ChemMedChem

Transthyretin Mimetics as Anti‐β‐Amyloid Agents: A Comparison of Peptide and Protein Approaches ()
Abstract β‐Amyloid (Aβ) aggregation is causally linked to neuronal pathology in Alzheimer's disease; therefore, several small molecules, antibodies, and peptides have been tested as anti‐Aβ agents. We developed two compounds based on the Aβ‐binding domain of transthyretin (TTR): a cyclic peptide cG8 and an engineered protein mTTR, and compared them for therapeutically relevant properties. Both mTTR and cG8 inhibit fibrillogenesis of Aβ, with mTTR inhibiting at a lower concentration than cG8. Both inhibit aggregation of amylin but not of α‐synuclein. They both bind more Aβ aggregates than monomer, and neither disaggregates preformed fibrils. cG8 retained more of its activity in the presence of biological materials and was more resistant to proteolysis than mTTR. We examined the effect of mTTR or cG8 on Aβ binding to human neurons. When mTTR was co‐incubated with Aβ under oligomer‐forming conditions, Aβ morphology was drastically changed and Aβ‐cell deposition significantly decreased. In contrast, cG8 did not affect morphology but decreased the amount of Aβ deposited. These results provide guidance for further evolution of TTR‐mimetic anti‐amyloid agents.
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Potent Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold ()
Abstract With the discovery that serine hydroxymethyltransferase (SHMT) is a druggable target for antimalarials, the aim of this study was to design novel inhibitors of this key enzyme in the folate biosynthesis cycle. Herein, 19 novel spirocyclic ligands based on either 2‐indolinone or dihydroindene scaffolds and featuring a pyrazolopyran core are reported. Strong target affinities for Plasmodium falciparum (Pf) SHMT (14–76 nm) and cellular potencies in the low nanomolar range (165–334 nm) were measured together with interesting selectivity against human cytosolic SHMT1 (hSHMT1). Four co‐crystal structures with Plasmodium vivax (Pv) SHMT solved at 2.2–2.4 Å resolution revealed the key role of the vinylogous cyanamide for anchoring ligands within the active site. The spirocyclic motif in the molecules enforces the pyrazolopyran core to adopt a substantially more curved conformation than that of previous non‐spirocyclic analogues. Finally, solvation of the spirocyclic lactam ring of the receptor‐bound ligands is discussed.
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Synthesis, Structure–Activity Relationship Studies, and ADMET Properties of 3‐Aminocyclohex‐2‐en‐1‐ones as Chemokine Receptor 2 (CXCR2) Antagonists ()
Abstract Herein we describe the synthesis and structure–activity relationships of 3‐aminocyclohex‐2‐en‐1‐one derivatives as novel chemokine receptor 2 (CXCR2) antagonists. Thirteen out of 44 derivatives were found to inhibit CXCR2 downstream signaling in a Tango assay specific for CXCR2, with IC50 values less than 10 μm. In silico ADMET prediction suggests that all active compounds possess drug‐like properties. None of these compounds show significant cytotoxicity, suggesting their potential application in inflammatory mediated diseases. A structure–activity relationship (SAR) map has been generated to gain better understanding of their binding mechanism to guide further optimization of these new CXCR2 antagonists.
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Antibody Epitope of Human α‐Galactosidase A Revealed by Affinity Mass Spectrometry: A Basis for Reversing Immunoreactivity in Enzyme Replacement Therapy of Fabry Disease ()
Abstract α‐Galactosidase (αGal) is a lysosomal enzyme that hydrolyses the terminal α‐galactosyl moiety from glycosphingolipids. Mutations in the encoding genes for αGal lead to defective or misfolded enzyme, which results in substrate accumulation and subsequent organ dysfunction. The metabolic disease caused by a deficiency of human α‐galactosidase A is known as Fabry disease or Fabry–Anderson disease, and it belongs to a larger group known as lysosomal storage diseases. An effective treatment for Fabry disease has been developed by enzyme replacement therapy (ERT), which involves infusions of purified recombinant enzyme in order to increase enzyme levels and decrease the amounts of accumulated substrate. However, immunoreactivity and IgG antibody formation are major, therapy‐limiting, and eventually life‐threatening complications of ERT. The present study focused on the epitope determination of human α‐galactosidase A against its antibody formed. Here we report the identification of the epitope of human αGal(309–332) recognized by a human monoclonal anti‐αGal antibody, using a combination of proteolytic excision of the immobilized immune complex and surface plasmon resonance biosensing mass spectrometry. The epitope peptide, αGal(309–332), was synthesized by solid‐phase peptide synthesis. Determination of its affinity by surface plasmon resonance analysis revealed a high binding affinity for the antibody (KD=39×10−9 m), which is nearly identical to that of the full‐length enzyme (KD=16×10−9 m). The proteolytic excision affinity mass spectrometry method is shown here to be an efficient tool for epitope identification of an immunogenic lysosomal enzyme. Because the full‐length αGal and the antibody epitope showed similar binding affinities, this provides a basis for reversing immunogenicity upon ERT by: 1) treatment of patients with the epitope peptide to neutralize antibodies, or 2) removal of antibodies by apheresis, and thus significantly improving the response to ERT.
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Design, Synthesis, and Biological Evaluation of Bivalent Ligands Targeting Dopamine D2‐Like Receptors and the μ‐Opioid Receptor ()
Abstract Currently, there is mounting evidence that intermolecular receptor–receptor interactions may result in altered receptor recognition, pharmacology and signaling. Heterobivalent ligands have been proven useful as molecular probes for confirming and targeting heteromeric receptors. This report describes the design and synthesis of novel heterobivalent ligands for dopamine D2‐like receptors (D2‐likeR) and the μ‐opioid receptor (μOR) and their evaluation using ligand binding and functional assays. Interestingly, we identified a potent bivalent ligand that contains a short 18‐atom linker and combines good potency with high efficacy both in β‐arrestin 2 recruitment for μOR and MAPK‐P for D4R. Furthermore, this compound was characterized by a biphasic competition binding curve for the D4R–μOR heterodimer, indicative of a bivalent binding mode. As this compound possibly bridges the D4R–μOR heterodimer, it could be used as a pharmacological tool to further investigate the interactions of D4R and μOR.
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Novel Peroxides as Promising Anticancer Agents with Unexpected Depressed Antimalarial Activity ()
Abstract Twenty six peroxides belonging to bridged 1,2,4,5‐tetraoxanes, bridged 1,2,4‐trioxolanes (ozonides), and tricyclic monoperoxides were evaluated for their in vitro antimalarial activity against Plasmodium falciparum (3D7) and for their cytotoxic activities against immortalized human normal fibroblast (CCD19Lu), liver (LO2), and lung (BEAS‐2B) cell lines as well as human liver (HepG2) and lung (A549) cancer‐cell lines. Synthetic ozonides were shown to have the highest cytotoxicity on HepG2 (IC50=0.19–0.59 μm), and some of these compounds selectively targeted liver cancer (selectivity index values for compounds 13 a and 14 a are 20 and 28, respectively) at levels that, in some cases, were higher than those of paclitaxel, artemisinin, and artesunic acid. In contrast some ozonides showed only moderate antimalarial activity against the chloroquine‐sensitive 3D7 strain of P. falciparum (IC50 from 2.76 to 24.2 μm; 12 b, IC50=2.76 μm; 13 a, IC50=20.14 μm; 14 a, IC50=6.32 μm). These results suggest that these derivatives have divergent mechanisms of action against cancer cells and malaria‐infected cells. A cyclic voltammetry study of the peroxides was performed, but most of the compounds did not show direct correlation in oxidative capacity–activity. Our findings offer a new source of antimalarial and anticancer agents through structural modification of peroxide compounds.
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Biological Evaluation and X‐ray Co‐crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma ()
Abstract The tropical diseases human African trypanosomiasis, Chagas disease, and the various forms of leishmaniasis are caused by parasites of the family of trypanosomatids. These protozoa possess a unique redox metabolism based on trypanothione and trypanothione reductase (TR), making TR a promising drug target. We report the optimization of properties and potency of cyclohexylpyrrolidine inhibitors of TR by structure‐based design. The best inhibitors were freely soluble and showed competitive inhibition constants (Ki) against Trypanosoma (T.) brucei TR and T. cruzi TR and in vitro activities (half‐maximal inhibitory concentration, IC50) against these parasites in the low micromolar range, with high selectivity against human glutathione reductase. X‐ray co‐crystal structures confirmed the binding of the ligands to the hydrophobic wall of the “mepacrine binding site” with the new, solubility‐providing vectors oriented toward the surface of the large active site.
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Biophysical Techniques in Drug Discovery. Edited by Angeles Canales ()
ChemMedChem, Volume 13, Issue 9, Page 980-980, May 8, 2018.
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Early 2018 Update: Board Members, Preprints, and Special Issues ()
ChemMedChem, Volume 13, Issue 9, Page 861-868, May 8, 2018.
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Front Cover: Novel Peroxides as Promising Anticancer Agents with Unexpected Depressed Antimalarial Activity (ChemMedChem 9/2018) ()
ChemMedChem, Volume 13, Issue 9, Page 860-860, May 8, 2018.
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Design of Modular G‐quadruplex Ligands ()
Abstract Guanine‐rich nucleic acid sequences able to form four‐stranded structures (G‐quadruplexes, G4) play key cellular regulatory roles and are considered as promising drug targets for anticancer therapy. On the basis of the organization of their structural elements, G4 ligands can be divided into three major families: one, fused heteroaromatic polycyclic systems; two, macrocycles; three, modular aromatic compounds. The design of modular G4 ligands emerged as the answer to achieve not only more drug‐like compounds but also more selective ligands by targeting the diversity of the G4 loops and grooves. The rationale behind the design of a very comprehensive set of ligands, with particular focus on the structural features required for binding to G4, is discussed and combined with the corresponding biochemical/biological data to highlight key structure–G4 interaction relationships. Analysis of the data suggests that the shape of the ligand is the major factor behind the G4 stabilizing effect of the ligands. The information here critically reviewed will certainly contribute to the development of new and better G4 ligands with application either as therapeutics or probes.
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Chemical Features Important for Activity in a Class of Inhibitors Targeting the Wip1 Flap Subdomain ()
Abstract The wild‐type p53 induced phosphatase 1, Wip1 (PP2Cδ), is a protein phosphatase 2C (PP2C) family serine/threonine phosphatase that negatively regulates the function of the tumor suppressor p53 and several of its positive regulators such as ATM, Chk1, Chk2, Mdm2, and p38 MAPK. Wip1 dephosphorylates and inactivates its protein targets, which are critical for cellular stress responses. Additionally, Wip1 is frequently amplified and overexpressed in several human cancer types. Because of its negative role in regulating the function of tumor suppressor proteins, Wip1 has been identified as a potential therapeutic target in various types of cancers. Based on a recently reported Wip1 inhibitor (G‐1), we performed an extensive structure–activity relationship (SAR) analysis. This led us to interesting findings in SAR trends and to the discovery of new chemical analogues with good specificity and bioavailability.
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Synthesis, Characterization, and Initial Biological Evaluation of [99mTc]Tc‐Tricarbonyl‐labeled DPA‐α‐MSH Peptide Derivatives for Potential Melanoma Imaging ()
Abstract α‐Melanocyte stimulating hormone (α‐MSH) derivatives target the melanocortin‐1 receptor (MC1R) specifically and selectively. In this study, the α‐MSH‐derived peptide NAP‐NS1 (Nle‐Asp‐His‐d‐Phe‐Arg‐Trp‐Gly‐NH2) with and without linkers was conjugated with 5‐(bis(pyridin‐2‐ylmethyl)amino)pentanoic acid (DPA‐COOH) and labeled with [99mTc]Tc‐tricarbonyl by two methods. With the one‐pot method the labeling was faster than with the two‐pot method, while obtaining similarly high yields. Negligible trans‐chelation and high stability in physiological solutions was determined for the [99mTc]Tc‐tricarbonyl–peptide conjugates. Coupling an ethylene glycol (EG)‐based linker increased the hydrophilicity. The peptide derivatives displayed high binding affinity in murine B16F10 melanoma cells as well as in human MeWo and TXM13 melanoma cell homogenates. Preliminary in vivo studies with one of the [99mTc]Tc‐tricarbonyl–peptide conjugates showed good stability in blood and both renal and hepatobiliary excretion. Biodistribution was performed on healthy rats to gain initial insight into the potential relevance of the 99mTc‐labeled peptides for in vivo imaging.
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Niclosamide, a Drug with Many (Re)purposes ()
Abstract Niclosamide is an anthelmintic drug that has been used for over 50 years mainly to treat tapeworm infections. However, with the increase in drug repurposing initiatives, niclosamide has emerged as a true hit in many screens against various diseases. Indeed, from being an anthelmintic drug, it has now shown potential in treating Parkinson's disease, diabetes, viral and microbial infections, as well as various cancers. Such diverse pharmacological activities are a result of niclosamide's ability to uncouple mitochondrial phosphorylation and modulate a selection of signaling pathways, such as Wnt/β‐catenin, mTOR and JAK/STAT3, which are implicated in many diseases. In this highlight, we discuss the plethora of diseases that niclosamide has shown promise in treating.
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Claramines: A New Class Of Broad‐Spectrum Antimicrobial Agents With Bimodal Activity ()
Abstract The emergence of multidrug‐resistant bacteria and pathogens has created an urgent need for the development of new antibiotics. Herein we report our investigations into the broad‐spectrum activity of an easily prepared water‐soluble polyaminosterol compound, namely claramine A1, against both drug‐sensitive and drug‐resistant Gram‐negative and Gram‐positive bacterial strains. We also report its peculiar mechanism of action, which differs from that of all the other well‐known classes of antibiotics, toward Gram‐negative and Gram‐positive bacteria. Given their low cytotoxicity, this class of compounds based on claramine A1 could constitute an effective response to combat the emergence of multidrug‐resistant bacteria and nosocomial diseases.
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Discovery of Molidustat (BAY 85‐3934): A Small‐Molecule Oral HIF‐Prolyl Hydroxylase (HIF‐PH) Inhibitor for the Treatment of Renal Anemia ()
Abstract Small‐molecule inhibitors of hypoxia‐inducible factor prolyl hydroxylases (HIF‐PHs) are currently under clinical development as novel treatment options for chronic kidney disease (CKD) associated anemia. Inhibition of HIF‐PH mimics hypoxia and leads to increased erythropoietin (EPO) expression and subsequently increased erythropoiesis. Herein we describe the discovery, synthesis, structure–activity relationship (SAR), and proposed binding mode of novel 2,4‐diheteroaryl‐1,2‐dihydro‐3H‐pyrazol‐3‐ones as orally bioavailable HIF‐PH inhibitors for the treatment of anemia. High‐throughput screening of our corporate compound library identified BAY‐908 as a promising hit. The lead optimization program then resulted in the identification of molidustat (BAY 85‐3934), a novel small‐molecule oral HIF‐PH inhibitor. Molidustat is currently being investigated in clinical phase III trials as molidustat sodium for the treatment of anemia in patients with CKD.
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Dithionated Nucleobases as Effective Photodynamic Agents against Human Epidermoid Carcinoma Cells ()
Abstract Sulfur‐substituted nucleobases (i.e., thiobases) are a prospective class of compounds for clinical and cosmetic topical phototherapies. Recent investigations of several thiobases have revealed the ultrafast and efficient population of reactive triplet states upon ultraviolet‐A (UVA) irradiation and the subsequent generation of singlet oxygen in high yield. In this contribution, we examine the photosensitizing activities of three of the most promising thiobase derivatives discovered to date: 2,4‐dithiothymine, 2,4‐dithiouracil, and 2,6‐dithiopurine. These derivatives are shown to decrease the proliferation of human epidermoid carcinoma cells by up to 63 % in vitro, only upon activation with a low dose of UVA radiation (5 J cm−2). The generation of reactive oxygen species plays a minor role in the mode of action, suggesting these dithiobases may be effective within oxygen‐deficient environments. Importantly, the photosensitized activity correlates with the magnitude of the triplet lifetime, which should guide the molecular design of next‐generation photodynamic agents.
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Synthesis, Pharmacological Evaluation, and Docking Studies of Novel Pyridazinone‐Based Cannabinoid Receptor Type 2 Ligands ()
Abstract In recent years, cannabinoid type 2 receptors (CB2R) have emerged as promising therapeutic targets in a wide variety of diseases. Selective ligands of CB2R are devoid of the psychoactive effects typically observed for CB1R ligands. Based on our recent studies on a class of pyridazinone 4‐carboxamides, further structural modifications of the pyridazinone core were made to better investigate the structure–activity relationships for this promising scaffold with the aim to develop potent CB2R ligands. In binding assays, two of the new synthesized compounds [6‐(3,4‐dichlorophenyl)‐2‐(4‐fluorobenzyl)‐cis‐N‐(4‐methylcyclohexyl)‐3‐oxo‐2,3‐dihydropyridazine‐4‐carboxamide (2) and 6‐(4‐chloro‐3‐methylphenyl)‐cis‐N‐(4‐methylcyclohexyl)‐3‐oxo‐2‐pentyl‐2,3‐dihydropyridazine‐4‐carboxamide (22)] showed high CB2R affinity, with Ki values of 2.1 and 1.6 nm, respectively. In addition, functional assays of these compounds and other new active related derivatives revealed their pharmacological profiles as CB2R inverse agonists. Compound 22 displayed the highest CB2R selectivity and potency, presenting a favorable in silico pharmacokinetic profile. Furthermore, a molecular modeling study revealed how 22 produces inverse agonism through blocking the movement of the toggle‐switch residue, W6.48.
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Identifying Small‐Molecule Binding Sites for Epigenetic Proteins at Domain–Domain Interfaces ()
Abstract Epigenetics is a rapidly growing field in drug discovery. Of particular interest is the role of post‐translational modifications to histones and the proteins that read, write, and erase such modifications. The development of inhibitors for reader domains has focused on single domains. One of the major difficulties of designing inhibitors for reader domains is that, with the notable exception of bromodomains, they tend not to possess a well‐enclosed binding site amenable to small‐molecule inhibition. As many of the proteins in epigenetic regulation have multiple domains, there are opportunities for designing inhibitors that bind at a domain–domain interface which provide a more suitable interaction pocket. Examination of X‐ray structures of multiple domains involved in recognising and modifying post‐translational histone marks using the SiteMap algorithm identified potential binding sites at domain–domain interfaces. For the tandem plant homeodomain–bromodomain of SP100C, a potential inter‐domain site identified computationally was validated experimentally by the discovery of ligands by X‐ray crystallographic fragment screening.
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Fluorinated GluN2B Receptor Antagonists with a 3‐Benzazepine Scaffold Designed for PET Studies ()
Abstract To analyze the N‐methyl‐d‐aspartate (NMDA) receptor distribution in the central nervous system, fluorinated ligands that selectively address the ifenprodil binding site of GluN2B‐subunit‐containing NMDA receptors were developed. Various strategies to introduce a fluorine atom into the potent GluN2B ligand 2 (3‐(4‐phenylbutyl)‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepin‐1,7‐diol) were pursued, including replacement of the benzylic OH moiety with a fluorine atom (13) and introduction of fluoroethoxy moieties at various positions (14 (7‐position), 17 (9‐position), 18a–c (1‐position)). With respect to GluN2B affinity and selectivity over related receptors, the fluoroethoxy derivatives 14 and 18a are the most promising ligands. Radiosynthesis of fluoroethoxy derivative [18F]14 was performed by nucleophilic substitution of the phenol 2 with 2‐[18F]fluoroethyl tosylate. On rat brain slices the fluorinated PET tracer [18F]14 accumulated in regions with high density of NMDA receptors containing GluN2B subunits. The bound radioactivity could not be replaced by (S)‐glutamate. However, the GluN2B ligands eliprodil, Ro 25‐6981, and the non‐labeled 3‐benzazepine 14 were able to abolish the specific binding of [18F]14.
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Carboxylate Analogues of Aryl‐Urea‐Substituted Fatty Acids That Target the Mitochondria in MDA‐MB‐231 Breast Cancer Cells to Promote Cell Death ()
Abstract Selective targeting of the tumor cell mitochondrion is a viable approach for the development of anticancer agents because the organelle is functionally different from the mitochondria of normal cells. We recently developed a novel aryl‐urea fatty acid, 16({[4‐chloro‐3‐(trifluoromethyl)phenyl]carbamoyl}amino)hexadecanoic acid (1) that was found to disrupt mitochondria and to activate apoptosis in MDA‐MB‐231 breast cancer cells. However, there is currently little information on the structural requirements for the activity of compound 1 analogues. The present study evaluated the role of the carboxylic acid group on the anticancer activity of 1. Bioisosteric replacement of the carboxylate in 1 maintained activity. Thus, like 1, the sulfonic acid analogue 1‐SA and the oxo‐thiadiazole analogue 1‐OT were also found to target the mitochondrion and to activate cell killing capacity. The hydroxamic acid analogue 1‐HA also killed MDA‐MB‐231 cells, but its onset of action was slower than that of 1‐SA and 1‐OT. In contrast, replacement of the carboxylate with non‐bioisosteric amido and methylamido groups produced analogues that minimally altered mitochondrial function and showed little capacity to decrease tumor cell viability. These findings suggest that the carboxylate moiety in the novel mitochondrially targeted agent 1 is an important determinant of the kinetics and efficacy of anticancer cell activities of compound 1 analogues. Further development of carboxylate‐modified analogues of aryl‐urea fatty acids as potential anticancer agents could now be warranted.
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Halogenated Bis(methoxybenzylidene)‐4‐piperidone Curcuminoids with Improved Anticancer Activity ()
Abstract A series of readily available curcuminoids with a halogenated bis(4‐methoxy/4,5‐dimethoxybenzylidene)‐4‐piperidone structure were prepared and analyzed for their cytotoxic impact on eight human cancer cell lines of five different entities. The known 3,4,5‐trimethoxybenzylidene curcuminoid 2 a and the new bis‐(3‐bromophenyl) and bis‐(3,5‐dibromophenyl) derivatives 3 c and 3 d proved to be more strongly antiproliferative than the known curcuminoid EF24 against six of these cell lines. Compounds 2 a and 3 c caused a distinct increase of reactive oxygen species, which eventually elicited apoptosis in 518A2 melanoma cells. Compound 2 a arrested 518A2 melanoma cells in G1 phase of the cell cycle and had no effect on the expression of pro‐metastatic matrix metalloproteinases MMP‐2 and MMP‐9, whereas 3 c led to an accumulation of 518A2 cells in the G2/M phase and to a downregulation of MMP‐2 expression. In addition, treatment with 2 a and 3 c resulted in significant inhibition of colony formation in HCT116 cells. Both 2 a and 3 c showed antiangiogenic activity, for example, by inhibiting the formation of sub‐intestinal veins (SIV) in zebrafish embryos. Compound 3 c was also well tolerated by mice and inhibited the growth of HCT116 colon cancer xenografts.
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Discovery of Benzimidazole–Quinolone Hybrids as New Cleaving Agents toward Drug‐Resistant Pseudomonas aeruginosa DNA ()
Abstract A series of benzimidazole–quinolone hybrids as new potential antimicrobial agents were designed and synthesized. Bioactive assays indicated that some of the prepared compounds exhibited potent antibacterial and antifungal activities. Notably, 2‐fluorobenzyl derivative 5 b (ethyl 7‐chloro‐6‐fluoro‐1‐[[1‐[(2‐fluorophenyl)methyl]benzimidazol‐2‐yl]methyl]‐4‐oxo‐quinoline‐3‐carboxylate) showed remarkable antimicrobial activity against resistant Pseudomonas aeruginosa and Candida tropicalis isolated from infected patients. Active molecule 5 b could not only rapidly kill the tested strains, but also exhibit low toxicity toward Hep‐2 cells. It was more difficult to trigger the development of bacterial resistance of P. aeruginosa against 5 b than that against norfloxacin. Molecular docking demonstrated that 5 b could effectively bind with topoisomerase IV–DNA complexes, and quantum chemical studies theoretically elucidated the good antimicrobial activity of compound 5 b. Preliminary experimental reaction mechanism exploration suggested that derivative 5 b could not intercalate into DNA isolated from drug‐resistant P. aeruginosa, but was able to cleave DNA effectively, which might further block DNA replication to exert powerful bioactivities. In addition, compound 5 b is a promising antibacterial agent with membrane disruption abilities.
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Skeletal Optimization of Cytotoxic Lipidic Dialkynylcarbinols ()
Abstract In line with a recent study of the pharmacological potential of bioinspired synthetic acetylenic lipids, after identification of the terminal dialkynylcarbinol (DAC) and butadiynyl alkynylcarbinol (BAC) moieties as functional antitumor pharmacophoric units, this work specifically addresses the issue of carbon backbone length. A systematic variation of the aliphatic chain length was thus carried out in both the DAC and BAC series. The critical impact of the length of the lipidic skeleton was first confirmed in the racemic series, with the highest cytotoxic activity observed for C17 to C18 backbones. Enantiomerically enriched samples were prepared by asymmetric synthesis of the optimal C18 DAC and C17 BAC derivatives. Samples with upgraded enantiomeric purity were alternatively produced by enzymatic kinetic resolution. Eutomers possessing the S configuration displayed cytotoxicity IC50 values as low as 15 nm against HCT116 cancer cells, the highest level of activity reached to date in this series.
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A (+)‐Larixol Congener with High Affinity and Subtype Selectivity toward TRPC6 ()
Abstract Natural products have many health benefits, and their application can improve the quality of life. Recently, the diterpene (+)‐larixol and its acetylated congeners demonstrated selective inhibition of the second‐messenger‐gated cation channel transient receptor potential canonical 6 (TRPC6) over its close isoforms TRPC3 and TRPC7. Building on this knowledge, we expanded these findings by chemical diversification of (+)‐larixol mostly at position C6. Implementing high‐throughput Ca2+ FLIPR screening assays and electrophysiological patch‐clamp recordings, we showcase larixyl N‐methylcarbamate, termed SH045, as a compound with nanomolar affinity and 13‐fold subtype selectivity over TRPC3 in stably expressing HEK293 cells. Expanding on this finding, TRPC6 inhibition was also observed in rat pulmonary smooth muscle cells. Furthermore, treatment of isolated perfused lung preparations with SH045 led to a decrease in lung ischemia‐reperfusion edema (LIRE), a life‐threatening condition associated with TRPC6 that may occur after organ transplantation. Taken together, and given the inexpensive, straightforward, and scalable preparation of SH045, we report a TRPC6 blocker that holds promise for the translational treatment of LIRE.
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Tuning the Hydrophobicity of a Mitochondria‐Targeted NO Photodonor ()
Abstract A few compounds in which the nitric oxide (NO) photodonor N‐[4‐nitro‐3‐(trifluoromethyl)phenyl]propane‐1,3‐diamine is joined to the mitochondria‐targeting alkyltriphenylphosphonium moiety via flexible spacers of variable length were synthesized. The lipophilicity of the products was evaluated by measuring their partition coefficients in n‐octanol/water. The obtained values, markedly lower than those calculated, are consistent with the likely collapsed conformation assumed by the compounds in solution, as suggested by molecular dynamics simulations. The capacity of the compounds to release NO under visible light irradiation was evaluated by measuring nitrite production by means of the Griess reaction. The accumulation of compounds in the mitochondria of human lung adenocarcinoma A549 cells was assessed by UPLC–MS. Interestingly, compound 13 [(9‐((3‐((4‐nitro‐3‐(trifluoromethyl)phenyl)amino)propyl)amino)‐9‐oxononyl) triphenylphosphonium bromide] displayed both the highest accumulation value and high toxicity toward A549 cells upon irradiation‐mediated NO release in mitochondria.
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Anticancer Gold(III) Peptidomimetics: From Synthesis to in vitro and ex vivo Biological Evaluations ()
Abstract Five new AuIII‐peptidodithiocarbamato complexes of the type [AuIIIBr2(dtc‐AA1‐AA2‐OR] (in which AA1=N‐methylglycine (Sar), l/d‐Pro; AA2=l/d‐Ala, α‐aminoisobutyric acid (Aib); R=OtBu, triethylene glycol methyl ether), differing with regard to the amino acid sequence and/or the chiral amino acid configuration, were designed to enhance tumor selectivity and bioavailability. The gold(III)‐based moiety was functionalized to exploit the targeting properties of the peptidomimetic ligand toward two peptide transporters (namely PEPT1 and PEPT2), which are upregulated in several tumor cells. The compounds were synthesized and fully characterized, mainly by means of elemental analysis, one‐ and two‐dimensional NMR spectroscopy, FT‐IR, and UV/Vis spectrophotometry. The crystal structures of three compounds were also solved by X‐ray diffraction. In vitro cytotoxicity studies using a panel of human tumor cell lines (A549 [non‐small‐cell lung carcinoma], MCF‐7 [breast cancer], A2780 [ovarian carcinoma], H1975 [non‐small‐cell lung carcinoma], H460 [large‐cell lung carcinoma], and A431 [human epidermoid carcinoma]) showed the dtc‐Pro‐Aib‐OtBu derivative to be very effective, with GI50 values much lower than those of cisplatin. This complex was thus selected for evaluating stability under physiological conditions and possible interactions with serum albumin, as well in PARP‐1 enzyme inhibition assays and preliminary ex vivo toxicity experiments on healthy rat tissues.
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Cytotoxic Activity and Structure–Activity Relationship of Triazole‐Containing Bis(Aryl Ether) Macrocycles ()
Abstract Cancer continues to be a worldwide health problem. Certain macrocyclic molecules have become attractive therapeutic alternatives for this disease because of their efficacy and, frequently, their novel mechanisms of action. Herein, we report the synthesis of a series of 20‐, 21‐, and 22‐membered macrocycles containing triazole and bis(aryl ether) moieties. The compounds were prepared by a multicomponent approach from readily available commercial substrates. Notably, some of the compounds displayed interesting cytotoxicity against cancer (PC‐3) and breast (MCF‐7) cell lines, especially those bearing an aliphatic or a trifluoromethyl substituent on the N‐phenyl moiety (IC50<13 μm). Additionally, some of the compounds were able to induce apoptosis relative to the solvent control; in particular, (Z)‐N‐cyclohexyl‐7‐oxo‐6‐[4‐(trifluoromethyl)phenyl]‐11H‐3,10‐dioxa‐6‐aza‐1(4,1)‐triazola‐4(1,3),9(1,4)‐dibenzenacyclotridecaphane‐5‐carboxamide (12 f) was the most potent in this regard (22.7 % of apoptosis).
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Antibiotic Drug Discovery: New Targets and Molecular Entities. Edited by Steven M. Firestine and Troy Lister ()
ChemMedChem, EarlyView.
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Discovery of Molidustat (BAY 85‐3934): A Small‐Molecule Oral HIF‐Prolyl Hydroxylase (HIF‐PH) Inhibitor for the Treatment of Renal Anemia ()
ChemMedChem, EarlyView.
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Optimization of Pyrazoles as Phenol Surrogates to Yield Potent Inhibitors of Macrophage Migration Inhibitory Factor ()
ChemMedChem, EarlyView.
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Discovery of Benzimidazole–Quinolone Hybrids as New Cleaving Agents toward Drug‐Resistant Pseudomonas aeruginosa DNA ()
ChemMedChem, EarlyView.
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The Current Status of O‐Heterocycles: A Synthetic and Medicinal Overview ()
Abstract O‐Heterocycles have been explored in the field of medicinal chemistry for a long time, but their significance has not been duly recognised and they are often shunned in favour of N‐heterocycles. The design of bioactive molecules for nearly every pathophysiological condition is primarily focused on novel N‐heterocycles. The main reasons for such bias include the ease of synthesis and possible mimicking of physiological molecules by N‐heterocycles. But considering only this criterion rarely provides breakthrough molecules for a given disease condition, and instead the risks of toxicity or side effects are increased with such molecules. On the other hand, owing to improved synthetic feasibility, O‐heterocycles have established themselves as equally potent lead molecules for a wide range of pathophysiological conditions. In the last decade there have been hundreds of reports validating the fact that equally potent molecules can be designed and developed by using O‐heterocycles, and these are also expected to have comparably low toxicity. Even so, researchers tend to remain biased toward the use of N‐heterocycles over O‐heterocycles. Thus, this review provides a critical analysis of the synthesis and medicinal attributes of O‐heterocycles, such as pyrones, oxazolones, furanones, oxetanes, oxazolidinones, and dioxolonones, and others, reported in the last five years, underlining the need for and the advantages guiding researchers toward them.
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Optimization of Pyrazoles as Phenol Surrogates to Yield Potent Inhibitors of Macrophage Migration Inhibitory Factor ()
Abstract Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is implicated in the regulation of inflammation, cell proliferation, and neurological disorders. MIF is also an enzyme that functions as a keto–enol tautomerase. Most potent MIF tautomerase inhibitors incorporate a phenol, which hydrogen bonds to Asn97 in the active site. Starting from a 113‐μm docking hit, we report results of structure‐based and computer‐aided design that have provided substituted pyrazoles as phenol alternatives with potencies of 60–70 nm. Crystal structures of complexes of MIF with the pyrazoles highlight the contributions of hydrogen bonding with Lys32 and Asn97, and aryl–aryl interactions with Tyr36, Tyr95, and Phe113 to the binding.
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Late‐Stage Functionalization of Drug‐Like Molecules Using Diversinates ()
Abstract Late‐stage functionalization (LSF) is a powerful method to quickly generate new analogues of a lead structure without resorting to de novo synthesis. We have leveraged Baran Diversinates to carry out late‐stage functionalizations on lead structures from internal drug discovery projects and accurately predicted regioselectivities using computational methods. Our functionalization successfully afforded specific regioisomers which were in line with our predictions. To enhance reactivity, decrease reaction time, and increase reaction yields, we have developed new functionalization conditions involving iron(III) catalysis. Finally, we demonstrate how our LSF reactions using Baran Diversinates can lead to new analogues with improved in vitro DMPK parameters.
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Nucleoside‐Based Self‐Assembling Drugs for Localized Drug Delivery ()
Abstract We have synthesized a range of gelators based on the nucleoside analogues gemcitabine and lamivudine, characterizing representative gels from the series using rheology and transmission electron microscopy. Growth inhibition studies of gemcitabine derivatives confirmed the feasibility of these compounds as novel treatments, indicating the potential of nucleoside‐based gelators for localized drug delivery.
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