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1.
ChemMedChem ; 16(21): 3326-3341, 2021 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-34288488

RESUMO

Free fatty acid receptor 2 (FFA2) is a sensor for short-chain fatty acids that has been identified as an interesting potential drug target for treatment of metabolic and inflammatory diseases. Although several ligand series are known for the receptor, there is still a need for improved compounds. One of the most potent and frequently used antagonists is the amide-substituted phenylbutanoic acid known as CATPB (1). We here report the structure-activity relationship exploration of this compound, leading to the identification of homologues with increased potency. The preferred compound 37 (TUG-1958) was found, besides improved potency, to have high solubility and favorable pharmacokinetic properties.


Assuntos
Amidas/farmacologia , Descoberta de Drogas , Fenilbutiratos/farmacologia , Receptores de Superfície Celular/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Animais , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Fenilbutiratos/síntese química , Fenilbutiratos/química , Receptores de Superfície Celular/metabolismo , Relação Estrutura-Atividade
2.
Mol Psychiatry ; 26(8): 4004-4015, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-31628418

RESUMO

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder with only symptomatic care available. Genome-wide association (GWA) studies can provide a starting point in the search for novel drug targets and possibilities of drug repurposing. Here, we explored the druggable genome in ADHD by utilising GWA studies on ADHD and its co-morbid conditions. First, we explored whether the genes targeted by current ADHD drugs show association with the disorder and/or its co-morbidities. Second, we aimed to identify genes and pathways involved in the biological processes underlying ADHD that can be targeted by pharmacological agents. These ADHD-associated druggable genes and pathways were also examined in co-morbidities of ADHD, as commonalities in their aetiology and management may lead to novel pharmacological insights. Strikingly, none of the genes encoding targets of first-line pharmacotherapeutics for ADHD were significantly associated with the disorder, suggesting that FDA-approved ADHD drugs may act through different mechanisms than those underlying ADHD. In the examined druggable genome, three loci on chromosomes 1, 4 and 12 revealed significant association with ADHD and contained nine druggable genes, five of which encode established drug targets for malignancies, autoimmune and neurodevelopmental disorders. To conclude, we present a framework to assess the druggable genome in a disorder, exemplified by ADHD. We highlight signal transduction and cell adhesion as potential novel avenues for ADHD treatment. Our findings add to knowledge on known ADHD drugs and present the exploration of druggable genome associated with ADHD, which may offer interventions at the aetiological level of the disorder.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtornos do Neurodesenvolvimento , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Comorbidade , Estudo de Associação Genômica Ampla , Humanos
3.
Molecules ; 25(20)2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33096668

RESUMO

Phorbazoles are polychlorinated heterocyclic secondary metabolites isolated from a marine sponge and several of these natural products have shown inhibitory activity against cancer cells. In this work, a synthesis of the trichlorinated phorbazole B using late stage electrophilic chlorination was developed. The synthesis relied on the use of an oxazole precursor, which was protected with an iodine in the reactive 4-position, followed by complete chlorination of all pyrrole positions. Attempts to prepare phorbazole A and C, which contain a 3,4-dichlorinated pyrrole, were unsuccessful as the desired chlorination pattern on the pyrrole could not be obtained. The identities of the dichlorinated intermediates and products were determined using NMR techniques including NOESY/ROESY, 1,1-ADEQUATE and high-resolution CLIP-HSQMBC.


Assuntos
Compostos Heterocíclicos/síntese química , Hidrocarbonetos Clorados/síntese química , Compostos Heterocíclicos/química , Hidrocarbonetos Clorados/química , Estrutura Molecular , Estereoisomerismo
4.
Chem Sci ; 11(44): 12081-12088, 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34094423

RESUMO

Structural features of proton-deficient heteroaromatic natural products, such as the breitfussins, can severely complicate their characterization by NMR spectroscopy. For the breitfussins in particular, the constitution of the five-membered oxazole central ring cannot be unequivocally established via conventional NMR methods when the 4'-position is halogenated. The level of difficulty is exacerbated by 4'-iodination, as the accuracy with which theoretical NMR parameters are determined relies extensively on computational treatment of the relativistic effects of the iodine atom. It is demonstrated in the present study, that the structure of a 4'-iodo breitfussin analog can be unequivocally established by anisotropic NMR methods, by adopting a reduced singular value decomposition (SVD) protocol that leverages the planar structures exhibited by its conformers.

5.
J Med Chem ; 62(22): 10167-10181, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31647655

RESUMO

In this work, we demonstrate that the indole-oxazole-pyrrole framework of the breitfussin family of natural products is a promising scaffold for kinase inhibition. Six new halogenated natural products, breitfussin C-H (3 - 8) were isolated and characterized from the Arctic, marine hydrozoan Thuiaria breitfussi. The structures of two of the new natural products were also confirmed by total synthesis. Two of the breitfussins (3 and 4) were found to selectively inhibit the survival of several cancer cell lines, with the lowest IC50 value of 340 nM measured against the drug-resistant triple negative breast cancer cell line MDA-MB-468, while leaving the majority of the tested cell lines not or significantly less affected. When tested against panels of protein kinases, 3 gave IC50 and Kd values as low as 200 and 390 nM against the PIM1 and DRAK1 kinases, respectively. The activity was confirmed to be mediated through ATP competitive binding in the ATP binding pocket of the kinases. Furthermore, evaluation of potential off-target and toxicological effects, as well as relevant in vitro ADME parameters for 3 revealed that the breitfussin scaffold holds promise for the development of selective kinase inhibitors.


Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/química , Regiões Árticas , Sítios de Ligação , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Embrião não Mamífero/efeitos dos fármacos , Feminino , Humanos , Hidrocarbonetos Bromados/química , Hidrozoários/química , Indóis/química , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/toxicidade , Proteínas Proto-Oncogênicas c-pim-1/química , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Testes de Toxicidade , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Peixe-Zebra/embriologia
6.
J Med Chem ; 60(13): 5638-5645, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28570808

RESUMO

The free fatty acid receptor 2 (FFA2/GPR43) is considered a potential target for treatment of metabolic and inflammatory diseases. Here we describe the development of the first fluorescent tracer for FFA2 intended as a tool for assessment of thermodynamic and kinetic binding parameters of unlabeled ligands. Starting with a known azetidine FFA2 antagonist, we used a carboxylic acid moiety known not to be critical for receptor interaction as attachment point for a nitrobenzoxadiazole (NBD) fluorophore. This led to the development of 4 (TUG-1609), a fluorescent tracer for FFA2 with favorable spectroscopic properties and high affinity, as determined by bioluminescence resonance energy transfer (BRET)-based saturation and kinetic binding experiments, as well as a high specific to nonspecific BRET binding signal. A BRET-based competition binding assay with 4 was also established and used to determine binding constants and kinetics of unlabeled ligands.


Assuntos
Corantes Fluorescentes/química , Oxidiazóis/química , Receptores de Superfície Celular/análise , Azetidinas/química , Azetidinas/metabolismo , Sítios de Ligação , Ligação Competitiva , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Corantes Fluorescentes/metabolismo , Humanos , Ligantes , Oxidiazóis/metabolismo , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/metabolismo , Espectrometria de Fluorescência
7.
Mol Cell Biol ; 36(20): 2583-95, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27503855

RESUMO

Ligands with improved potency and selectivity for free fatty acid receptor 2 (FFA2R) have become available, and we here characterize the neutrophil responses induced by one such agonist (Cmp1) and one antagonist (CATPB). Cmp1 triggered an increase in the cytosolic concentration of Ca(2+), and the neutrophils were then desensitized to Cmp1 and to acetate, a naturally occurring FFA2R agonist. The antagonist CATPB selectively inhibited responses induced by Cmp1 or acetate. The activated FFA2R induced superoxide anion secretion at a low level in naive blood neutrophils. This response was largely increased by tumor necrosis factor alpha (TNF-α) in a process associated with a recruitment of easily mobilizable granules, but neutrophils recruited to an aseptic inflammation in vivo were nonresponding. Superoxide production induced by Cmp1 was increased in latrunculin A-treated neutrophils, but no reactivation of desensitized FFA2R was induced by this drug, suggesting that the cytoskeleton is not directly involved in terminating the response. The functional and regulatory differences between the receptors that recognize short-chain fatty acids and formylated peptides, respectively, imply different roles of these receptors in the orchestration of inflammation and confirm the usefulness of a selective FFA2R agonist and antagonist as tools for the exploration of the precise role of the FFA2R.


Assuntos
Citoesqueleto/metabolismo , Neutrófilos/efeitos dos fármacos , Receptores de Superfície Celular/agonistas , Fator de Necrose Tumoral alfa/farmacologia , Acetatos/farmacologia , Cálcio/metabolismo , Humanos , Inflamação , Neutrófilos/metabolismo , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Superóxidos/metabolismo
8.
Org Biomol Chem ; 14(2): 430-433, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26586516

RESUMO

A protocol for amide coupling by in situ formation of acyl fluorides and reaction with amines at elevated temperature has been developed and found to be efficient for coupling of sterically hindered substrates and electron deficient amines where standard methods failed.

9.
J Biol Chem ; 291(1): 303-17, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26518871

RESUMO

Short chain fatty acids (SCFAs) are produced in the gut by bacterial fermentation of poorly digested carbohydrates. A key mediator of their actions is the G protein-coupled free fatty acid 2 (FFA2) receptor, and this has been suggested as a therapeutic target for the treatment of both metabolic and inflammatory diseases. However, a lack of understanding of the molecular determinants dictating how ligands bind to this receptor has hindered development. We have developed a novel radiolabeled FFA2 antagonist to probe ligand binding to FFA2, and in combination with mutagenesis and molecular modeling studies, we define how agonist and antagonist ligands interact with the receptor. Although both agonist and antagonist ligands contain negatively charged carboxylates that interact with two key positively charged arginine residues in transmembrane domains V and VII of FFA2, there are clear differences in how these interactions occur. Specifically, although agonists require interaction with both arginine residues to bind the receptor, antagonists require an interaction with only one of the two. Moreover, different chemical series of antagonist interact preferentially with different arginine residues. A homology model capable of rationalizing these observations was developed and provides a tool that will be invaluable for identifying improved FFA2 agonists and antagonists to further define function and therapeutic opportunities of this receptor.


Assuntos
Aminoácidos/metabolismo , Receptores de Superfície Celular/agonistas , Receptores de Superfície Celular/antagonistas & inibidores , Sítios de Ligação , Ligação Competitiva , Butiratos/química , Butiratos/farmacologia , Ácido Butírico/farmacologia , Ésteres/metabolismo , Células HEK293 , Humanos , Cinética , Ligantes , Modelos Moleculares , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Receptores de Superfície Celular/química , Tiofenos/química , Tiofenos/farmacologia , Trítio/metabolismo
10.
J Biol Chem ; 288(24): 17296-312, 2013 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-23589301

RESUMO

FFA2 is a G protein-coupled receptor that responds to short chain fatty acids and has generated interest as a therapeutic target for metabolic and inflammatory conditions. However, definition of its functions has been slowed by a dearth of selective ligands that can distinguish it from the closely related FFA3. At present, the only selective ligands described for FFA2 suffer from poor potency, altered signaling due to allosteric modes of action, or a lack of function at non-human orthologs of the receptor. To address the need for novel selective ligands, we synthesized two compounds potentially having FFA2 activity and examined the molecular basis of their function. These compounds were confirmed to be potent and selective orthosteric FFA2 agonists. A combination of ligand structure-activity relationship, pharmacological analysis, homology modeling, species ortholog comparisons, and mutagenesis studies were then employed to define the molecular basis of selectivity and function of these ligands. From this, we identified key residues within both extracellular loop 2 and the transmembrane domain regions of FFA2 critical for ligand function. One of these ligands was active with reasonable potency at rodent orthologs of FFA2 and demonstrated the role of FFA2 in inhibition of lipolysis and glucagon-like peptide-1 secretion in murine-derived 3T3-L1 and STC-1 cell lines, respectively. Together, these findings describe the first potent and selective FFA2 orthosteric agonists and demonstrate key aspects of ligand interaction within the binding site of FFA2 that will be invaluable in future ligand development at this receptor.


Assuntos
Butiratos/farmacologia , Ciclopropanos/farmacologia , Receptores de Superfície Celular/agonistas , Tiazóis/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Regulação Alostérica , Motivos de Aminoácidos , Substituição de Aminoácidos , Animais , Benzenoacetamidas/farmacologia , Sítios de Ligação , Ciclopropanos/química , Células Enteroendócrinas/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Células HEK293 , Humanos , Lipólise/efeitos dos fármacos , Camundongos , Modelos Moleculares , Mutagênese Sítio-Dirigida , Ligação Proteica , Estrutura Terciária de Proteína , Ratos , Receptores de Superfície Celular/química , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Tiazóis/química
11.
J Biol Chem ; 287(49): 41195-209, 2012 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-23066016

RESUMO

Free fatty acid receptors 2 and 3 (FFA2 and FFA3) are G protein-coupled receptors for short chain free fatty acids (SCFAs). They respond to the same set of endogenous ligands but with distinct rank-order of potency such that acetate (C2) has been described as FFA2-selective, whereas propionate (C3) is non-selective. Although C2 was confirmed to be selective for human FFA2 over FFA3, this ligand was not selective between the mouse orthologs. Moreover, although C3 was indeed not selective between the human orthologs, it displayed clear selectivity for mouse FFA3 over mouse FFA2. This altered selectivity to C2 and C3 resulted from broad differences in SCFAs potency at the mouse orthologs. In studies to define the molecular basis for these observations, marked variation in ligand-independent constitutive activity was identified using a [(35)S]GTPγS assay. The orthologs with higher potency for the SCFAs, human FFA2 and mouse FFA3, displayed high constitutive activity in this assay, whereas the orthologs with lower potency for the agonist ligands, mouse FFA2 and human FFA3, did not. Sequence alignments of the second extracellular loop identified single negatively charged residues in FFA2 and FFA3 not conserved between species and predicted to form ionic lock interactions with arginine residues within the FFA2 or FFA3 agonist binding pocket to regulate constitutive activity and SCFA potency. Reciprocal mutation of these residues between species orthologs resulted in the induction (or repression) of constitutive activity and in most cases also yielded corresponding changes in SCFA potency.


Assuntos
Receptores de Superfície Celular/química , Receptores Acoplados a Proteínas G/química , Sequência de Aminoácidos , Animais , Ácido Butírico/química , Ácidos Graxos/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Humanos , Íons , Ligantes , Camundongos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Mutação , Ligação Proteica , Estrutura Terciária de Proteína , Ratos , Homologia de Sequência de Aminoácidos , Transdução de Sinais
12.
J Pharm Bioallied Sci ; 4(3): 255-6, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22923970
13.
Chemistry ; 17(46): 12946-54, 2011 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-22012682

RESUMO

The synthesis of homochiral homo-oligomers of cis- and trans-3-aminotetrahydrofuran-2-carboxylic acids (parent cis- and trans-furanoid-ß-amino acids, referred to as "cis-/trans-FAA") has been carried out to understand their secondary structures and their dependence on the ring heteroatom. The oligomers of two diastereomers have been shown to have a distinct left-handed helicity. The cis-FAA homo-oligomers show a 14-helix structure, in contrast to the homo-oligomers of cis-ACPC, which adopt a sheet like structure. The trans-FAA homo-oligomers were found to adopt a 12-helix structure, the same trend found in trans-ACPC homo-oligomers. With the help of ab initio calculations, the structural features of cis-ACPC and cis-FAA hexamers were compared. We believe that the more compact packing of the cis-FAA hexapeptide should be due to a more favorable interaction between the ring and the backbone amide hydrogen.


Assuntos
Aminoácidos/síntese química , Peptídeos/síntese química , Aminoácidos/química , Azidas/química , Ácidos Carboxílicos/química , Furanos/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Peptídeos/química , Estrutura Secundária de Proteína , Estereoisomerismo
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