ChemMedChem

Synthesis, determination of the lipophilicity, anticonvulsant activity and preliminary safety of new derivatives of N-[(4-arylpiperazin-1-yl)-alkyl]-pyrrolidine-2,5-dione ()
A new series of derivatives of 1,3-substituted pyrrolidine-2,5-dione as potential anticonvulsant agents are described in this paper. Initial pharmacological screening for these compounds was performed using acute models of seizures (MES and scPTZ tests) in mice after intraperitoneal administration. A quantitative pharmacological research revealed that the most promising compound were N-[{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-propyl]-3-benzhydryl-pyrrolidine-2,5-dione monohydrochloride (11) with ED50=75.9 mg/kg (MES test) and N-[{4-(3,4-dichlorophenyl)-piperazin-1-yl}-ethyl]-3-methyl-pyrrolidine-2,5-dione monohydrochloride (18) with ED50=88.2 mg/kg (MES test) and ED50=65.7 kg/mg (scPTZ test). These compounds displayed a more beneficial protective index than well-known antiepileptic drugs. The plausible mechanism of the action of the compounds 11 and 18 (molecule 11 blocked sodium channel (site 2) and 18 both sodium (site 2) and L-type calcium channels) and their preliminary safety in vitro were evaluated. Besides, the lipophilicity of all synthesized compounds was determined using the UPLC/MS method.
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C2-modified Sparteine derivatives are a new class of potentially long-acting Na channel blockers ()
The lupin alkaloid Sparteine is a well-known chiral diamine with a range of applications in asymmetric synthesis, as well as a blocker of voltage-gated Na channels (VGSCs). However, there is only scarce information on the VGSC-blocking activity of Sparteine derivatives where the structure of the parent alkaloid is retained. Herein, building on the recent renewed availability of Sparteine and derivatives we report how modification of Sparteine in position 2 produces irreversible blockers of VGSCs. These compounds could be clinically envisaged as long-lasting local anesthetics.
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IChem: A Versatile Toolkit for Detecting, Comparing and Predicting Protein-Ligand Interactions ()
Structure-based ligand design requires to exactly describing the topology of molecular entities under scrutiny. IChem is a software wrapping up the many contributions of our group in this area over the last decade. It facilitates and automates many tasks (e.g. ligand/co-factor atom typing, identification of key water molecules) usually let to the modeler's choice. It therefore permits the detection of molecular interactions between two molecules, whatever their nature, in a very precise and flexible manner. Moreover, IChem enables the conversion of intricate three-dimensional (3D) molecular objects into simple representations (fingerprints, graphs) that facilitate knowledge acquisition at a very high throughput. The toolkit is an ideal companion for setting-up and performing many structure-based design computations.
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Rationalizing Promiscuity Cliffs ()
Compound promiscuity can be viewed in different ways. We distinguish "bad" promiscuity resulting from chemical liabilities, non-specific binding, or assay artifacts from "good" promiscuity representing true multi-target activities. Investigating multi-target activities of small molecules is scientifically stimulating and therapeutically relevant. To better understand the molecular basis of multi-target activities, structure-promiscuity relationships (SPRs) are explored. For this purpose, "promiscuity cliffs" (PCs) have been introduced, which can be rationalized as an extension of the activity cliff (AC) concept. A PC is defined as a pair of structural analogs that are active against different numbers of targets (given a difference threshold). As discussed herein. PCs frequently capture surprising SPRs and encode many experimentally testable hypotheses.
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Computational Macrocyclization: From de novo Macrocycle Generation to Binding Affinity Estimation ()
Macrocycles play an increasing role in drug discovery but their synthesis is often demanding. Computational tools suggesting macrocyclization based on a known binding mode and estimating their binding affinity could have a substantial impact on the medicinal chemistry design process. For both tasks, we established a workflow with high practical value. For five diverse pharmaceutical targets we show that the effect of macrocyclization on binding can be calculated robustly and accurately. Applying the method to macrocycles designed by LigMac, a search tool for de novo macrocyclization, our results suggest that we have a robust protocol in hand to design macrocycles and prioritize them prior to synthesis.
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Structure-Activity Studies of N-Butyl-1-deoxynojirimycin (NB-DNJ) Analogs: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2 ()
Analogs of N-butyl-1-deoxynojirimycin (NB-DNJ) were prepared and assayed for inhibition of ceramide-specific glucosyltransferase (CGT), non-lysosomal -glucosidase 2 (GBA2) and the lysosomal -glucosidase 1 (GBA1). Compounds 6a-6f that carry sterically demanding nitrogen substituents, and compound 14, devoid of the C3 and C5 hydroxyl groups present in DNJ/NB-DGJ (N-butyl-deoxygalactojirimycin showed no inhibitory activity for CGT or GBA2. Inversion of stereochemistry at C4 of N-(n-butyl)- and N-(n-nonyl)-DGJ (compounds 25) also led to a loss of activity in these assays. The aminocyclopentitols N-(n-butyl)- (36a), N-(n-nonyl)-4-amino-5-(hydroxymethyl)cyclopentane- (36b), and N-(1-(pentyloxy)methyl)adamantan-1-yl)-1,2,3-triol (36f), were selective inhibitors of GBA1 and GBA2 that did not inhibit CGT (>1mM) with the exception of 36f, which inhibited CGT with an IC50 of 1 mM. The N-butyl analog 36a was 1000-fold selective for inhibiting GBA1 over GBA2 (Ki values of 32 nM and 3.3 μM for GBA1 and GBA2, respectively). The N-nonyl analog 36b displayed a Ki of <<14 nM for GBA1 inhibition and a Ki of 43 nM for GBA2. The N-(1-(pentyloxy)methyl)adamantan-1-yl) derivative 36f had Ki values of ~16 nM and 14 nM for GBA1 and GBA2, respectively. The related N-bis-substituted aminocyclopentitols were significantly less potent inhibitors than their mono-substituted analogs. The aminocyclopentitol scaffold should hold promise for further inhibitor development.
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Deciphering structure-activity relationships in a series of 2,2-dimethylchromans acting as inhibitors of insulin release and smooth muscle relaxants ()
4,6-Disubstituted 2,2-dimethylchromans are reported as pharmacologically active compounds mainly targeting the ATP-sensitive potassium channels (KATP channels). The present study is an attempt to characterize the impact of the nature of the substituent introduced at the 4- and 6-position of 2,2-dimethylchromans on their capacities to inhibit insulin release from pancreatic β-cells or to relax vascular smooth muscle cells, both biological responses supposed to reflect interaction with specific ion channels. Starting from the core structure 4-amino-2,2-dimethylchroman, the progressive increase of the steric hindrance of the chemical functions introduced at the 4-position (amino, formamido, acetamido, arylureido/thioureido) and at the 6-position (amino, formamido, acetamido, alkoxycarbonylamino) led to a progressive magnification of the inhibitory effect on the insulin releasing process and, to a lesser extent, of the vasorelaxant activity. Moreover, the dextrorotatory enantiomer of one selected 2,2-dimethylchroman racemic compound (29) was more potent than its levorotatory counterpart at inhibiting the insulin secretory process. Additional pharmacological investigations suggested, however, that the myorelaxant activity of (11) and (15) resulted from a direct Ca++ entry blockade.
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Sugar-Coated Nanobullet: Growth Inhibition of Cancer Cells In-duced by Metformin Loaded Glyconanoparticles ()
Metformin, a widely used drug for treating type-2 diabetes, has now been discovered to reduce cancer proliferation. However, further efforts are needed to design effective metformin delivery vehicles, instead of bare metformin. Here, we report a high-efficient transport nanostructure based on core-shell glyconanoparticles (GNPs), with gold as the core and dextran as the shell interspersed with metformin molecules. The dextran shell facilitates the entrance of GNPs into living cells, which allows the following release of metformin. Using MCF-7 breast cancer cells as the example, significant cell growth inhibition is observed after the treatment of metformin-dotted GNPs (MGNPs). Compared with bare metformin or bare GNPs, MGNPs show stronger cell inhibition capability with good biocompatibility. Furthermore, inactivation of mitochondria and activation of p53 protein are observed during the MGNP treatment, which provides evidence on the metformin-induced cell apoptosis pathways. This work provides a new therapeutic tool for the treatment of cancer.
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Mitochondrial-targeting Polyamine−Protoporphyrin Conjugates for Photodynamic Therapy ()
Two polyamine derivatives of protoporphyrin IX (PPIX) were tested as photodynamic therapy (PDT) agents in HT29 colorectal cancer and HEP3B liver cancer cell lines. These molecules exhibit excellent singlet oxygen quantum yields and show strong in vitro PDT efficacy after 660 nm laser irradiation whereas exogenous PPIX itself exhibits much weaker PDT effects. Confocal imaging studies reveal that a protoporphyrin derivative with eight amine moieties, has excellent water-solubility, and localizes mainly in the mitochondria of both HT29 and HEP3B cells, whereas the cellular distribution of a protoporphyrin derivative with four amine moieties is not as specific. This work demonstrates that polyamine moieties on macrocycles can enhance PDT efficacy by targeting mitochondria.
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Mimicking Intermolecular Interactions of Tight Protein-Protein Complexes for Small-Molecule Antagonists ()
Tight protein-protein interactions (Kd < 100 nM) that occur over a large binding interface (> 1,000 Å2) are highly challenging to disrupt with small molecules. Historically, the design of small molecules to inhibit protein-protein interactions has focused on mimicking the position of interface protein ligand sidechains. Here, we explore mimicry of the pairwise intermolecular interactions of the native protein ligand with residues of the protein receptor to enrich commercial libraries for small-molecule inhibitors of tight interaction (Kd = 1 nM) between the urokinase receptor (uPAR) and its ligand urokinase (uPA). We introduce three methods for rank-ordering small molecules docked to uPAR: (i) a new fingerprint approach that represents uPA's pairwise interaction energies with uPAR residues; (ii) a pharmacophore approach to identify small molecules that mimic the position of uPA interface residues; and (iii) a combined fingerprint and pharmacophore approach. Our work led to small molecules with novel chemotypes that inhibited a tight uPAR*uPA interaction with single-digit micromolar IC50s. We also report the extensive work that identified several of the hits as either lacking stability, thiol reactive, or redox active. This work suggests that mimicking the binding profile of the native ligand and the position of interface residues can be an effective strategy to enrich commercial libraries for small-molecule inhibitors of tight protein-protein interactions.
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Structure-Activity Relationship within a new series at σ₁ and σ₂R ligands: identification of a novel σ₂R agonist (BS148) with selective toxicity against metastatic melanoma ()
A new series of spiro-cyclic sigma ligands were prepared and studied. Most were found to have a high affinity and selectivity for σ₁R; compounds 7b, 15b and 16a were shown to be σ₁R agonists, while 16b was proven to be the only σ₁R antagonist. Only 16a (BS148) exhibited σ₂R selectivity and was able to inhibit the growth of metastatic malignant melanoma cell lines, whilst not affecting normal human melanocytes. BS148's anti-proliferative activity suggests a σ₂R agonist profile. Further, preliminary investigations indicate that, at least a part, the mechanism of metastatic malignant melanoma cell death induced by BS148 is due to apoptosis.
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Synthesis and Evaluation of In Vitro Biological Properties of Ferrocenyl Side-Chain-Decorated Paclitaxel ()
Taxanes, including paclitaxel, are widely used in cancer therapy. In an attempt to overcome some of the disadvantages entailed with taxane chemotherapy, we devised the synthesis of ferrocenyl-decorated paclitaxels and studied their biological properties. The cytotoxic activity was measured in a panel of human cancer cell lines of different tissue origin including also multidrug resistant ones. A structure-activity study of paclitaxel ferrocenylation revealed that the N-benzoyl ferrocenyl substituted derivative was the most cytotoxic. In contrast, substitution of the 3'-phenyl group of paclitaxel with a ferrocenyl moiety led to formation of relatively less potent antiproliferative agents. However, they were able to overcome multidrug resistance as they were virtually unrecognized by ABCB1, a major cellular exporter of taxanes. Interestingly, redox properties of ferrocenyl derivatives seemed to play a less important role in the mode of action of the investigated compounds as there was no correlation between intracellular redox activity and cytotoxicity/cell cycle distribution of cells. The antiproliferative activity of ferrocenyl taxanes strongly depended on the substitution position and good polymerisation inducers, as confirmed by molecular docking, were usually more cytotoxic, while compounds with stronger pro-oxidative properties exhibited lower antiproliferative activity.
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Functional N-Formyl Peptide Receptor 2 (FPR2) Antagonists Based on Ureidopropanamide Scaffold Have Potential to Protect Against Inflammation-associated Oxidative Stress. ()
Formyl peptide receptor-2 (FPR2) is a G protein-coupled receptor belonging to the N-formyl peptide receptor (FPR) family that plays critical roles in peripheral and brain inflammatory responses. FPR2 has been proposed as a target for the development of drugs that could facilitate the resolution of chronic inflammatory reactions by enhancing endogenous anti-inflammation systems. Starting from the structure of the FPR2 agonists (R)- and (S)-4 and 2, we designed a new series of ureidopropanamide derivatives with the goal of converting functional activity from agonism to antagonism and to develop new FPR2 antagonists. Although none of the compounds behaved as antagonist, some of the compounds were able to induce receptor desensitization, thus functionally behaving as antagonists. Evaluation of these compounds in an in vitro model of neuroinflammation showed that they reduced reactive oxygen species (ROS) production in mouse microglial N9 cells after stimulation with lipopolysaccharide (LPS). These FPR2 ligands may protect cells from damage due to inflammation-associated oxidative stress.
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Calcium Coordination Solids for pH-Triggered Release of Olsalazine ()
Calcium coordination solids were synthesized and evaluated for delivery of olsalazine (H₄olz), an anti-inflammatory compound used for treatment of ulcerative colitis. The materials include one-dimensional Ca(H₂olz)·4H₂O chains, two-dimensional Ca(H₂olz)·2H₂O sheets, and a three-dimensional metal-organic framework Ca(H₂olz)·2DMF (DMF = N,N-dimethylformamide). The framework undergoes structural changes in response to solvent, forming a dense Ca(H₂olz) phase when exposed to aqueous HCl. The compounds Ca(H₂olz)·xH₂O (x = 0, 2, 4) were each pressed into pellets and exposed to simulated gastrointestinal fluids to mimic the passage of a pill from the acidic stomach to the pH-neutral intestines. All three calcium materials exhibited a delayed release of olsalazine compared to Na₂(H₂olz), the commercial formulation, illustrating how formulation of a drug within an extended coordination solid can serve to tune its solubility and performance.
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Potent Pyrimidine and Pyrrolopyrimidine Inhibitors of Testis-Specific Serine/Threonine Kinase 2 (TSSK2) ()
Testis-specific serine/threonine kinase 2 (TSSK2) is an important target for reversible male contraception. A high-throughput screen of ≈17 000 compounds using a mobility shift assay identified two potent series of inhibitors having a pyrrolopyrimidine or pyrimidine core. The pyrrolopyrimidine 10 (IC50 22 nm; GSK2163632A) and the pyrimidine 17 (IC50 31 nm; ALK inhibitor 1) are the most potent TSSK2 inhibitors in these series, which contain the first sub-100 nanomolar inhibitors of any TSSK isoform reported, except for the broad kinase inhibitor staurosporine. The novel, potent pyrimidine TSSK2 inhibitor compound 19 (IC50 66 nm; 2-[[5-chloro-2-[2-methoxy-4-(1-methylpiperidin-4-yl)anilino]pyrimidin-4-yl]amino]-N-methylbenzenesulfonamide) lacks the potential for metabolic activation. Compound 19 had a potency rank order of TSSK1>TSSK2>TSSK3>TSSK6, indicating that potent dual inhibitors of TSSK1/2 can be identified, which may be required for a complete contraceptive effect. The future availability of a TSSK2 crystal structure will facilitate structure-based discovery of selective TSSK inhibitors from these pyrrolopyrimidine and pyrimidine scaffolds. Sperm beware! Testis-specific serine/threonine kinase 2 (TSSK2) plays an important role in spermiogenesis and fertilization. A robust mobility shift assay high-throughput screen identified a pyrrolopyrimidine and a pyrimidine series of TSSK2 ATP site inhibitors. A pyrimidine analogue lacking metabolic liability was identified as a potent dual inhibitor of TSSK2 and TSSK1, demonstrating the potential to identify inhibitors of multiple TSSKs for male contraception.
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Impact of a Central Scaffold on the Binding Affinity of Fragment Pairs Isolated from DNA-Encoded Self-Assembling Chemical Libraries ()
The screening of encoded self-assembling chemical libraries allows the identification of fragment pairs that bind to adjacent pockets on target proteins of interest. For practical applications, it is necessary to link these ligand pairs into discrete organic molecules, devoid of any nucleic acid component. Here we describe the discovery of a synergistic binding pair for acid alpha-1 glycoprotein and a chemical strategy for the identification of optimal linkers, connecting the two fragments. The procedure yielded a set of small organic ligands, the best of which exhibited a dissociation constant of 9.9 nm, as measured in solution by fluorescence polarization. The missing link: The screening of encoded self-assembling chemical libraries allows the identification of fragment pairs that bind to adjacent pockets on target proteins of interest. For practical application, these ligand pairs must be linked into discrete organic molecules, devoid of any nucleic acid component. Here we describe the discovery of a synergistic binding pair for acid alpha-1 glycoprotein and a chemical strategy for the identification of optimal linkers, connecting the two fragments.
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DNA Microcapsule for Photo-Triggered Drug Release Systems ()
In this study we constructed spherical photo-responsive microcapsules composed of three photo-switchable DNA strands. These strands first formed a three-way junction (TWJ) motif that further self-assembled to form microspheres through hybridization of the sticky-end regions of each branch. To serve as the photo-switch, multiple unmodified azobenzene (Azo) or 2,6-dimethyl-4-(methylthio)azobenzene (SDM-Azo) were introduced into the sticky-end regions via a d-threoninol linker. The DNA capsule structure deformed upon trans-to-cis isomerization of Azo or SDM-Azo induced by specific light irradiation. In addition, photo-triggered release of encapsulated small molecules from the DNA microcapsule was successfully achieved. Moreover, we demonstrated that photo-triggered release of doxorubicin caused cytotoxicity to cultured cells. This biocompatible photo-responsive microcapsule has potential application as a photo-controlled drug-release system. Let there be light: We designed a photo-sensing DNA microcapsule. This DNA microcapsule was formed by assembly of the Y-shaped DNA-building blocks in which azobenzenes were located within the connecting regions. Upon irradiation with light, the microcapsules were found to rapidly collapse, thus releasing doped compounds through the cis isomerization of azobenzene units positioned at connecting regions between the building blocks.
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Identification of Atuveciclib (BAY 1143572), the First Highly Selective, Clinical PTEFb/CDK9 Inhibitor for the Treatment of Cancer ()
Selective inhibition of exclusively transcription-regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY-958, lead optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification of the orally available clinical candidate atuveciclib (BAY 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAY 1143572 exhibited the best overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats. BAY 1143572 is the first potent and highly selective PTEFb/CDK9 inhibitor to enter clinical trials for the treatment of cancer. The benzyl sulfoximine atuveciclib (BAY 1143572), a potent and highly selective oral PTEFb/CDK9 inhibitor, exhibited the most promising overall profile with respect to potency, selectivity, physicochemical properties, and in vivo PK as well as in vivo potency in animal models during lead optimization. BAY 1143572 is the first selective PTEFb/CDK9 inhibitor to enter clinical evaluation for the treatment of cancer.
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(R-X-R)4-Motif Peptides Containing Conformationally Constrained Cyclohexane-Derived Spacers: Effect on Cellular Uptake ()
Arginine-rich peptides having the (R-X-R)n motif are among the most effective cell-penetrating peptides (CPPs). Herein we report a several-fold increase in the efficacy of such CPPs if the linear flexible spacer (-X-) in the (R-X-R) motif is replaced by constrained cyclic 1,4-substituted-cyclohexane-derived spacers. Internalization of these oligomers in mammalian cell lines was found to be an energy-dependent process. Incorporation of these constrained, non-proteinogenic amino acid spacers in the CPPs is shown to enhance their proteolytic stability. The “X” factor: An optimum balance between constraint and flexibility in the 1,4-substituted-cyclohexane-derived spacer “X” in arginine-rich (R-X-R)-motif peptides leads to enhanced cell-penetration properties. These peptides are also resistant to proteolytic degradation.
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Biomedical Nanomaterials. Edited by Yuliang Zhao and Youqing Shen ()
Wiley-VCH, Weinheim 2016. 476 pp., hardcover, €159.00.—ISBN  978-3-527-33798-9
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Anti-aging Drugs: From Basic Research to Clinical Practice. Edited by Alexander M. Vaiserman ()
RSC, Cambridge 2017. 570 pp., hardcover, £199.00.—ISBN 978-1-78262-435-6
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Lipid-Coated Gold Nanoparticles Functionalized by Folic Acid as Gene Vectors for Targeted Gene Delivery in vitro and in vivo ()
Lipid-based nanoparticles as gene vectors have attracted considerable attention for their high gene transfection efficiency and low cytotoxicity. In our previous work, we synthesized gold nanoparticles/dimethyldioctadecylammonium bromide (DODAB)/dioleoylphosphatidylethanolamine (DOPE) (GDD) as anionic lipid- and pH-sensitive gene vectors. To further realize targeted gene transfection, a series of gold nanoparticles/DODAB/DOPE/DOPE-folic acid (DOPE-FA) with various ratios of DOPE-FA were prepared and termed as GFn (for which n=1.0, 2.5, 5.0, 7.5, or 10.0 %). The gene transfection efficiency mediated by GF2.5 can reach about 85 % for MCF-7 (FA-receptor-positive cells), higher than those of the negative control (GDD, 35 %) and positive control (Lipofectamine 2000, 65 %). However, GF2.5 does not further promote gene transfection into A549 (FA-receptor-negative cells). The higher gene transfection efficiency for MCF-7 cells can be attributed to enhanced cellular uptake efficiency mediated by the FA targeting ability. Furthermore, GF2.5 was also found to accumulate at the specific tumor site and showed enhanced in vivo gene delivery ability. In addition, no significant harm was observed for the main tissues of the mice after treatment with GF2.5. Therefore, GF2.5, with the targeting ability and improved transfection efficiency, shows promise for its utility in gene therapy for tumor cells that overexpress FA receptors. We believe the results of this study will find more broad applications in gene therapy. Cancer specific: We synthesized gold nanoparticles protected by folic acid (FA)-functionalized lipids for targeted and highly efficient gene transfection. We found that such nanoparticles can significantly increase the efficiency of gene delivery with high selectivity and low toxicity by enhancing the cellular uptake into FA-receptor-positive tumor cells (such as MCF-7) in vitro and in vivo, whereas they did not assist gene transfection for FA-receptor-negative cells (such as A549).
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Encapsulating Active Pharmaceutical Ingredients in Self-Assembling Adamantanes with Short DNA Zippers ()
Formulating pharmaceutically active ingredients for drug delivery is a challenge. There is a need for new drug delivery systems that take up therapeutic molecules and release them into biological systems. We propose a novel mode of encapsulation that involves matrices formed through co-assembly of drugs with adamantane hybrids that feature four CG dimers as sticky ends. Such adamantanes are accessible via inexpensive solution-phase syntheses, and the resulting materials show attractive properties for controlled release. This is demonstrated for two different hybrids and a series of drugs, including anticancer drugs, antibiotics, and cyclosporin. Up to 20 molar equivalents of active pharmaceutical ingredients (APIs) are encapsulated in hybrid materials. Encapsulation is demonstrated for DNA-binding and several non-DNA binding compounds. Nanoparticles were detected that range in size from 114–835 nm average diameter, and ζ potentials were found to be between −29 and +28 mV. Release of doxorubicin into serum at near-constant rates for 10 days was shown, demonstrating the potential for slow release. The encapsulation and release in self-assembling matrices of dinucleotide-bearing adamantanes appears to be broadly applicable and may thus lead to new drug delivery systems for APIs. A new formulation for a broad range of active pharmaceutical ingredients (APIs): Branched oligonucleotide hybrids with adamantanes as core and CG dimer arms as molecular zippers encapsulate drugs efficiently that are as different in structure as imatinib and cyclosporin A. The resulting nanostructured compounds release APIs, such as doxorubicin, at near-constant rate for up to 10 days, making them promising candidates for drug delivery.
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Minor Structural Variations of Small Molecules Tune Regulatory Activities toward Pathological Factors in Alzheimer's Disease ()
Chemical tools have been valuable for establishing a better understanding of the relationships between metal ion dyshomeostasis, the abnormal aggregation and accumulation of amyloid-β (Aβ), and oxidative stress in Alzheimer's disease (AD). Still, very little information is available to correlate the structures of chemical tools with specific reactivities used to uncover such relationships. Recently, slight structural variations to the framework of a chemical tool were found to drastically determine the tool's reactivities toward multiple pathological facets to various extents. Herein, we report our rational design and characterization of a structural series to illustrate the extent to which the reactivities of small molecules vary toward different targets as a result of minor structural modifications. These compounds were rationally and systematically modified based on consideration of properties, including ionization potentials and metal binding, to afford their desired reactivities with metal-free or metal-bound Aβ, reactive oxygen species (ROS), and free organic radicals. Our results show that although small molecules are structurally similar, they can interact with multiple factors associated with AD pathogenesis and alleviate their reactivities to different degrees. Together, our studies demonstrate the rational structure-directed design that can be used to develop chemical tools capable of regulating individual or interrelated pathological features in AD. Small change, big effect: Herein, we report a series of compounds to illustrate the extent to which the reactivities of small molecules vary toward different targets as a result of minor structural modifications. We disclose a rational design approach for the development of chemical tools capable of targeting and regulating multiple pathological factors, including metal ions and metal-associated amyloid-β species found in Alzheimer's disease.
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A Dithiol Compound Binds to the Zinc Finger Protein TRAF6 and Suppresses Its Ubiquitination ()
Despite various inhibitors targeting the zinc center(s) of enzymes, drugs that target zinc fingers have not been examined in detail. We previously developed a dithiol compound named SN-1 that has an inhibitory effect on the function of zinc finger transcription factors, but its mechanism of action has not yet been elucidated. To establish a general principle for new drugs, the details of the action of SN-1 against a zinc finger protein were examined. As a zinc-finger-containing protein, we focused on TRAF6, which is related to cancer and inflammation. Binding of SN-1 to TRAF6 and its effect on TRAF6 ubiquitination were examined in vitro, and the binding mode was calculated by computational methodology. Furthermore, ubiquitination of TRAF6 and downstream signaling was examined by cell-based experiments. The results show that SN-1 binds to TRAF6, inhibiting its auto-ubiquitination and downstream NF-κB signaling. Docking studies indicate that SN-1 binds directly to the first zinc finger of TRAF6. This binding disrupts the neighboring structure, that is, the RING finger domain, to suppress the ubiquitin ligase activity of TRAF6. Taken together, this study provides a platform for developing new small molecules that target zinc finger proteins. A dithiol compound named SN-1 binds to TRAF6, inhibiting its auto-ubiquitination and downstream signaling. SN-1 is considered to bind directly to the first zinc finger of TRAF6, disrupting the neighboring RING finger domain, to suppress the ubiquitin ligase activity of TRAF6. This study provides a platform for developing new small molecules that target zinc finger proteins.
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Fine and Clean Photothermally Controlled NIR Drug Delivery from Biocompatible Nickel-bis(dithiolene)-Containing Liposomes ()
This work demonstrates that metal-bis(dithiolene) complexes can be efficiently incorporated inside organic nanocarriers and, that under near-infrared (NIR) irradiation, their high photothermal activity can be finely used to release encapsulated drugs on demand. In contrast to gold nanoparticles and other organic NIR dyes, nickel-bis(dithiolene) complexes do not produce singlet oxygen under irradiation, a highly desirable characteristic to preserve the chemical integrity and activity of the loaded drug during the NIR-triggered release from the nanocarriers. Finally, cytotoxicity experiments performed on various cell lines have shown that the incorporation of such metal complexes do not increase the toxicity of the final liposomal formulation. These results offer great promise for the development of innovative biocompatible drug nanocargos that are able to safely deliver their content on demand under NIR laser irradiation. Moreover, this work demonstrates that metal-bis(dithiolene) complexes, owing to their versatility of functionalization and metal complexation, are attractive photothermal agents for the development of original NIR-responsive materials for application not only in biotechnology but also in materials science. Safe and on demand: The incorporation of nickel-bis(dithiolene) complexes inside biocompatible liposomes allows the fine photothermal control of drug release without any increase in cytotoxicity or any production of singlet oxygen.
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Matched Molecular Pair Analysis on Large Melting Point Datasets: A Big Data Perspective ()
A matched molecular pair (MMP) analysis was used to examine the change in melting point (MP) between pairs of similar molecules in a set of ∼275k compounds. We found many cases in which the change in MP (ΔMP) of compounds correlates with changes in functional groups. In line with the results of a previous study, correlations between ΔMP and simple molecular descriptors, such as the number of hydrogen bond donors, were identified. In using a larger dataset, covering a wider chemical space and range of melting points, we observed that this method remains stable and scales well with larger datasets. This MMP-based method could find use as a simple privacy-preserving technique to analyze large proprietary databases and share findings between participating research groups. An MMP for MPs: A matched molecular pair analysis was used to examine the change in melting point (ΔMP) between molecules in a set of ∼275 000 compounds. We found many cases in which the ΔMP correlates with changes in functional groups and simple descriptors, such as number of hydrogen bond donors and acceptors. We observed that this method remains stable and scales well with larger datasets, indicating its utility as a simple privacy-preserving technique to analyze large proprietary databases and share findings.
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Heme Oxygenase Database (HemeOxDB) and QSAR Analysis of Isoform 1 Inhibitors ()
Due to increasing interest in the field of heme oxygenases (HOs), we built a ligand database called HemeOxDB that includes the entire set of known HO-1 and HO-2 inhibitors, resulting in more than 400 compounds. The HemeOxDB is available online at http://www.researchdsf.unict.it/hemeoxdb/, and having a robust search engine allows end users to build complex queries, sort tabulated results, and generate color-coded two- and three-dimensional graphs. This database will grow to be a tool for the design of potent and selective HO-1 or HO-2 inhibitors. We were also interested in virtually searching for alternative inhibitors, and, for the first time in the field of HOs, a quantitative structure–activity relationship (QSAR) model was built using half-maximal inhibitory concentration (IC50) values of the whole set of known HO-1 inhibitors, taken from the HemeOxDB and employing the Monte Carlo technique. The statistical quality suggested that the model is robust and possesses desirable predictive potential. The screening of US Food and Drug Administration (FDA)-approved drugs, external to our dataset, suggested new predicted inhibitors, opening the way for replacing imidazole groups. The HemeOxDB and the QSAR model reported herein may help in prospectively identifying or repurposing new drugs with optimal structural attributes for HO enzyme inhibition. Heme oxygenase inhibitors: A collection of the whole set of heme oxygenase (HO) inhibitors is reported, and inhibitors of heme oxygenase-1 (HO-1) were used in creating a Monte Carlo based QSAR model. The screening of a number of FDA-approved drugs with the developed model revealed that top-scored compounds share common sulfonylurea or sulfonyl acetamide functions, which may be novel replacements for the imidazole used in the vast majority of HO-1 inhibitors.
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Kinome-Wide Profiling Prediction of Small Molecules ()
Extensive kinase profiling data, covering more than half of the human kinome, are available nowadays and allow the construction of activity prediction models of high practical utility. Proteochemometric (PCM) approaches use compound and protein descriptors, which enables the extrapolation of bioactivity values to thus far unexplored kinases. In this study, the potential of PCM to make large-scale predictions on the entire kinome is explored, considering the applicability on novel compounds and kinases, including clinically relevant mutants. A rigorous validation indicates high predictive power on left-out kinases and superiority over individual kinase QSAR models for new compounds. Furthermore, external validation on clinically relevant mutant kinases reveals an excellent predictive power for mutations spread across the ATP binding site. Kinome-wide prediction of kinase inhibitors: The capabilities of proteochemometric (PCM) models to make large-scale predictions on the entire kinome was explored. The combination of a compound fingerprint with a protein fingerprint 1) improves the activity prediction for each kinase relative to individually trained models and 2) enables prediction of the activity of compounds for the entire kinome, including cancer-related resistance mutations.
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Front Cover: Development of Substrate-Derived Sirtuin Inhibitors with Potential Anticancer Activity (ChemMedChem 20/2017) ()
The Front Cover shows how sirtuin deacetylase inhibitors can be designed based on identified sirtuin-substrate proteins. We identified acetylated K52 of the Rho-regulator RohGDIα (PDB: 5FR2) to be selectively deacetylated by Sirt2 (PDB: 5FYQ). As the lysine acetylation mimic mutation K52Q in RhoGDIα impairs proliferation of cervical cancer cells, we used this information to design a selective and potent peptidic Sirt2 inhibitor with potential anticancer activity. Replacing K52 with trifluoroacetyl-lysine and combining this substrate-derived sequence with a cell-penetrating peptide sequence (sC18-tag) and a cathepsin-protease (CP) cleavage site allows efficient intracellular delivery. More information can be found in the Full Paper by Michael Lammers et al. on page 1703 in Issue 20, 2017 (DOI: 10.1002/cmdc.201700414).
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Cover Feature: Synthesis and Microbiological Evaluation of Novel Tetracyclic Fluoroquinolones (ChemMedChem 20/2017) ()
The Cover Feature shows the conceptual conversion of clinafloxacin to its tetracyclic analog by addition of a 7-membered ring, thereby conformationally fixing the amino-pyrrolidine ring out of plane from the bicyclic quinolone core. The compound is shown bound to one of its targets, topoisomerase IV from S. pneumoniae (PDB 4kpf, I. Laponogov et al., Open Biol. 2016, 6, DOI: 10.1098/rsob.160157) and stacking to its DNA template, depicted schematically in orange. The modification of this fluoroquinolone core resulted in a remarkable enhancement of microbiological potency toward both Gram-positive and Gram-negative bacteria. This presents an excellent advantage in our fight against multidrug-resistant bacteria. More information can be found in the Communication by Heinz E. Moser et al. on page 1687 in Issue 20, 2017 (DOI: 10.1002/cmdc.201700426).
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Update of Antitubercular Prodrugs from a Molecular Perspective: Mechanisms of Action, Bioactivation Pathways, and Associated Resistance ()
The place of prodrugs in the current antitubercular therapeutic arsenal is preponderant, since two of the four first-line antitubercular agents, isoniazid (INH) and pyrazinamide (PZA), need to be activated by Mycobacterium tuberculosis before exerting their activity. In addition, six other prodrugs can be found in the second- and third-line therapeutic regimens. The emergence of mycobacterial strains resistant to one or several antitubercular agents is one of the main issues of the antitubercular therapy. In the case of prodrugs, the resistance phenomenon is often related to a mutation in the gene encoding for the activation enzymes, resulting thus in a default of these enzymes that are no more able to activate prodrugs. Consequently, identification of the prodrugs targets and a better understanding of their modes of action and also of their activation mechanisms are of crucial importance. Related to their molecular mechanism of activation, these prodrugs may thus be classified in four categories: activation via oxidation (catalase–peroxidase (KatG) or flavin monooxygenase (EthA) enzymes), condensation (FolP1 and FolC), hydrolysis (by the amidase PncA) and reduction (by the nitroreductase DnD) mechanisms. For each prodrug, these mechanisms are described in details, as well as the mechanism of action of its active metabolite. Finally, the reported resistance related to these mechanisms of activation/action are also addressed in a molecular perspective. The place of prodrugs (bioprecusors) in the current antitubercular therapeutic arsenal is preponderant. This review focuses on recent advances in the field of gaining a molecular-level understanding of bioactivation pathways as well as on the proposed mechanisms of action of the active metabolites. In addition, the reported resistance related to these mechanisms of activation/action are also addressed from a molecular perspective.
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WNK Signaling Inhibitors as Potential Antihypertensive Drugs ()
Since the discovery of WNK mutations that cause an inherited form of hypertension in humans, there has been increasing interest in targeting WNK signaling as a novel strategy for modulating blood pressure. This notion is now supported by numerous mouse models with impaired WNK signaling that exhibit reduced blood pressure. Biochemical analyses of the various protein components that make up this signaling pathway have identified a number of plausible molecular targets that are amenable to targeting by small molecules. To date, a selection of small-molecule WNK signaling inhibitors have been identified and have shown promise in suppressing the activity of WNK signaling in cells and in animals. In this Minireview, we briefly discuss the WNK signaling pathway and provide an overview of the various druggable targets within this cascade, as well as the different WNK signaling inhibitors discovered to date. Various components of the WNK signaling cascade have been validated in vivo as viable targets for antihypertensive drugs. A selection of kinase and protein–protein interaction inhibitors, which have shown great promise in lowering blood pressure in vivo, have been reported. Herein we provide insight into the discovery the various reported WNK signaling inhibitors and offer an outlook into the future of targeting the WNK signaling pathway.
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Synthesis and Microbiological Evaluation of Novel Tetracyclic Fluoroquinolones ()
Conformationally constrained tetracyclic fluoroquinolones (FQs) were synthesized and profiled for their microbiological spectrum. The installation of a seven-membered ring between the pyrrolidine substituents and the C8 position on the FQ core scaffold resulted in a remarkable enhancement of microbiological potency toward both Gram-positive and Gram-negative bacteria. Focused optimization of seven-membered ring composition, stereochemistry, and amine placement led to the discovery of the two lead compounds that were selected for further progression. Conformationally constrained tetracyclic fluoroquinolones (FQs) were synthesized and profiled for their microbiological spectrum. Installation of a seven-membered ring between the pyrrolidine substituents and the C8 position on the FQ scaffold resulted in a remarkable enhancement in potency on both Gram-positive and Gram-negative bacteria. Focused optimization of seven-membered ring composition, stereochemistry, and amine placement yielded the two lead compounds 36 and 40.
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Dynamic Combinatorial Chemistry to Identify Binders of ThiT, an S-Component of the Energy-Coupling Factor Transporter for Thiamine ()
We applied dynamic combinatorial chemistry (DCC) to identify ligands of ThiT, the S-component of the energy-coupling factor (ECF) transporter for thiamine in Lactococcus lactis. We used a pre-equilibrated dynamic combinatorial library (DCL) and saturation-transfer difference (STD) NMR spectroscopy to identify ligands of ThiT. This is the first report in which DCC is used for fragment growing to an ill-defined pocket, and one of the first reports for its application with an integral membrane protein as target. Dynamic tools for moving targets: We applied dynamic combinatorial chemistry and saturation-transfer difference 1H NMR spectroscopy with detergent to identify binders of the energy-coupling factor transporter for thiamine that target the flexible pocket of this transmembrane protein. This is the first report in which DCC is used for fragment growing to an ill-defined pocket, and one of the first reports for its application with an integral membrane protein as target.
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Porphyrin Derivatives Inhibit the Interaction between Receptor Activator of NF-κB and Its Ligand ()
Receptor activator of NF-κB (RANK), a member of the TNF-receptor superfamily, plays an important role in bone resorption and stimulates immune and epithelial cell activation. Denosumab, a human monoclonal antibody that blocks the RANK ligand (RANKL), is approved for the treatment of osteoporosis and bone metastasis. However, a small molecule that inhibits the RANK–RANKL interaction would be beneficial to decrease cost and to facilitate treatments with orally available therapeutic agents. Herein we report the discovery of the first nonpeptidic inhibitors of RANK–RANKL interactions. In screening a chemical library by competitive ELISA, the porphyrin verteporfin was identified as a hit. Derivatives were screened, and the chlorin-macrocycle-containing pheophorbide A and purpurin 18 were found to bind recombinant RANKL, to inhibit RANK–RANKL interactions in the ELISA, and to suppress the RANKL-dependent activation of model cells and the differentiation of RANK-expressing precursors into osteoclasts. This discovery of a family of small molecules that inhibit RANK activation presents an initial basis for further development of nonpeptidic therapeutic agents targeting the interaction between RANK and RANKL. Pulling RANK: Receptor activator of NF-κB (RANK) plays a key role in bone resorption and stimulates immune and epithelial cell activation. A small-molecule inhibitor of the interaction between RANK and its ligand (RANKL) would facilitate treatments with orally available drugs. Herein we report the first nonpeptidic inhibitors of RANK–RANKL interactions. This discovery of a group of small molecules that block RANK activation provides an initial basis for further development of nonpeptidic agents that target the interaction between RANK and RANKL.
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Development of Substrate-Derived Sirtuin Inhibitors with Potential Anticancer Activity ()
RhoGDIα is a key regulator of Rho proteins, coordinating their GTP/GDP and membrane/cytosol cycle. Recently, it was demonstrated by quantitative mass spectrometry that RhoGDIα is heavily targeted by post-translational lysine acetylation. For one site in its N-terminal domain, namely K52, we reported earlier that acetylation completely switches off RhoGDIα function. Herein we show that K52-acetylated RhoGDIα is specifically deacetylated by the sirtuin deacetylase Sirt2. We show that acetylation at K52 decelerates cervical cancer cell proliferation, suggesting RhoGDIα acetylation to be a promising therapeutic target. We demonstrate that treatment of cervical cancer cells with a RhoGDIα-derived K52-trifluoroacetylated, substrate-derived peptidic sirtuin inhibitor severely impairs cell proliferation. Finally, we conclude that the potency of substrate-derived sirtuin inhibitors depends on structural features, the substrate-derived amino acid sequence as a determinant for selectivity, as well as the presence of an acetyl-lysine analogue to increase its potency. These data reveal a prospective therapeutic potential for novel substrate-derived sirtuin inhibitors. Substrate-based sirtuin inhibitors: Sirtuin deacetylases play important roles in the development of severe diseases such as cancer and neurodegenerative disorders. Therapeutics that tackle sirtuin activity must be potent and selective. We describe how sirtuin inhibitors can be designed based on identified non-histone substrates, taking RhoGDIα as an example. We show that using substrate-based peptides carrying an acetyl-lysine analogue, such as trifluoroacetyl-lysine, in combination with cell-penetrating peptides is a promising strategy to develop selective and potent sirtuin inhibitors for therapeutic applications.
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Solubility-Improved 10-O-Substituted SN-38 Derivatives with Antitumor Activity ()
With the objective of improving the poor water solubility of the potent antitumor compound SN-38, 10-O-substituted SN-38 derivatives were developed by the introduction of fluoroalkyl, fluorobenzoyl, or bromobenzoyl groups. The 10-O-fluoropropyl-substituted compound 2 {(S)-4,11-diethyl-9-(3-fluoropropoxy)-4-hydroxy-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione} was found to be 17-fold more soluble than SN-38 in phosphate-buffered saline, and it exhibited a level of biological activity ≈50 % that of SN-38 in a cytotoxicity assay using the prostate cancer cell line PC-3. Five other derivatives did not show solubility improvements to the same extent, but their activities in cytotoxicity assays were nearly the same as that of SN-38. In vivo studies of 2 with PC-3 tumor-bearing mice revealed that it has higher antitumor activity than SN-38, even at lower dosage. These results will promote the medicinal chemistry application of 10-O-modifications of SN-38 and help reestablish the potential this drug. Furthermore, the inclusion of fluoro and bromo substituents means that the synthetic strategy developed here may be used to obtain 18F- or 76Br-labeled SN-38 derivatives for in vivo positron emission tomography studies. Higher caliber than a 38: To improve the poor water solubility of the potent antitumor compound SN-38, 10-O-substituted derivatives of this compound were developed. The 10-O-fluoropropyl-substituted derivative was found to be 17-fold more soluble than SN-38 in phosphate-buffered saline. An in vivo study of this derivative conducted using PC-3 tumor-bearing mice revealed that it has higher antitumor activity than SN-38.
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A Selective Biligand Inhibitor of CK2 Increases Caspase-3 Activity in Cancer Cells and Inhibits Platelet Aggregation ()
Cancer cells express high levels of CK2, and its inhibition leads to apoptosis. CK2 has therefore emerged as a new drug target for cancer therapy. A biligand inhibitor ARC-772 was constructed by conjugating 4-(2-amino-1,3-thiazol-5-yl)benzoic acid and a carboxylate-rich peptoid. ARC-772 was found to bind CK2 with a Kd value of 0.3 nm and showed remarkable CK2 inhibitory selectivity in a panel of 140 protein kinases (Gini coefficient: 0.75 at c=100 nm). ARC-775, the acetoxymethyl ester prodrug of ARC-772, was efficiently taken up by cells. Once internalized, the inhibitor is activated by cellular esterase activity. In HeLa cancer cells ARC-775 was found to activate caspase-3 (an apoptosis marker) at sub-micromolar concentrations (EC50=0.3 μm), a 20-fold lower extracellular concentration than CX-4945, the only CK2 inhibitor under clinical trials. At micromolar concentrations, ARC-775 was also found to inhibit ADP-induced aggregation of human platelets. The overall results of this study demonstrate that oligo-anionic biligand inhibitors have good potential for drug development. True multitasking: Biligand inhibitors that may be developed into drug candidates or applied to study signaling pathways regulated by CK2 were constructed. Per-esterification of inhibitor ARC-772 [shown, Kd(CK2)=0.3 nm] supported intracellular uptake [shown, c (in cells)=100 μm]. Relative to CX-4945 (currently in clinical trials), ARC-772 revealed higher cellular efficiency.
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Corrigendum: Simultaneous Multiple MS Binding Assays Addressing D1 and D2 Dopamine Receptors ()

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