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1.
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
2.
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
3.
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
4.
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
5.
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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