Current Medicinal Chemistry (v.17, #25)
Turning Tumor-Promoting Copper into an Anti-Cancer Weapon via High-Throughput Chemistry by F. Wang, P. Jiao, M. Qi, M. Frezza, Q.P. Dou, B. Yan (2685-2698).
Copper is an essential element for multiple biological processes. Its concentration is elevated to a very high level in cancer tissues for promoting cancer development through processes such as angiogenesis. Organic chelators of copper can passively reduce cellular copper and serve the role as inhibitors of angiogenesis. However, they can also actively attack cellular targets such as proteasome, which plays a critical role in cancer development and survival. The discovery of such molecules initially relied on a step by step synthesis followed by biological assays. Today high-throughput chemistry and high-throughput screening have significantly expedited the copper-binding molecules discovery to turn and#x201C;cancer-promotingand#x201D; copper into anti-cancer agents.
The Scatter Factor Signaling Pathways as Therapeutic Associated Target in Cancer Treatment by P. Accornero, L.M. Pavone, M. Baratta (2699-2712).
Receptor tyrosine kinases (RTKs) are key regulators of critical cellular processes such as proliferation, differentiation, neo-vascularization, and tissue repair. In addition to their importance in the regulation of normal physiology, aberrant expression of certain RTKs has also been associated to the development and progression of many types of cancer. c-Met and RON are two RTKs with closely related sequences, structural homology, and similar functional properties. Both these receptors, once activated by their respective ligands, the Hepatocyte Growth Factor/Scatter Factor (HGF/SF1) and the Macrophage Stimulating Protein/Scatter Factor 2 (MSP/SF2), can induce cell migration, invasion and proliferation. Soon after its discovery in the mid-1980s, c-Met attracted a great interest because of its role in modulating cell motility. Moreover, the causal role for c-Met activating mutations in human cancer propelled an intensive drug discovery effort throughout academic institutions and pharmaceutical companies. While c-Met is now a well-accepted target for anticancer drug design, less is known about the role of RON in cancer and less has been done to target this receptor. In this review we will discuss the biological relevance of c-Met and RON, their deregulation in human cancers and the progress, so far, in identifying c-Met and RON signaling inhibitors. Finally, we will focus on the development of therapeutic strategies and drug efficacy studies based on interfering the scatter factor signaling pathways.
Targeting Death Receptors to Fight Cancer: From Biological Rational to Clinical Implementation by S. Mocellin (2713-2728).
Considering that most currently available chemotherapeutic drugs work by inducing cell apoptosis, it is not surprising that many expectations in cancer research come from the therapeutic exploitation of the naturally occurring death pathways. Receptor mediated apoptosis depends upon the engagement of specific ligands with their respective membrane receptors and - within the frame of complex regulatory networks - modulates some key physiological and pathological processes such as lymphocyte survival, inflammation and infectious diseases. A pivotal observation was that some of these pathways may be over activated in cancer under particular circumstances, which opened the avenue for tumor- specific therapeutic interventions. Although one death-related ligand (e.g., tumor necrosis factor, TNF) is currently the basis of effective anticancer regimens in the clinical setting, the systemic toxicity is hampering its wide therapeutic exploitation. However, strategies to split the therapeutic from the toxic TNF activity are being devised. Furthermore, other death receptor pathways (e.g., Fas/FasL, TRAIL/TRAIL receptor) are being intensively investigated in order to therapeutically exploit their activity against cancer. This article summarizes the current knowledge on the molecular features of death receptor pathways that make them an attractive target for anticancer therapeutics. In addition, the results so far obtained in the clinical oncology setting as well as the issues to be faced while interfering with these pathways for therapeutic purposes will be overviewed.
Organometallic Complexes: New Tools for Chemotherapy by N. Chavain, C. Biot (2729-2745).
The importance of organometallics can be noticed by their presence in all life organisms. The most known natural organometallic molecule is vitamin B12, a porphyrin containing a cobalt atom, useful for several enzymatic transformations. Based on the remarkable properties of this class of compounds, a new area of medicinal research was developed. Gerard Jaouen was the first to introduce the term of and#x201C;bioorganometallic chemistryand#x201D; in 1985 although the first organometallic therapeutical was Salvarsanand#174;, discovered by Paul Ehrlich (Nobel Prize in Medicine in 1908). Bioorganometallic chemistry consists of the synthesis and the study of organometallic complexes, complexes with at least one metal-carbon bond, in a biological and medicinal interest. This field of research was accentuated by the discovery of the ferrocene in 1951 by Pauson and Kealy, confirmed in 1952 by Wilkinson (Nobel Prize in 1973). Today, bioorganometallic chemistry includes 5 main domains: (1) organometallic therapeuticals, (2) toxicology and environment, (3) molecular recognition in aqueous phases, (4) enzymes, proteins and peptides, (5) bioanalysis and pharmaceutical sensors. In this review, we focused on organometallic therapeuticals. The exceptional properties of organometallics are first described and then, an overview on the main organometallic complexes used for drug design is presented. This review gives an idea how organometallics can be used for the rational design of new drugs.
Involvement of Cytosolic Phospholipase A2, Calcium Independent Phospholipase A2 and Plasmalogen Selective Phospholipase A2 in Neurodegenerative and Neuropsychiatric Conditions by W.-Y. Ong, T. Farooqui, A.A. Farooqui (2746-2763).
Enzymes belonging to the PLA2 superfamily catalyze the hydrolysis of unsaturated fatty acids from the sn-2 position of glycerol moiety of neural membrane phospholipids. The PLA2 superfamily is classified into cytosolic PLA2 (cPLA2), calcium-independent PLA2 (iPLA2), plasmalogen-selective PLA2 (PlsEtn-PLA2) and secretory PLA2 (sPLA2). PLA2 paralogs/splice variants/isozymes are part of a complex signal transduction network that maintains cross-talk among excitatory amino acid and dopamine receptors through the generation of second messengers. Individual paralogs, splice variants and multiple forms of PLA2 may have unique enzymatic properties, tissue and subcellular localizations and roles in various physiological and pathological situations, hence tight regulation of all PLA2 isoforms is essential for normal brain function. Quantitative RT-PCR analyses show significantly higher expression of iPLA2 than cPLA2 in all regions of the rat brain. Upregulation of the cPLA2 family is involved in degradation of neural membrane phospholipids and generation of arachidonic acid-derived lipid metabolites that have been implicated in nociception, neuroinflammation, oxidative stress and neurodegeneration. In contrast, studies using a selective iPLA2 inhibitor, bromoenol lactone, or antisense oligonucleotide indicate that iPLA2 is an important and#x201C;housekeepingand#x201D; enzyme under normal conditions, whose activity is required for the prevention of vacuous chewing movements, and deficits in prepulse inhibition of the auditory startle reflex, a finding in human patients with schizophrenia. These studies support the view that PLA2 activity may not only play a crucial role in neurodegeneration, but depending on the isoform, could also be essential in prevention of neuropsychiatric diseases. These findings could open new doors for understanding and treatment of neurodegenerative and neuropsychiatric diseases.
New Therapeutic Strategy for Parkinson's and Alzheimer's Disease by E. Esposito, S. Cuzzocrea (2764-2774).
The development of potential neuroprotective therapies for neurodegenerative diseases (Parkinson's and Alzheimer's Disease) must be based on understanding their molecular and biochemical pathogenesis. Many potential pathways of neuronal cell death have been implicated in a mouse model of neurodegenerative disease, including excitotoxicity, toxicity from reactive oxygen species (superoxide anion, nitric oxide, hydroxyl radical), apoptosis (caspase-dependent and -independent pathways), necrosis and glial injury. Some agents that act on these pathways may be available for protecting the brain against chronic neurodegenerative conditions like Parkinson's and Alzheimer's disease. Drugs currently used to treat neurological disease and injuries provide temporary relief of symptoms but do not stop or slow the underlying neurodegenerative process. Restorative therapies for Parkinson's Disease are currently focused on cell replacement and administration of growth factors and small-molecule neurotrophic agents. The new experimental drugs, by contrast, target the common, underlying cause of destructive process of brain cell death. For example, p53 inhibitors attack a key protein involved in nerve cell death and represent a new strategy for preserving brain function following sudden injury or chronic disease. Analogues of pifithrin-alpha (PFT), which was shown in previous studies to inhibit p53, were designed, synthesized and tested to see whether they would work against cultured brain cells and animal models of neurodegenerative disease. Moreover, several agents based on the predominant anti-amyloid strategy, targeting amyloid-beta (Aand#946;) peptide, which aggregates in the plaques that are a hallmark of Alzheimer's disease, would affect disease progression. Researchers are already making great strides in developing a vaccine for this progressive brain disorder. Immunization could offer a way to blunt or even prevent the deadly, memory-robbing disease. Here we review many of potential neuroprotective therapies, and strategies that might be suited to the development of innovative approaches that prevent degeneration and restore function in Parkinson's disease.
Synthesis and Preliminary Screening of Novel Tryptamines as 5-HT4 Receptor Ligands by A. Hanna-Elias, D.T. Manallack, I. Berque-Bestel, H.R. Irving, I.M. Coupar, M.N. Iskander (2775-2787).
For the development of novel 5-HT4 receptor ligands we have designed and synthesized two series of 5- methoxytryptamine derivatives varying the substitution on the primary amine. Their biological activities were evaluated in a receptor binding assay where a subset of compounds showed comparable potency to the agonists serotonin and 5- methoxytryptamine. Structure-activity analyses have highlighted promising avenues for further synthetic work and binding modes were proposed by docking these compounds into a homology model of the 5-HT4 receptor.
Studies of Benzothiadiazine Derivatives as Hepatitis C Virus NS5B Polymerase Inhibitors Using 3D-QSAR, Molecular Docking and Molecular Dynamics by X. Wang, W. Yang, X. Xu, H. Zhang, Y. Li, Y. Wang (2788-2803).
In order to explore the structure-activity correlation of benzothiadiazine series as inhibitors of genotype 1a HCV polymerase, a set of ligand- and receptor-based 3D-QSAR models were, for the first time, developed in the present work employing Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) for 239 promising molecules. In addition, homology modeling, docking analysis, and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these inhibitors at the allosteric site of the enzyme. The statistical model validations assure the reliability of the obtained QSAR models. Changes in the binding affinity of the inhibitors attributing to modifications in the aromatic rings could be rationalized by the steric, electrostatic, hydrophobic, and hydrogen bond acceptor properties. (i) Hydrophobic substituents with similar size of benzo group like isosteres are preferential at positions 1 and 2 (ring B of benzothiadiazines). (ii) Substituents at position-3 containing a linear alkyl chain (four or five carbon atoms) or a branched alkyl chain (five-eight carbons) can increase the inhibitory activity by one to two orders of magnitude. (iii) A polar substituent like methanesulfonamide group at position-14 can enhance the activity of the drug by providing a hydrogen bonding interaction with the protein target. The results obtained from this work provide important guidelines in design of novel benzothiadiazine analogs as inhibitors of HCV genotype 1a NS5B.
Non-ATP Competitive Protein Kinase Inhibitors by L. Garuti, M. Roberti, G. Bottegoni (2804-2821).
Protein kinases represent an attractive target in oncology drug discovery. Most of kinase inhibitors are ATP-competitive and are called type I inhibitors. The ATP-binding pocket is highly conserved among members of the kinase family and it is difficult to find selective agents. Moreover, the ATP-competitive inhibitors must compete with high intracellular ATP levels leading to a discrepancy between IC50s measured by biochemical versus cellular assays. The non-ATP competitive inhibitors, called type II and type III inhibitors, offer the possibility to overcome these problems. These inhibitors act by inducing a conformational shift in the target enzyme such that the kinase is no longer able to function. In the DFG-out form, the phenylalanine side chain moves to a new position. This movement creates a hydrophobic pocket available for occupation by the inhibitor. Some common features are present in these inhibitors. They contain a heterocyclic system that forms one or two hydrogen bonds with the kinase hinge residue. They also contain a hydrophobic moiety that occupies the pocket formed by the shift of phenylalanine from the DFG motif. Moreover, all the inhibitors bear a hydrogen bond donor-acceptor pair, usually urea or amide, that links the hinge-binding portion to the hydrophobic moiety and interacts with the allosteric site. Examples of non ATP-competitive inhibitors are available for various kinases. In this review small molecules capable of inducing the DFG-out conformation are reported, especially focusing on structural feature, SAR and biological properties.
Medicinal Chemistry of ATP Synthase: A Potential Drug Target of Dietary Polyphenols and Amphibian Antimicrobial Peptides by Zulfiqar Ahmad, Thomas F. Laughlin (2822-2836).
In this review we discuss the inhibitory effects of dietary polyphenols and amphibian antimicrobial/antitumor peptides on ATP synthase. In the beginning general structural features highlighting catalytic and motor functions of ATP synthase will be described. Some details on the presence of ATP synthase on the surface of several animal cell types, where it is associated with multiple cellular processes making it an interesting drug target with respect to dietary polyphenols and amphibian antimicrobial peptides will also be reviewed. ATP synthase is known to have distinct polyphenol and peptide binding sites at the interface of and#945;/and#946; subunits. Molecular interaction of polyphenols and peptides with ATP synthase at their respective binding sites will be discussed. Binding and inhibition of other proteins or enzymes will also be covered so as to understand the therapeutic roles of both types of molecules. Lastly, the effects of polyphenols and peptides on the inhibition of Escherichia coli cell growth through their action on ATP synthase will also be presented.