Current Medicinal Chemistry (v.18, #3)
Quassinoids: From Traditional Drugs to New Cancer Therapeutics by G. Fiaschetti, M. A. Grotzer, T. Shalaby, D. Castelletti, A. Arcaro (316-328).
Quassinoids are a group of compounds extracted from plants of the Simaroubaceae family, which have been used for many years in folk medicine. These molecules gained notoriety after the initial discovery of the anti-leukemic activity of one member, bruceantin, in 1975. Currently over 150 quassinoids have been isolated and classified based on their chemical structures and biological properties investigated in vitro and in vivo. Many molecules display a wide range of inhibitory effects, including anti-inflammatory, anti-viral, anti-malarial and anti-proliferative effects on various tumor cell types. Although often the exact mechanism of action of the single agents remains unclear, some agents have been shown to affect protein synthesis in general, or specifically HIF-1and#945; and MYC, membrane polarization and the apoptotic machinery. Considering that future research into chemical modifications is likely to generate more active and less toxic derivatives of natural quassinoids, this family represents a powerful source of promising small molecules targeting key prosurvival signaling pathways relevant for diverse pathologies. Here, we review available knowledge of functionality and possible applications of quassinoids and quassinoid derivatives, spanning traditional use to the potential impact on modern medicine as cancer therapeutics.
Drug Transporters in Chemotherapy Induced Peripheral Neurotoxicity:Current Knowledge and Clinical Implications by C. Ceresa, G. Cavaletti (329-341).
Several antineoplastic drugs induce severe and dose-limiting peripheral neurotoxicity that can significatly affect the quality of life of cancer patients and cause chronic discomfort. Despite extensive investigation, the fine mechanisms of this side-effect remain unclear. It has recently been suggested that several classes of drug transporters are involved in the genesis of chemotherapyinduced peripheral neurotoxicity. Furthermore, the differential distribution and activity of these transporters could also explain the higher sensitivity of the peripheral rather than central nervous system tissues to the toxic action of the anticancer agents. These observations may have important therapeutic implications. In fact, the characterization of the proteins that mediate significant transport of clinically relevant drugs in the nervous system, and the understanding of their changes in the different pathological conditions are important in order to elucidate pathogenetic mechanisms and to identify new potential therapeutic targets so as to limit the severity of chemotherapy-induced peripheral neurotoxicity. This review will be focused on the most recent research progress on the role of drug transporters in chemotherapy-induced peripheral neurotoxicity, and we will discuss the possibility of targeting these transporters as a new and interesting potential strategy for the treatment of the neurotoxic side-effects of antineoplastic drugs.
Novel, Selective CDK9 Inhibitors for the Treatment of HIV Infection by G. Nemeth, Z. Varga, Z. Greff, G. Bencze, A. Sipos, C. Szantai-Kis, F. Baska, A. Gyuris, K. Kelemenics, Z. Szathmary, J. Minarovits, G. Keri, L. Orfi (342-358).
Cyclin Dependent Kinases (CDKs) are important regulators of cell cycle and gene expression. Since an up-todate review about the pharmacological inhibitors of CDK family (CDK1-10) is not available; therefore in the present paper we briefly summarize the most relevant inhibitors and point out the low number of selective inhibitors. Among CDKs, CDK9 is a validated pathological target in HIV infection, inflammation and cardiac hypertrophy; however selective CDK9 inhibitors are still not available. We present a selective inhibitor family of CDK9 based on the 4-phenylamino-6- phenylpyrimidine nucleus. We show a convenient synthetic method to prepare a useful intermediate and its derivatisation resulting in novel compounds. The CDK9 inhibitory activity of the derivatives was measured in specific kinase assay and the CDK inhibitory profile of the best ones (IC50 > 100nM) was determined. The most selective compounds had high selectivity over CDK1, 2, 3, 5, 6, 7 and showed at least one order of magnitude higher inhibitory activity over CDK4 inhibition. The most selective molecules were examined in cytotoxicity assays and their ability to inhibit HIV-1 replication was determined in cellular assays.
Recent Advances in DAPYs and Related Analogues as HIV-1 NNRTIs by Xuwang Chen, Peng Zhan, Dongyue Li, Erik De Clercq, Xinyong Liu (359-376).
HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) nowadays represent most promising anti- AIDS drugs that specifically inhibit HIV-1 reverse transcriptase (RT). They have a unique antiviral potency, high specificity and low cytotoxicity. However, to a great extent, the efficacy of HIV-1 NNRTIs is compounded by rapid emergence of drug resistant virus strains, which calls for continuous efforts to develop novel HIV-1 NNRTIs. Diarylpyrimidine (DAPY) derivatives, one family of NNRTIs with superior activity profiles against wild-type HIV-1 and mutant strains, have attracted considerable attention over the past few years. Among the potent lead DAPY compounds, etravirine was approved by FDA in January 2008, and its analogue rilpivirine (TMC278) has advanced to phase III clinical trials. The successful development of DAPYs results from a multidisciplinary approach involving traditional medicinal chemistry, structural biology, crystallography and computational chemistry. Recently, a number of novel characteristics of DAPYs including conformational flexibility, positional adaptability, key hydrogen bonds and specifically targeting conserved residues of RT, have been identified, providing valuable avenues for further optimization and development of new DAPY analogues as promising anti-HIV drug candidates. In this review, we first present a brief historical account of the medicinal chemistry of the DAPY NNRTIs, then focus on the extensive structural modifications, SAR studies, and binding mode analysis based on crystallographic and molecular modeling. Other structural related NNRTI scaffolds will also be reviewed.
Voltage-Gated Sodium Channels: Mutations, Channelopathies and Targets by G. S.B. Andavan, R. Lemmens-Gruber (377-397).
Voltage-gated sodium channels produce fast depolarization, which is responsible for the rising phase of the action potential in neurons, muscles and heart. These channels are very large membrane proteins and are encoded by ten genes in mammals. Sodium channels are a crucial component of excitable tissues; hence, they are a target for various neurotoxins that are produced by plants and animals for defence and protection, such as tetrodotoxin, scorpion toxins and batrachotoxin. Several mutations in various sodium channel subtypes cause multiple inherited diseases known as channelopathies. When these mutated sodium channel subtypes are expressed in various tissues, channelopathies in brain, skeletal muscle and cardiac muscle develop as well as neuropathic pain. In this review, we discuss aspects of voltage-gated sodium channel genes with an emphasis on cardiac muscle sodium channels. In addition, we report novel mutations that underlie a spectrum of diseases, such as Brugada, long QT syndrome and inherited conduction disorders. Furthermore, this review explains commonalities and differences among the channel subtypes, the channelopathies caused by the sodium channel gene mutation and the specificity of toxins and blockers of the channel subtypes.
Intestinal Epithelial Barrier Dysfunction in Disease and Possible Therapeutical Interventions by R.-M. Catalioto, C. A. Maggi, S. Giuliani (398-426).
The intestinal epithelial monolayer constitutes a physical and functional barrier between the organism and the external environment. It regulates nutrients absorption, water and ion fluxes, and represents the first defensive barrier against toxins and enteric pathogens. Epithelial cells are linked together at the apical junctional complex by tight junctions that reduce the extracellular space and the passage of charge entities while forming a physical barrier to lipophilic molecules. Cultured intestinal epithelial cells have been extensively used to study intestinal absorption of newly synthesized drugs and the regulation of tight junctions structure and function. In vitro mild irritants, proinflammatory cytokines, toxins and pathogens, and adverse environmental conditions open tight junctions and increase paracellular permeability, an effect often accompanied by immune activation of the enterocytes. Conversely, inhibition of proinflammatory cytokines, exposure to growth factors and probiotics, among others, exert a protective effect. Impaired barrier function results from activation of signalling pathways that lead to alteration of junctional proteins expression and/or distribution. In vivo, intestinal barrier dysfunction is associated with various intestinal and non-intestinal disorders including inflammatory bowel disease, celiac disease, and diarrhoeal infection. This review will describe the current knowledge of the mechanisms regulating tight junctions and intestinal permeability, how these findings have lead to a better understanding of barrier alteration in human intestinal disorders, and what the emerging therapies to treat these pathologies are.
The Role of the Cytochrome P450 Polymorphisms in Clopidogrel Efficacy and Clinical Utility by D. Tousoulis, G. Siasos, M. Zaromytidou, N. Papageorgiou, E. Stefanadi, E. Oikonomou, C. Stefanadis (427-438).
Clopidogrel, an antiplatelet agent, prevents platelet aggregation by inhibiting the adenosine disphosphate (ADP) P2Y12 receptor, which is located on the platelet surface. Although dual antiplatelet therapy appears to be efficient, a considerable number of patients continue to experience adverse cardiovascular events, such as stent thrombosis. The percentage of low response to antiplatelet therapy varies from 4and#x25; to 30and#x25; of patients depending on the cut-off values. In addition, several factors such as poor absorption, drug-to-drug interactions, inadequate dosing, elevated body mass index, insulin resistance and the nature of acute coronary syndromes have been implicated in low clopidogrel response. Recently, studies have focused on the role of genetic polymorphisms encoding enzymes that participate in clopidogrel hepatic metabolism or receptors involved in intestinal absorption and ADP induced platelet aggregation, which may affect the percentage of platelet inhibition after clopidogrel administration. The management of clopidogrel resistance remains a controversial issue and additional studies are required to evaluate the safety and efficacy of increased loading of clopidogrel or replacement with other new antiplatelet agents such as prasugrel.
Structural and Functional Properties of Human Multidrug Resistance Protein 1 (MRP1/ABCC1) by S.-M. He, R. Li, J. R. Kanwar, S.-F. Zhou (439-481).
Multidrug ABC transporters such as P-glycoprotein (P-gp/MDR1/ABCB1) and multidrug resistance protein 1 (MRP1/ABCC1) play an important role in the extrusion of drugs from the cell and their overexpression can be a cause of failure of anticancer and antimicrobial chemotherapy. Recently, the mouse P-gp/Abcb1a structure has been determined and this has significantly enhanced our understanding of the structure-activity relationship (SAR) of mammalian ABC transporters. This paper highlights our current knowledge on the structural and functional properties and the SAR of human MRP1/ABCC1. Although the crystal structure of MRP1/ABCC1 has yet to be resolved, the current topological model of MRP1/ABCC1 contains two transmembrane domains (TMD1 and TMD2) each followed by a nucleotide binding domain (NBD) plus a third NH2-terminal TMD0. MRP1/ABCC1 is expressed in the liver, kidney, intestine, brain and other tissues. MRP1/ABCC1 transports a structurally diverse array of important endogenous substances (e.g. leukotrienes and estrogen conjugates) and xenobiotics and their metabolites, including various conjugates, anticancer drugs, heavy metals, organic anions and lipids. Cells that highly express MRP1/ABCC1 confer resistance to a variety of natural product anticancer drugs such as vinca alkaloids (e.g. vincristine), anthracyclines (e.g. etoposide) and epipodophyllotoxins (e.g. doxorubicin and mitoxantrone). MRP1/ABCC1 is associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. However, most compounds that efficiently reverse P-gp/ABCB1-mediated multidrug resistance have only low affinity for MRP1/ABCC1 and there are only a few effective and relatively specific MRP1/ABCC1 inhibitors available. A number of site-directed mutagenesis studies, biophysical and photolabeling studies, SAR and QSAR, molecular docking and homology modeling studies have documented the role of multiple residues in determining the substrate specificity and inhibitor selectivity of MRP1/ABCC1. Most of these residues are located in the TMs of TMD1 and TMD2, in particular TMs 4, 6, 7, 8, 10, 11, 14, 16, and 17, or in close proximity to the membrane/cytosol interface of MRP1/ABCC1. The exact transporting mechanism of MRP1/ABCC1 is unclear. MRP1/ABCC1 and other multidrug transporters are front-line mediators of drug resistance in cancers and represent important therapeutic targets in future chemotherapy. The crystal structure of human MRP1/ABCC1 is expected to be resolved in the near future and this will provide an insight into the SAR of MRP1/ABCC1 and allow for rational design of anticancer drugs and potent and selective MRP1/ABCC1 inhibitors.