RESUMO
Target- and phenotype-agnostic assessments of biological activity have emerged as viable strategies for prioritizing scaffolds, structural features, and synthetic pathways in screening sets, with the goal of increasing performance diversity. Here, we describe the synthesis of a small library of functionalized stereoisomeric azetidines and its biological annotation by "cell painting," a multiplexed, high-content imaging assay capable of measuring many hundreds of compound-induced changes in cell morphology in a quantitative and unbiased fashion. Using this approach, we systematically compare the degrees to which a core scaffold's biological activity, inferred from its effects on cell morphology, is affected by variations in stereochemistry and appendages. We show that stereoisomerism and appendage diversification can produce effects of similar magnitude, and that the concurrent use of these strategies results in a broader sampling of biological activity.
Assuntos
Azetidinas/química , Bibliotecas de Moléculas Pequenas/química , Azetidinas/síntese química , Linhagem Celular Tumoral , Humanos , Conformação Molecular , Imagem Óptica , Bibliotecas de Moléculas Pequenas/síntese química , EstereoisomerismoRESUMO
The development of new antimalarial therapeutics is necessary to address the increasing resistance to current drugs. Bicyclic azetidines targeting Plasmodium falciparum phenylalanyl-tRNA synthetase comprise one promising new class of antimalarials, especially due to their activities against three stages of the parasite's life cycle, but a lengthy synthetic route to these compounds may affect the feasibility of delivering new therapeutic agents within the cost constraints of antimalarial drugs. Here, we report an efficient synthesis of antimalarial compound BRD3914 (EC50 = 15 nM) that hinges on a Pd-catalyzed, directed C(sp3)-H arylation of azetidines at the C3 position. This newly developed protocol exhibits a broad substrate scope and provides access to valuable, stereochemically defined building blocks. BRD3914 was evaluated in P. falciparum-infected mice, providing a cure after four oral doses.
Assuntos
Antimaláricos/síntese química , Antimaláricos/uso terapêutico , Azetidinas/síntese química , Azetidinas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Azetidinas/química , Azetidinas/farmacologia , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Compostos Bicíclicos com Pontes/uso terapêutico , Catálise , Modelos Animais de Doenças , Células Hep G2 , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Paládio/química , EstereoisomerismoRESUMO
Verruculogen and fumitremorgin A are bioactive alkaloids that contain a unique eight-membered endoperoxide. Although related natural products such as fumitremorgins B and C have been previously synthesized, we report the first synthesis of the more complex, endoperoxide-containing members of this family. A concise route to verruculogen and fumitremorgin A relied not only on a hydroperoxide/indole hemiaminal cyclization, but also on the ability to access the seemingly simple starting material, 6-methoxytryptophan. An iridium-catalyzed C-H borylation/Chan-Lam procedure guided by an N-TIPS group enabled the conversion of a tryptophan derivative into a 6-methoxytryptophan derivative, proving to be a general way to functionalize the C6 position of an N,C3-disubstituted indole for the synthesis of indole-containing natural products and pharmaceuticals.
Assuntos
Indenos/síntese química , Indóis/síntese química , Catálise , Técnicas de Química Sintética , Indenos/química , Indóis/química , Irídio/química , Estrutura Molecular , Triptofano/análogos & derivados , Triptofano/químicaRESUMO
A combination of ruthenium and photoredox catalysis allowed the ortho olefination of phenols. Using visible light, the direct C-H functionalization of o-(2-pyridyl)phenols occurred, and diverse phenol ethers were obtained in good yields. The regeneration of the ruthenium catalyst was accomplished by a photoredox-catalyzed oxidative process.
Assuntos
Compostos Organometálicos/química , Oxidantes/síntese química , Fenóis/química , Rutênio/química , Catálise , Estrutura Molecular , Oxidantes/química , Oxirredução , Processos FotoquímicosRESUMO
Direct, oxidative metal-catalyzed C-H functionalizations of arenes are important in synthetic organic chemistry. Often, (over-)stoichoimetric amounts of organic or inorganic oxidants have to be used in these reactions. The combination of rhodium and photoredox catalysis with visible light allows the direct C-H olefination of arenes. Small amounts (1â mol%) of a photoredox catalyst resulted in the efficient C-H functionalization of a broad range of substrates under mild conditions.
RESUMO
A combined palladium- and photoredox-catalyzed C-H olefination enables the synthesis of indoles. By using visible light, the direct C-H activation of aromatic enamines can be achieved and a variety of indole derivatives can be obtained in good yields under mild reaction conditions.
Assuntos
Indóis/síntese química , Paládio/química , Catálise , Luz , Estrutura MolecularRESUMO
Previous studies have shown that bicyclic azetidines are potent and selective inhibitors of apicomplexan phenylalanine tRNA synthetase (PheRS), leading to parasite growth inhibition in vitro and in vivo, including in models of Toxoplasma infection. Despite these useful properties, additional optimization is required for the development of efficacious treatments of toxoplasmosis from this inhibitor series, in particular, to achieve optimal exposure in the brain. Here, we describe a series of PheRS inhibitors built on a new bicyclic pyrrolidine core scaffold designed to retain the exit-vector geometry of the isomeric bicyclic azetidine core scaffold while offering avenues to sample diverse chemical space. Relative to the parent series, bicyclic pyrrolidines retain reasonable potency and target selectivity for parasite PheRS vs host. Further structure-activity relationship studies revealed that the introduction of aliphatic groups improved potency and ADME and PK properties, including brain exposure. The identification of this new scaffold provides potential opportunities to extend the analogue series to further improve selectivity and potency and ultimately deliver a novel, efficacious treatment of toxoplasmosis.
Assuntos
Encéfalo , Fenilalanina-tRNA Ligase , Pirrolidinas , Toxoplasma , Toxoplasma/efeitos dos fármacos , Toxoplasma/enzimologia , Pirrolidinas/farmacologia , Pirrolidinas/química , Animais , Encéfalo/parasitologia , Relação Estrutura-Atividade , Fenilalanina-tRNA Ligase/antagonistas & inibidores , Fenilalanina-tRNA Ligase/química , Antiparasitários/farmacologia , Antiparasitários/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Camundongos , Toxoplasmose/tratamento farmacológico , Humanos , Azetidinas/farmacologia , Azetidinas/químicaRESUMO
Previous studies have shown that bicyclic azetidines are potent and selective inhibitors of apicomplexan phenylalanine tRNA synthetase (PheRS), leading to parasite growth inhibition in vitro and in vivo, including in models of Toxoplasma infection. Despite these useful properties, additional optimization is required for the development of efficacious treatments of toxoplasmosis from this inhibitor series, in particular to achieve sufficient exposure in the brain. Here, we describe a series of PheRS inhibitors built on a new bicyclic pyrrolidine core scaffold designed to retain the exit-vector geometry of the isomeric bicyclic azetidine core scaffold while offering avenues to sample diverse chemical space. Relative to the parent series, bicyclic pyrrolidines retain reasonable potency and target selectivity for parasite PheRS vs. host. Further structure-activity relationship studies revealed that the introduction of aliphatic groups improved potency, ADME and PK properties, including brain exposure. The identification of this new scaffold provides potential opportunities to extend the analog series to further improve selectivity and potency and ultimately deliver a novel, efficacious treatment of toxoplasmosis.
RESUMO
Let there be light: A heterogeneous photocatalytic system based on easily recyclable TiO(2) or ZnO allows cross dehydrogenative coupling reactions of tertiary amines. The newly developed protocols have successfully been applied to various C-C and C-P bond-forming reactions to provide nitro amines as well as amino ketones, nitriles and phosphonates.
RESUMO
An efficient and stereospecific Pd-catalyzed protocol for the C-H arylation of pyroglutamic acid derivatives that uses 8-aminoquinoline as a directing group is described. The reaction was shown to proceed efficiently with a variety of aryl and heteroaryl iodides bearing different functional groups, giving C3-arylated cis products in good to high yields. Removal of the 8-aminoquinoline unit from these C-H arylation products enables access to synthetically useful cis and trans pyroglutamic acid-based building blocks.