Showing papers in "Future Medicinal Chemistry in 2013"
TL;DR: It is expected that in the near future, several boron-containing drugs should become available in the market with better efficacy and potency than existing drugs.
Abstract: Advances in the field of boron chemistry have expanded the application of boron from material use to medicine. Boron-based drugs represent a new class of molecules that possess several biomedical applications including use as imaging agents for both optical and nuclear imaging as well as therapeutic agents with anticancer, antiviral, antibacterial, antifungal and other disease-specific activities. For example, bortezomib (Velcade®), the only drug in clinical use with boron as an active element, was approved in 2003 as a proteasome inhibitor for the treatment of multiple myeloma and non-Hodgkin’s lymphoma. Several other boron-based compounds are in various phases of clinical trials, which illustrates the promise of this approach for medicinal chemists working in the area of boron chemistry. It is expected that in the near future, several boron-containing drugs should become available in the market with better efficacy and potency than existing drugs. This article discusses the current status of the develop...
192 citations
TL;DR: This article attempts to provide an update on recent progress in identification of mitochondria-associated molecules as potential anticancer targets and the respective targeting compounds.
Abstract: Mitochondria are double membrane-enveloped organelles that play a central role in cellular metabolism, calcium homeostasis, redox signaling and cell fates. They function as main generators of ATP, metabolites for the construction of macromolecules and reactive oxygen species. In many cancer cells, mitochondria seem dysfunctional, manifested by a shift of energy metabolism from oxidative phosphorylation to active glycolysis and an increase in reactive oxygen species generation. These metabolic changes are often associated with upregulation of NAD(P)H oxidase. Importantly, the metabolic reprogramming in a cancer cell is mechanistically linked to oncogenic signals. Targeting mitochondria as a cancer therapeutic strategy has attracted much attention in the recent years and multiple review articles in this area have been published. This article attempts to provide an update on recent progress in identification of mitochondria-associated molecules as potential anticancer targets and the respective targeting compounds.
182 citations
TL;DR: 4H-chromenes have strong cytotoxicity against a panel of human cancer cell lines involving pathways that include microtubule depolarization and tumor vasculature disruption.
Abstract: Cancer is a major devastating disease, and is a leading cause of death worldwide Despite the progress in cancer treatment, cancer mortality rate remains high Therefore, the discovery and development of improved anticancer drugs to treat cancer are needed 4H-chromenes have strong cytotoxicity against a panel of human cancer cell lines involving pathways that include microtubule depolarization and tumor vasculature disruption A chromene analog, Crolibulin™ (EPC2407) is currently in Phase I/II clinical trials for the treatment of advanced solid tumors This article reviews the general synthesis, biological activities and structure-activity relatinships of different classes of chromenes
123 citations
TL;DR: The HIF complex acts as a transcription factor for many genes that increase tumor survival and proliferation, and indirectly affects HIF but there have been no clinically approved direct HIF inhibitors.
Abstract: Hypoxia is a significant feature of solid tumor cancers. Hypoxia leads to a more malignant phenotype that is resistant to chemotherapy and radiation, is more invasive and has greater metastatic potential. Hypoxia activates the hypoxia inducible factor (HIF) pathway, which mediates the biological effects of hypoxia in tissues. The HIF complex acts as a transcription factor for many genes that increase tumor survival and proliferation. To date, many HIF pathway inhibitors indirectly affect HIF but there have been no clinically approved direct HIF inhibitors. This can be attributed to the complexity of the HIF pathway, as well as to the challenges of inhibiting protein–protein interactions.
116 citations
TL;DR: DNA binding and in silico studies indicated quite good binding with DNA; requirements for good anticancer drugs.
Abstract: Background: Over the last few decades, metal-based drugs, particularly cisplatin and its analogs have been used for the treatment of various cancers. Currently, scientists are developing other metal complexes as anticancer agents to eliminate the toxicity associated with platinum drugs. Results: Claisen-Schmidt condensation was used to synthesize the pyrazoline-based ligand; (5-(4-chlorophenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide), followed by the synthesis of its complexes with copper(II), nickel(II) and iron(III) metal ions. DNA binding and in silico studies indicated quite good binding with DNA; requirements for good anticancer drugs. Conclusion: DNA binding constants for ligand, copper, nickel and iron complexes were 1.42 × 104, 3.16 × 104, 5.82 × 105 and 6.72 × 105 M-1, respectively, indicating strong binding with DNA. All the reported compounds were slightly hemolytic towards rabbit red blood corpuscles and exhibited moderate activities against MCF-7 cancer cell lines.
112 citations
TL;DR: The activation of prodrugs by the cytochrome P450 system provides a highly versatile approach to prodrug design that is particularly adaptable for targeting drug activation to the liver, to tumors or to hypoxic tissues.
Abstract: A prodrug is a compound that has negligible, or lower, activity against a specified pharmacological target than one of its major metabolites. Prodrugs can be used to improve drug delivery or pharmacokinetics, to decrease toxicity, or to target the drug to specific cells or tissues. Ester and phosphate hydrolysis are widely used in prodrug design because of their simplicity, but such approaches are relatively ineffective for targeting drugs to specific sites. The activation of prodrugs by the cytochrome P450 system provides a highly versatile approach to prodrug design that is particularly adaptable for targeting drug activation to the liver, to tumors or to hypoxic tissues.
108 citations
TL;DR: The regulation and roles of glutamine metabolism within cancer cells are outlined and possible strategies for, and the consequences of, impacting these processes therapeutically are discussed.
Abstract: The metabolic adaptations that support oncogenic growth can also render cancer cells dependent on certain nutrients. Along with the Warburg effect, increased utilization of glutamine is one of the metabolic hallmarks of the transformed state. Glutamine catabolism is positively regulated by multiple oncogenic signals, including those transmitted by the Rho family of GTPases and by c-Myc. The recent identification of mechanistically distinct inhibitors of glutaminase, which can selectively block cellular transformation, has revived interest in the possibility of targeting glutamine metabolism in cancer therapy. Here, we outline the regulation and roles of glutamine metabolism within cancer cells and discuss possible strategies for, and the consequences of, impacting these processes therapeutically.
106 citations
TL;DR: Diverse strategies are discussed within this review, including creating new AGs that are unaffected by AMEs; developing inhibitors of AMEs to be co-delivered with AGs; or regulating AME expression.
Abstract: Shortly after the discovery of the first antibiotics, bacterial resistance began to emerge. Many mechanisms give rise to resistance; the most prevalent mechanism of resistance to the aminoglycoside (AG) family of antibiotics is the action of aminoglycoside-modifying enzymes (AMEs). Since the identification of these modifying enzymes, many efforts have been put forth to prevent their damaging alterations of AGs. These diverse strategies are discussed within this review, including: creating new AGs that are unaffected by AMEs; developing inhibitors of AMEs to be co-delivered with AGs; or regulating AME expression. Modern high-throughput methods as well as drug combinations and repurposing are highlighted as recent drug-discovery efforts towards fighting the increasing antibiotic resistance crisis.
102 citations
101 citations
TL;DR: In this article, insights into the biochemical action of CO are presented and the efficacy of CO and CO-RMs in preclinical disease models are discussed and critically addressed.
Abstract: Since the discovery that CO acts as a cytoprotective and homeostatic molecule, increasing research efforts have been devoted to the exploitation of its therapeutic effects. Both endogenous and exogenous CO improves experimental lung, vascular and cardiac injuries and protects against several inflammatory states. The technology is now in place to bring CO to clinical applications, but the use of the gaseous molecule poses several problems. The challenges associated with the clinical implementation of the gas have in part been answered by the development of CO-releasing molecules (CO-RMs). As stable solid forms of CO, these molecules represent an alternative to the administration of carbon monoxide (orally or by injection). In this article, we present insights into the biochemical action of CO and discuss the efficacy of CO and CO-RMs in preclinical disease models. Recent advances in the CO-RMs field are critically addressed.
100 citations
TL;DR: This review will provide a brief overview of the characteristics and scientific/therapeutic applications of the presently identified small-molecule myosin inhibitors before discussing the future of myOSin inhibitor and activator design.
Abstract: Advances in screening and computational methods have enhanced recent efforts to discover/design small-molecule protein inhibitors. One attractive target for inhibition is the myosin family of motor proteins. Myosins function in a wide variety of cellular processes, from intracellular trafficking to cell motility, and are implicated in several human diseases (e.g., cancer, hypertrophic cardiomyopathy, deafness and many neurological disorders). Potent and selective myosin inhibitors are, therefore, not only a tool for understanding myosin function, but are also a resource for developing treatments for diseases involving myosin dysfunction or overactivity. This review will provide a brief overview of the characteristics and scientific/therapeutic applications of the presently identified small-molecule myosin inhibitors before discussing the future of myosin inhibitor and activator design.
TL;DR: An overview of TCS that are potential targets for such a strategy, small-molecules inhibitors of T CS identified to date are described, and assays for the identification of novel inhibitors are discussed.
Abstract: Infections caused by multidrug-resistant bacteria are a considerable and increasing global problem. The development of new antibiotics is not keeping pace with the rapid evolution of resistance to almost all clinically available drugs, and novel strategies are required to fight bacterial infections. One such strategy is the control of pathogenic behaviors, as opposed to simply killing bacteria. Bacterial two-component system (TCS) signal transduction pathways control many pathogenic bacterial behaviors, such as virulence, biofilm formation and antibiotic resistance and are, therefore, an attractive target for the development of new drugs. This review presents an overview of TCS that are potential targets for such a strategy, describes small-molecules inhibitors of TCS identified to date and discusses assays for the identification of novel inhibitors. The future perspective for the identification and use of inhibitors of TCS to potentially provide new therapeutic options for the treatment of drug-resistant bacterial infections is discussed.
TL;DR: The state-of-art of glutamic acid and its derivatives as anticancer agents is described and the effectivity of drug-delivery systems based on glutamic Acid for the delivery of anticancer drugs is explored.
Abstract: Throughout the history of human civilizations, cancer has been a major health problem. Its treatment has been interesting but challenging to scientists. Glutamic acid and its derivative glutamine are known to play interesting roles in cancer genesis, hence, it was realized that structurally variant glutamic acid derivatives may be designed and developed and, might be having antagonistic effects on cancer. The present article describes the state-of-art of glutamic acid and its derivatives as anticancer agents. Attempts have been made to explore the effectivity of drug-delivery systems based on glutamic acid for the delivery of anticancer drugs. Moreover, efforts have also been made to discuss the mechanism of action of glutamic acid derivatives as anticancer agents, clinical applications of glutamic acid derivatives, as well as recent developments and future perspectives of glutamic acid drug development have also been discussed.
TL;DR: The mechanisms of classical drug resistance and potential drug targets in Leishmania infection are described and the current drug-delivery systems and future perspectives towards Leishmaniasis treatment are covered.
Abstract: Leishmaniasis is a complex of diseases with numerous clinical manifestations for instance harshness from skin lesions to severe disfigurement and chronic systemic infection in the liver and spleen. So far, the most classical leishmaniasis therapy, despite its documented toxicities, remains pentavalent antimonial compounds. The available therapeutic modalities for leishmaniasis are overwhelmed with resistance to leishmaniasis therapy. Mechanisms of classical drug resistance are often related with the lower drug uptake, increased efflux, the faster drug metabolism, drug target modifications and over-expression of drug transporters. The high prevalence of leishmaniasis and the appearance of resistance to classical drugs reveal the demand to develop and explore novel, less toxic, low cost and more promising therapeutic modalities. The review describes the mechanisms of classical drug resistance and potential drug targets in Leishmania infection. Moreover, current drug-delivery systems and future perspectives towards Leishmaniasis treatment are also covered.
TL;DR: The current approaches and limitations of high-throughput screening discovery of hemozoin inhibitors are discussed, and new methods must be developed to validate the mechanism of action of these hit compounds within the malaria parasite.
Abstract: Recent initiatives to develop more effective and affordable drugs, controlling mosquitoes and development of a preventative vaccine have been launched with the goal of completely eradicating malaria. To this end, Novartis (Surrey, UK) and GlaxoSmithKline (Middlesex, UK) screened their chemical libraries of approximately two million small molecules for antimalarial properties, which resulted in a set of over 20,000 ‘highly druggable’ initial hits. Efforts in academia are centered on specific pathway targets. One such high-throughput screening effort has been focused on hemozoin formation, a unique heme detoxification pathway found in the malaria parasite. This review discusses the current approaches and limitations of high-throughput screening discovery of hemozoin inhibitors. In the future, new methods must be developed to validate the mechanism of action of these hit compounds within the parasite.
TL;DR: An overview of the pathophysiology of cholera diarrhea is provided and emerging drug targets for cholERA are discussed, which include V. cholerae virulence factors, V.cholerae motility, CT binding to GM1 receptor, CT internalization and intoxication, as well as cAMP metabolism and transport proteins involved in cAMP-activated Cl(-) secretion.
Abstract: Cholera is a diarrheal disease that remains an important global health problem with several hundreds of thousands of reported cases each year. This disease is caused by intestinal infection with Vibrio cholerae, which is a highly motile gram-negative bacterium with a single-sheathed flagellum. In the course of cholera pathogenesis, V. cholerae expresses a transcriptional activator ToxT, which subsequently transactivates expressions of two crucial virulence factors: toxin-coregulated pilus and cholera toxin (CT). These factors are responsible for intestinal colonization of V. cholerae and induction of fluid secretion, respectively. In intestinal epithelial cells, CT binds to GM1 ganglioside receptors on the apical membrane and undergoes retrograde vesicular trafficking to endoplasmic reticulum, where it exploits endoplasmic reticulum-associated protein degradation systems to release a catalytic A1 subunit of CT (CT A1) into cytoplasm. CT A1, in turn, catalyzes ADP ribosylation of α subunits of stimulatory G proteins, leading to a persistent activation of adenylate cyclase and an elevation of intracellular cAMP. Increased intracellular cAMP in human intestinal epithelial cells accounts for pathogenesis of profuse diarrhea and severe fluid loss in cholera. This review provides an overview of the pathophysiology of cholera diarrhea and discusses emerging drug targets for cholera, which include V. cholerae virulence factors, V. cholerae motility, CT binding to GM1 receptor, CT internalization and intoxication, as well as cAMP metabolism and transport proteins involved in cAMP-activated Cl(-) secretion. Future directions and perspectives of research on drug discovery and development for cholera are discussed.
TL;DR: This review provides an overview of the newly developed hLDH5 inhibitors, with a focus on the small-molecule inhibitors of this enzyme subtype displaying remarkable potencies and selectivities.
Abstract: The latest findings on the role played by human LDH5 (hLDH5) in the promotion of glycolysis in invasive tumor cells indicates that this enzyme subtype is a promising therapeutic target for invasive cancer. Compounds able to selectively inhibit hLDH5 hold promise for the cure of neoplastic diseases. hLDH5 has so far been a rather unexplored target, since its importance in the promotion of cancer progression has been neglected for decades. This enzyme should also be considered as a challenging target due the high polar character (mostly cationic) of its ligand cavity. Recently, significant progresses have been reached with small-molecule inhibitors of hLDH5 displaying remarkable potencies and selectivities. This review provides an overview of the newly developed hLDH5 inhibitors. The roles of hLDH isoforms will be briefly discussed, and then the inhibitors will be grouped into chemical classes. Furthermore, general pharmacophore features will be emphasized throughout the structural subgroups analyzed.
TL;DR: The significance of flavaglines as a new class of pharmacological agents is described and recent developments in their synthesis, structure-activity relationships, identification of their molecular targets and modes of action are presented.
Abstract: Flavaglines are complex natural products that are found in several medicinal plants of Southeast Asia in the genus Aglaia; these compounds have shown exceptional anticancer and cytoprotective activities. This review describes the significance of flavaglines as a new class of pharmacological agents and presents recent developments in their synthesis, structure-activity relationships, identification of their molecular targets and modes of action. Flavaglines display a unique profile of anticancer activities that are mediated by two classes of unrelated proteins: prohibitins and the translation initiation factor eIF4A. The identification of these molecular targets is expected to accelerate advancement toward clinical studies. The selectivity of cytotoxicity towards cancer cells has been shown to be due to an inhibition of the transcription factor HSF1 and an upregulation of the tumor suppressor TXNIP. In addition, flavaglines display potent anti-inflammatory, cardioprotective and neuroprotective activities; however, the mechanisms underlying these activities are yet to be elucidated.
TL;DR: The role of retinal microvasculature complications during progression of DR, along with recent efforts to normalize such alterations for better therapeutic outcome, will be underlined.
Abstract: Retinal microvascular alterations have been observed during diabetic retinopathy (DR) due to the retinal susceptibility towards subtle pathological alterations. Therefore, retinal microvascular pathology is essential to understand the nature of retinal degenerations during DR. In this review, the role of retinal microvasculature complications during progression of DR, along with recent efforts to normalize such alterations for better therapeutic outcome, will be underlined. In addition, current therapeutics and future directions for advancement of standard treatment for DR patients will be discussed.
TL;DR: agents demonstrating utility in Phase III clinical trials, including eribulin, ixabepilone, cabazitaxel and trastuzumab-DM1 will be highlighted, as well as novel agents currently in development and future directions for MTAs.
Abstract: Anticancer drugs directed against the microtubule, including taxanes and vinca alkaloids, have been the backbone of many chemotherapy regimes for decades. These drugs have, however, significant limitations, which have prompted the development of novel microtubule targeting agents (MTAs). This article will discuss MTAs for anticancer therapies and recent debates regarding their mechanisms of action. Furthermore, the limitations of taxanes, including hypersensitivity reactions, neurotoxicity, drug resistance and lack of validated biomarkers to guide therapy will be discussed, all of which have driven the development of novel agents. The mechanisms of action and drug development of new generations of MTAs will also be outlined. Agents demonstrating utility in Phase III clinical trials, including eribulin, ixabepilone, cabazitaxel and trastuzumab-DM1 will be highlighted, as well as novel agents currently in development and future directions for MTAs.
TL;DR: Despite the progress in the development of new antibacterial agents, it is inevitable that resistant strains of bacteria will emerge in response to the widespread use of a particular antibiotic and limit its lifetime.
Abstract: In order to provide effective treatment options for infections caused by multidrug-resistant bacteria, innovative antibiotics are necessary, preferably with novel modes of action and/or belonging to novel classes of drugs. Naturally occurring cyclic lipodepsipeptides, which contain one or more ester bonds along with the amide bonds, have emerged as promising candidates for the development of new antibiotics. Some of these natural products are either already marketed or in advanced stages of clinical development. However, despite the progress in the development of new antibacterial agents, it is inevitable that resistant strains of bacteria will emerge in response to the widespread use of a particular antibiotic and limit its lifetime. Therefore, development of new antibiotics remains our most efficient way to counteract bacterial resistance.
TL;DR: An overview of specific projects that have focused on targeting the parasite's mitochondrial electron transport chain and common barriers to progress and opportunities for novel chemistry and potential additional electron transportChain targets are discussed in the context of the target candidate profiles for uncomplicated malaria.
Abstract: Despite intense efforts, there has not been a truly new antimalarial, possessing a novel mechanism of action, registered for over 10 years. By virtue of a novel mode of action, it is hoped that the global challenge of multidrug-resistant parasites can be overcome, as well as developing drugs that possess prophylaxis and/or transmission-blocking properties, towards an elimination agenda. Many target-based and whole-cell screening drug development programs have been undertaken in recent years and here an overview of specific projects that have focused on targeting the parasite's mitochondrial electron transport chain is presented. Medicinal chemistry activity has largely focused on inhibitors of the parasite cytochrome bc1 Complex (Complex III) including acridinediones, pyridones and quinolone aryl esters, as well as inhibitors of dihydroorotate dehydrogenase that includes triazolopyrimidines and benzimidazoles. Common barriers to progress and opportunities for novel chemistry and potential additional electron transport chain targets are discussed in the context of the target candidate profiles for uncomplicated malaria.
TL;DR: The impact of post-translational modifications and co-chaperones on the efficacy of Hsp90 inhibitors are reviewed.
Abstract: Hsp90 is a molecular chaperone and important driver of stabilization and activation of several oncogenic proteins that are involved in the malignant transformation of tumor cells. Therefore, it is not surprising that Hsp90 has been reported to be a promising target for the treatment of several neoplasias, such as non-small-cell lung cancer and HER2-positive breast cancer. Hsp90 chaperone function depends on its ability to bind and hydrolyze ATP and Hsp90 inhibitors have been shown to compete with nucleotides for binding to Hsp90. Multiple factors, such as co-chaperones and post-translational modification, are involved in regulating Hsp90 ATPase activity. Here, the impact of post-translational modifications and co-chaperones on the efficacy of Hsp90 inhibitors are reviewed.
TL;DR: The medicinal potential of cap analogs in areas, such as cancer treatment, spinal muscular atrophy treatment, antiviral therapy and the improvement of the localization of nucleus-targeting drugs, are highlighted.
Abstract: Cap analogs are chemically modified derivatives of the unique cap structure present at the 5´ end of all eukaryotic mRNAs and several non-coding RNAs. Until recently, cap analogs have served primarily as tools in the study of RNA metabolism. Continuing advances in our understanding of cap biological functions (including RNA stabilization, pre-mRNA splicing, initiation of mRNA translation, as well as cellular transport of mRNAs and snRNAs) and the consequences of the disruption of these processes - resulting in serious medical disorders - have opened new possibilities for pharmaceutical applications of these compounds. In this review, the medicinal potential of cap analogs in areas, such as cancer treatment (including eIF4E targeting and mRNA-based immunotherapy), spinal muscular atrophy treatment, antiviral therapy and the improvement of the localization of nucleus-targeting drugs, are highlighted. Advances achieved to date, challenges, plausible solutions and prospects for the future development of cap analog-based drug design are described.
TL;DR: The extended antimicrobial activity, lack of plasmid-mediated resistance, large volume of distribution and minimal adverse effects of CP are therapeutically advantageous.
Abstract: Ciprofloxacin (CP) is a fluoroquinolone that is highly active against diverse microorganisms. At concentrations less than 1 µg/ml it is active against a diverse types of bacteria, including Staphylococcus aureus, Staphylococcus epidermidis, Bacillius subtilius, Escherichia coli and Mycobacterium tuberculosis. In addition, it has shown to be effective against other diseases such as malaria, cancer and AIDS. The extended antimicrobial activity, lack of plasmid-mediated resistance, large volume of distribution and minimal adverse effects of CP are therapeutically advantageous. In the pursuit of increasing their effectiveness against these diseases and prevent unwanted resistance, researchers have begun to synthesize a class of organic, inorganic and organometallic derivatives, which have displayed interesting activities. This review describes the development and recent advances on the evaluation of CP and its derivatives as a new class of drugs with potential for clinical development.
TL;DR: A structural approach is taken to outline some of the more promising MBL inhibitors and shed light on how the resistance conferred by this emerging class of enzymes may be circumvented in the future.
Abstract: The β-lactam antibiotics are essential for the treatment of a wide range of human bacterial diseases. However, a class of zinc-dependent hydrolases known as the metallo-β-lactamase (MBL) can confer bacteria with extended spectrum β-lactam resistance. To date, there are no clinically approved MBL inhibitors, making these enzymes a serious threat to human health. In this review, a structural approach is taken to outline some of the more promising MBL inhibitors and shed light on how the resistance conferred by this emerging class of enzymes may be circumvented in the future.
TL;DR: This review highlights the promise of peptide anti-infectives as the next generation of therapeutics and summarizes the challenges faced in, and lessons learned from, the past.
Abstract: Synthesis and large-scale manufacturing technologies are now available for the commercial production of even the most complex peptide anti-infectives. Married with the potential of this class of molecule as the next generation of effective, resistance-free and safe antimicrobials, and a much better understanding of their biology, pharmacology and pharmacodynamics, the first regulatory approvals and introduction into clinical practice of these promising drug candidates will likely be soon. This is a key juncture in the history/life cycle of peptide anti-infectives and, perhaps, their commercial and therapeutic potential is about to be realized. This review highlights the promise of these agents as the next generation of therapeutics and summarizes the challenges faced in, and lessons learned from, the past.
TL;DR: This review exhibits many anticancer ceramide analogs as downstream receptor agonists and ceramide-metabolizing enzyme inhibitors for anticancer strategy selection.
Abstract: Ceramide serves as a central mediator in sphingolipid metabolism and signaling pathways, regulating many fundamental cellular responses. It is referred to as a ‘tumor suppressor lipid’, since it powerfully potentiates signaling events that drive apoptosis, cell cycle arrest, and autophagic responses. In the typical cancer cell, ceramide levels and signaling are usually suppressed by overexpression of ceramide-metabolizing enzymes or downregulation of ceramide-generating enzymes. However, chemotherapeutic drugs as well as radiotherapy increase intracellular ceramide levels, while exogenously treating cancer cells with short-chain ceramides leads to anticancer effects. All evidence currently points to the fact that the upregulation of ceramide levels is a promising anticancer strategy. In this review, we exhibit many anticancer ceramide analogs as downstream receptor agonists and ceramide-metabolizing enzyme inhibitors.
TL;DR: The cAMP signaling system can trigger precise physiological cellular responses that depend on the fidelity of many protein-protein interactions, which act to bring together signaling intermediates at defined locations within cells.
Abstract: The cAMP signaling system can trigger precise physiological cellular responses that depend on the fidelity of many protein–protein interactions, which act to bring together signaling intermediates at defined locations within cells. In the heart, cAMP participates in the fine control of excitation–contraction coupling, hence, any disregulation of this signaling cascade can lead to cardiac disease. Due to the ubiquitous nature of the cAMP pathway, general inhibitors of cAMP signaling proteins such as PKA, EPAC and PDEs would act non-specifically and universally, increasing the likelihood of serious ‘off target’ effects. Recent advances in the discovery of peptides and small molecules that disrupt the protein–protein interactions that underpin cellular targeting of cAMP signaling proteins are described and discussed.
TL;DR: The structural data presented in this review show that TR also should be considered as a good target, because it is strongly inhibited by silver- and gold-containing compounds, which are active against Leishmania parasites and can be used for the development of novel antileishmanial agents.
Abstract: Leishmaniasis is a neglected disease that kills 60,000 people worldwide, and which is caused by the protozoa Leishmania. The enzymes of the trypanothione pathway: trypanothione synthetase-amidase, trypanothione reductase (TR) and tryparedoxin-dependent peroxidase are absent in human hosts, and are essential for parasite survival and druggable. The most promising target is trypanothione synthetase-amidase, which has been also chemically validated. However, the structural data presented in this review show that TR also should be considered as a good target. Indeed, it is strongly inhibited by silver- and gold-containing compounds, which are active against Leishmania parasites and can be used for the development of novel antileishmanial agents. Moreover, TR trypanothione-binding site is not featureless but contains a sub-pocket where inhibitors bind, potentially useful for the design of new lead compounds.