventually results in apoptosis. Forodesine is active in some experimental tumors in mice, however it could be used for the treatment of human T-cell proliferative disorders and it is undergoing phase II clinical trials for the treatment of T-cell non-Hodgkin’s lymphoma, which includes cutaneous T-cell lymphoma (CTCL). Moreover, recent preclinical and clinical data showed activity of forodesine in B-cell acute lympholastic leukemia (ALL).