Current Medicinal Chemistry

ISSN: 0929-8673

Current Medicinal Chemistry
Volume 15, Number 5, 2008

Contents


From Single- to Multi-Target Drugs in Cancer Therapy: When Aspecificity Becomes an Advantage Pp. 422-432
A. Petrelli and S. Giordano
[Abstract]


Anticancer Compounds as Leishmanicidal Drugs: Challenges in Chemotherapy and Future Perspectives Pp. 433-439
Miguel A. Fuertes, Paul A. Nguewa, Josefina Castilla, Carlos Alonso and José M. Pérez
[Abstract]


Chemoprevention of Cancer by Isothiocyanates and Anthocyanins:Mechanisms of Action and Structure-Activity Relationship Pp. 440-447
C. Fimognari, M. Lenzi and P. Hrelia
[Abstract]


Targeting Leukocytes in Immune Glomerular Diseases Pp. 448-458
A.R. Kitching, S.R. Holdsworth and M.J. Hickey
[Abstract]


Binary Actin-ADP-Ribosylating Toxins and their Use as Molecular Trojan Horses for Drug Delivery into Eukaryotic Cells Pp. 459-469
Holger Barth and Bradley G. Stiles
[Abstract]


Strategies to Overcome or Circumvent P-Glycoprotei Mediated Multidrug Resistance Pp. 470-476
Hongyu Yuan, Xun Li , Jifeng Wu, Jinpei Li, Xianjun Qu, Wenfang Xu and Wei Tang
[Abstract]


Role of Free Radicals and Poly(ADP-Ribose)Polymerase- in the Development of Spinal Cord Injury: New Potential Therapeutic Targets Pp. 477-487
T. Genovese and S. Cuzzocrea
[Abstract]


Pathways of Acetylcholine Synthesis, Transport and Release as Targets for Treatment of Adult-Onset Cognitive Dysfunction Pp. 488-498
F. Amenta and S.K. Tayebati
[Abstract]


Therapeutic Potential of Vitamin D for Multiple Sclerosis Pp. 499-505
Masaaki Niino, Toshiyuki Fukazawa, Seiji Kikuchi and Hidenao Sasaki
[Abstract]


Self-Adjuvanting Lipopeptide Vaccines Pp. 506-516
Peter M. Moyle and Istvan Toth
[Abstract]


Pseudomonas aeruginosa Serious Infections: Mono or Combination Antimicrobial Therapy? Pp. 517-522
Matteo Bassetti, Elda Righi and Claudio Viscoli
[Abstract]


Carbon Nanotubes for Biomaterials in Contact with Bone Pp. 523-527
Naoto Saito, Yuki Usui, Kaoru Aoki, Nobuyo Narita, Masayuki Shimizu, Nobuhide Ogiwara, Koichi Nakamura, Norio Ishigaki, Hiroyuki Kato, Seiichi Taruta and Morinobu Endo
[Abstract]




Abstracts


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From Single- to Multi-Target Drugs in Cancer Therapy: When Aspecificity Becomes an Advantage
A. Petrelli and S. Giordano

Targeted therapies by means of compounds that inhibit a specific target molecule represent a new perspective in the treatment of cancer. In contrast to conventional chemotherapy which acts on all dividing cells generating toxic effects and damage of normal tissues, targeted drugs allow to hit, in a more specific manner, subpopulations of cells directly involved in tumor progression. Molecules controlling cell proliferation and death, such as Tyrosine Kinase Receptors (RTKs) for growth factors, are among the best targets for this type of therapeutic approach. Two classes of compounds targeting RTKs are currently used in clinical practice: monoclonal antibodies and tyrosine kinase inhibitors. The era of targeted therapy began with the approval of Trastuzumab, a monoclonal antibody against HER2, for treatment of metastatic breast cancer, and Imatinib, a small tyrosine kinase inhibitor targeting BCR-Abl, in Chronic Myeloid Leukemia. Despite the initial enthusiasm for the efficacy of these treatments, clinicians had to face soon the problem of relapse, as almost invariably cancer patients developed drug resistance, often due to the activation of alternative RTKs pathways.

In this view, the rationale at the basis of targeting drugs is radically shifting. In the past, the main effort was aimed at developing highly specific inhibitors acting on single RTKs. Now, there is a general agreement that molecules interfering simultaneously with multiple RTKs might be more effective than single target agents. With the recent approval by FDA of Sorafenib and Sunitinib - targeting VEGFR, PDGFR, FLT-3 and c-Kit - a different scenario has been emerging, where a new generation of anti-cancer drugs, able to inhibit more than one pathway, would probably play a major role.

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Anticancer Compounds as Leishmanicidal Drugs: Challenges in Chemotherapy and Future Perspectives
Miguel A. Fuertes, Paul A. Nguewa, Josefina Castilla, Carlos Alonso and José M. Pérez

Leishmaniasis comprises a spectrum of parasitic illnesses caused by several species of the protozoan kinetoplastid parasite, Leishmania spp. The disease affects 12 million people around the world with an annual death rate of approximately 80,000 people.

Several drugs are available for treating leishmaniasis. For example, pentavalent antimonial compounds, such as sodium stibogluconate and meglumine antimonite are the drugs used in first-line chemotherapy. As second-line drugs, amphotericin B and pentamidine are used. However, current treatments against leishmaniasis are usually unsatisfactory due to some limitations including the route of administration of the drugs, their unaffordable cost and toxicity. Efforts have been made to develop new leishmanicidal drugs and to find new strategies of drug design. Hence, it is interesting to point out that the effectiveness of certain molecules as both anticancer drugs and antiprotozoal agents suggested that this class of compounds and their derivatives might be useful as antileishmanial agents.

This review summarizes the anticancer compounds that have been investigated against leishmaniasis. Some of such agents include: compounds with in vitro antileishmanial activities, molecules tested in clinical trials and registered patents. We finally discuss challenges in chemotherapy and future prospects in the treatment of leishmaniasis.


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Chemoprevention of Cancer by Isothiocyanates and Anthocyanins:Mechanisms of Action and Structure-Activity Relationship
C. Fimognari, M. Lenzi and P. Hrelia

Carcinogenesis is a multi-step, multi-path and multi-focal process, which involves a series of epigenetic and genetic alterations that begin with genomic instability and end with the development of cancer. This long and complex process presents opportunities for the development of interventions both in preventing cancer initiation and in treating the neoplasm during its premalignant stages. Failure and high systemic toxicity of conventional cancer therapies have accelerated the search for newer agents, which could prevent and/or slow-down cancer growth and have more human acceptability by being less or non-toxic. Now, it is recognized that diets rich in fruits and vegetables are associated with lower risk of cancer. Taking cue from these observations, there is a strong interest in isolating and characterizing the nutritive and non-nutritive components of fruits and vegetables as potential chemopreventive agents. Isothiocyanates and anthocyanins, present in widely consumed fruits and vegetables, are two such agents. In recent years, increasing body of evidence has underscored the cancer preventive efficacy of isothiocyanates and anthocyanins in both in vitro and in vivo animal models. In this review article, we will provide detailed insight into the chemopreventive efficacy of isothiocyanates and anthocyanins based on the evidence generated from various studies performed using cell culture or animal models of epithelial cancers. Moreover, we will discuss the potential clinical relevance of the observed chemopreventive effects of these agents.


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Targeting Leukocytes in Immune Glomerular Diseases
A.R. Kitching, S.R. Holdsworth and M.J. Hickey

The glomerulonephritides are a collection of separate diseases with differing pathogeneses that collectively are common and important causes of renal disease. Effective, non-toxic immunomodulatory treatments for glomerulonephritis are lacking. This review will focus on our understanding of the role of leukocytes in immune glomerular disease, specifically in severe and rapidly progressive forms of glomerulonephritis, and provide examples of potential therapeutic targets. The glomerulus is a high flow, high pressure capillary plexus bounded by arterioles that is vulnerable to a variety of immune or inflammatory insults. The variety in the pathogenesis of different forms of glomerulonephritis, together with the capacity of both humoral and cellular effector arms to induce injury, means that understanding the pathogenesis of glomerulonephritis is necessary to effectively apply new treatments. Leukocytes are involved in the pathogenesis of glomerulonephritis at several levels, including the loss of tolerance, adaptive immune responses directed by T cells, cellular effectors inducing injury in delayed type hypersensitivity-like reactions, and by macrophage/neutrophil recruitment via the deposition of circulating immune complexes or in situ immune complexes. Evidence is emerging that anti-neutrophil cytoplasmic antibodies activate neutrophils, leading to glomerular capillaritis. Some therapeutic options limit local inflammation, while others modify the underlying pathogenetic immune response. Areas of current interest include the relationship between infiltrating and local cells, limiting effector cell activation, particularly macrophages; as well as understanding and targeting leukocyte recruitment to this unique vasculature. Modifying pathogenetic T or B cells also is a promising strategy in both systemic autoimmunity affecting the kidney and organ specific autoimmunity.


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Binary Actin-ADP-Ribosylating Toxins and their Use as Molecular Trojan Horses for Drug Delivery into Eukaryotic Cells
Holger Barth and Bradley G. Stiles

Binary bacterial toxins are unique AB-type toxins, composed of two non-linked proteins that act as a binding/translocation component and an enzyme component. All known actin-ADP-ribosylating toxins from clostridia possess this binary structure. This toxin family is comprised of the prototypical Clostridium botulinum C2 toxin, Clostridium perfringens iota toxin, Clostridium difficile CDT, and Clostridium spiroforme toxin. Once in the cytosol of host cells, these toxins transfer an ADP-ribose moiety from nicotinamide-adenosine-dinucleotide onto G-actin that then leads to depolymerization of actin filaments.

In recent years much progress has been made towards understanding the cellular uptake mechanism of binary actin-ADP-ribosylating toxins, and in particular that of C2 toxin. Both components act in a precisely concerted manner to intoxicate eukaryotic cells. The binding/translocation (B-) component forms a complex with the enzyme (A-) component and mediates toxin binding to a cell-surface receptor. Following receptor-mediated endocytosis, the enzyme component escapes from acidic endosomes into the cytosol. Acidification of endosomes triggers pore formation by the binding/translocation component in endosomal membranes and the enzyme component subsequently translocates through the pore. This step requires a host cell chaperone, Hsp90.

Due to their unique structure, binary toxins are naturally “tailor made” for transporting foreign proteins into the cytosol of host cells. Several highly specific and cell-permeable recombinant fusion proteins have been designed and successfully used in experimental cell research. This review will focus on the recent progress in studying binary actin ADP-ribosylating toxins as highly effective virulence factors and innovative tools for cell physiology as well as pharmacology.

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Strategies to Overcome or Circumvent P-Glycoprotein Mediated Multidrug Resistance
Hongyu Yuan, Xun Li , Jifeng Wu, Jinpei Li, Xianjun Qu, Wenfang Xu and Wei Tang

Cancer patients who receive chemotherapy often experience intrinsic or acquired resistance to a broad spectrum of chemotherapeutic agents. The phenomenon, termed multidrug resistance (MDR), is often associated with the over-expression of P-glycoprotein, a transmembrane protein pump, which can enhance efflux of a various chemicals structurally unrelated at the expense of ATP depletion, resulting in decrease of the intracellular cytotoxic drug accumulation. The MDR has been a big threaten to the human health and the war fight for it continues. Although several other mechanisms for MDR are elucidated in recent years, considerable efforts attempting to inverse MDR are involved in exploring P-glycoprotein modulators and suppressing P-glycoprotein expression. In this review, we will report on the recent advances in various strategies for overcoming or circumventing MDR mediated by P-glycoprotein.


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Role of Free Radicals and Poly(ADP-Ribose)Polymerase-1 in the Development of Spinal Cord Injury: New Potential Therapeutic Targets
T. Genovese and S. Cuzzocrea

Oxidative stress results from an oxidant/antioxidant imbalance, an excess of oxidants and/or a depletion of antioxidants. A vast amount of circumstantial evidence implicates oxygen-derived free radicals (especially, superoxide and hydroxyl radical) and high energy oxidants (such as peroxynitrite) as mediators of secondary damage associated with spinal cord injury. Reactive oxygen species (ROS) (e.g., superoxide, peroxynitrite, hydroxyl radical and hydrogen peroxide) are all potential reactants capable of initiating DNA single strand breakage, with subsequent activation of the nuclear enzyme poly (ADP ribose) synthetase (PARS), leading to eventual severe energy depletion of the cells, and necrotic-type cell death. Moreover, Poly(ADP-ribosyl)ation is regulated by the synthesizing enzyme poly(ADP-ribose) polymerase-1 (PARP-1) and the degrading enzyme poly(ADP-ribose) glycohydrolase (PARG). Here, we review the roles of ROS, PARP-1 and PARG in spinal cord injury as well as the beneficial effect of the in vivo treatment with novel pharmacological tools (e.g. peroxynitrite decomposition catalysts, selective superoxide dismutase mimetics (SODm), PARP-1 and PARG inhibitors.


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Pathways of Acetylcholine Synthesis, Transport and Release as Targets for Treatment of Adult-Onset Cognitive Dysfunction
F. Amenta and S.K. Tayebati

Acetylcholine (ACh) is a neurotransmitter widely diffused in central, peripheral, autonomic and enteric nervous system. This paper has reviewed the main mechanisms of ACh synthesis, storage, and release. Presynaptic choline transport supports ACh production and release, and cholinergic terminals express a unique transporter critical for neurotransmitter release. Neurons cannot synthesize choline, which is ultimately derived from the diet and is delivered through the blood stream. ACh released from cholinergic synapses is hydrolyzed by acetylcholinesterase into choline and acetyl coenzyme A and almost 50% of choline derived from ACh hydrolysis is recovered by a high-affinity choline transporter. Parallel with the development of cholinergic hypothesis of geriatric memory dysfunction, cholinergic precursor loading strategy was tried for treating cognitive impairment occurring in Alzheimer’s disease. Controlled clinical studies denied clinical usefulness of choline and lecithin (phosphatidylcholine), whereas for other phospholipids involved in choline biosynthetic pathways such as cytidine 5'-diphosphocholine (CDP-choline) or alpha-glyceryl-phosphorylcholine (choline alphoscerate) a modest improvement of cognitive dysfunction in adult-onset dementia disorders is documented. These inconsistencies have probably a metabolic explanation. Free choline administration increases brain choline availability but it does not increase ACh synthesis/or release. Cholinergic precursors to serve for ACh biosynthesis should be incorporate and stored into phospholipids in brain. It is probable that appropriate ACh precursors and other correlated molecules (natural or synthesized) could represent a tool for developing therapeutic strategies by revisiting and updating treatments/supplementations coming out from this therapeutic stalemate.


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Therapeutic Potential of Vitamin D for Multiple Sclerosis
Masaaki Niino, Toshiyuki Fukazawa, Seiji Kikuchi and Hidenao Sasaki

Multiple sclerosis (MS) is a major inflammatory and demyelinating disease of the central nervous system and has an increasing prevalence in populations residing at higher latitudes. This observation may indicate a protective effect of sunlight exposure, which is reduced at higher latitudes and may contribute to insufficient levels of vitamin D in the MS population. The vitamin D hormone is important for bone metabolism and can regulate cell proliferation and differentiation as well as apoptosis and immune regulation in immune cells such as T helper cells and dendritic cells. Evidence from experimental autoimmune encephalomyelitis and prospective studies on MS suggests an important role of vitamin D as a modifiable environmental factor in MS. These provide guidance for future studies with regard to the potential role of vitamin D in the prevention and/or treatment of MS. Here, we first review the metabolism and immune functions of vitamin D. Then, we describe the current thinking on the etiology of vitamin D in MS and the accumulating evidence pointing to a link between vitamin D and MS. Further, we describe how genetic susceptibility interacts with environmental risk factors at the population level, MS-associated risk factors, and genetic studies related to the vitamin D receptor. This review also discusses the therapeutic potential of vitamin D for treating MS.


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Self-Adjuvanting Lipopeptide Vaccines
Peter M. Moyle and Istvan Toth

Despite the important role of adjuvants for vaccine development, relatively few adjuvants have been successfully incorporated into vaccines intended for human administration. This is in part due to the high toxicity associated with many experimental adjuvants. This lack of choice effectively hinders the ability to produce vaccines against many diseases, or to improve current vaccine formulations. The conjugation of immunostimulatory lipids to peptide antigens, to produce self-adjuvanting lipopeptide vaccines, has been tested in human clinical trials. These systems appear to have a number of advantages over more traditional adjuvants (e.g. alum salts) including the capacity for these vaccines to be administered via mucosal routes (e.g. orally or nasally) instead of by injection, elicitation of antigen-specific cytotoxic T-lymphocytes and mucosal immunity, as well as little-to-no observed toxicity. Several lipopeptide vaccine systems have been described in the literature, ranging from the conjugation of single fatty acid chains, to the conjugation of more complex lipids and glycolipids onto peptide antigens. The following review provides an overview of the most studied lipopeptide vaccine systems grouped into the following categories: 1) bacterial lipopeptides, including tri-palmitoyl-S-glyceryl cysteine (Pam₃Cys) and di-palmitoyl-S-glyceryl cysteine (Pam₂ Cys); 2) the lipid-core peptide (LCP) and multiple antigen lipophilic adjuvant carrier (MALAC) systems; 3) single-chain palmitoylated peptides; and 4) glycolipids (e.g. monophosphoryl lipid A). The review also discusses the potential mechanisms of action for lipopeptide and glycolipopeptide vaccines, as well as structure activity relationships, and provides examples of studies utilising each system.


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Pseudomonas aeruginosa Serious Infections: Mono or Combination Antimicrobial Therapy?
Matteo Bassetti, Elda Righi and Claudio Viscoli

P. aeruginosa is a serious cause of infection with reported rates of mortality being up to 61%. Several studies evidenced a correlation between hospital mortality due to P. aeruginosa bloodstream infections and an inappropriate antimicrobial treatment. Increasing resistance in P. aeruginosa isolates complicates the selection of adequate empirical therapy in severe infections and P. aeruginosa is often indistinguishable from other gram-negative bacterial infections. For these reasons, present guidelines for the treatment of suspected P. aeruginosa bacteraemia recommend the rapid introduction of empirical antimicrobial therapy that includes at least one antipseudomonal agent until having microbiological results. Current consensus favours the use of empirical combination, balancing the potential for greater toxicity against the lower emergence of antimicrobial resistance and the greater killing that might be achieved by combination therapies acting synergistically. Advantages and disadvantages of combination therapy towards monotherapy for P. aeruginosa severe infections, current antibiotics used for P. aeruginosa severe infections and main studies published on this issue are reviewed.


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Carbon Nanotubes for Biomaterials in Contact with Bone
Naoto Saito, Yuki Usui, Kaoru Aoki, Nobuyo Narita, Masayuki Shimizu, Nobuhide Ogiwara, Koichi Nakamura, Norio Ishigaki, Hiroyuki Kato, Seiichi Taruta and Morinobu Endo.

Carbon nanotubes (CNTs) possess exceptional mechanical, thermal, and electrical properties, facilitating their use as rein-forcements or additives in various materials to improve the properties of the materials. Furthermore, chemically modified CNTs can introduce novel functionalities. In the medical field, biomaterials are expected to be developed using CNTs for clinical use. Biomaterials often are placed adjacent to bone. The use of CNTs is anticipated in these biomaterials applied to bone mainly to improve their overall mechanical properties, for applications such as high-strength arthroplasty prostheses or fixation plates and screws that will not fail. In addition, CNTs are expected to be used as local drug delivery systems (DDS) and/or scaffolds to promote and guide bone tissue regeneration. However, studies examining the use of CNTs as biomaterials still are in the preliminary stages. In particular, the influence of CNTs on osteoblastic cells or bone tissue is extremely important for the use of CNTs in biomaterials placed in contact with bone, and some studies have explored this. This review paper clarifies the current state of knowledge in the context of the relationship between CNTs and bone to determine whether CNTs might perform in biomaterials in contact with bone, or as a DDS and/or scaffolding for bone regeneration.