RESUMO
A palladium-catalysed Buchwald-Hartwig amination for lenalidomide-derived aryl bromides was optimised using high throughput experimentation (HTE). The substrate scope of the optimised conditions was evaluated for a range of alkyl- and aryl- amines and functionalised aryl bromides. The methodology allows access to new cereblon-based bifunctional proteolysis targeting chimeras with a reduced step count and improved yields.
Assuntos
Aminas/química , Brometos/química , Lenalidomida/química , Proteólise/efeitos dos fármacos , Aminação , Ligantes , Ubiquitina-Proteína Ligases/metabolismoRESUMO
High throughput screening to identify inhibitors of the mTOR kinase revealed sulfonyl-morpholino-pyrimidine 1 as an attractive start point. The compound displayed good physicochemical properties and selectivity over related kinases such as PI3Kα. Library preparation of related analogs allowed the establishment of additional SAR understanding and in particular the requirement for a key hydrogen bond donor motif at the 4-position of the phenyl ring in compounds such as indole 19. Isosteric replacement of the indole functionality led to the identification of urea compounds such as 32 that show good levels of mTOR inhibition in both enzyme and cellular assays.
Assuntos
Antineoplásicos/síntese química , Morfolinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Sulfonas/síntese química , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Humanos , Ligação de Hidrogênio , Indóis/química , Concentração Inibidora 50 , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Sulfonas/farmacologia , Serina-Treonina Quinases TOR/química , Ureia/análogos & derivados , Ureia/químicaRESUMO
ATAD2 is an epigenetic bromodomain-containing target which is overexpressed in many cancers and has been suggested as a potential oncology target. While several small molecule inhibitors have been described in the literature, their cellular activity has proved to be underwhelming. In this work, we describe the identification of a novel series of ATAD2 inhibitors by high throughput screening, confirmation of the bromodomain region as the site of action, and the optimization campaign undertaken to improve the potency, selectivity, and permeability of the initial hit. The result is compound 5 (AZ13824374), a highly potent and selective ATAD2 inhibitor which shows cellular target engagement and antiproliferative activity in a range of breast cancer models.
Assuntos
ATPases Associadas a Diversas Atividades Celulares/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proteínas de Ligação a DNA/antagonistas & inibidores , Linhagem Celular Tumoral , Cristalografia por Raios X , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Modelos Moleculares , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Especificidade por Substrato , Ensaio Tumoral de Célula-TroncoRESUMO
Aberrant activity of the histone methyltransferase polycomb repressive complex 2 (PRC2) has been linked to several cancers, with small-molecule inhibitors of the catalytic subunit of the PRC2 enhancer of zeste homologue 2 (EZH2) being recently approved for the treatment of epithelioid sarcoma (ES) and follicular lymphoma (FL). Compounds binding to the EED subunit of PRC2 have recently emerged as allosteric inhibitors of PRC2 methyltransferase activity. In contrast to orthosteric inhibitors that target EZH2, small molecules that bind to EED retain their efficacy in EZH2 inhibitor-resistant cell lines. In this paper we disclose the discovery of potent and orally bioavailable EED ligands with good solubilities. The solubility of the EED ligands was optimized through a variety of design tactics, with the resulting compounds exhibiting in vivo efficacy in EZH2-driven tumors.
Assuntos
Inibidores Enzimáticos/farmacologia , Complexo Repressor Polycomb 2/antagonistas & inibidores , Regulação Alostérica , Animais , Domínio Catalítico , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/química , Proteína Potenciadora do Homólogo 2 de Zeste/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Compostos Heterocíclicos/química , Humanos , Ligantes , Complexo Repressor Polycomb 2/química , Ratos , Relação Estrutura-AtividadeRESUMO
The facile synthesis of both saturated and unsaturated tricyclic pyrrolo-pyridones starting from a single readily available, common monocyclic reagent has been developed. An intermolecular annulation via a tandem Buchwald-Hartwig/Heck reaction led to the synthesis of ß-carbolinones. The analogous semisaturated tricyclic pyrrolo-pyridones were prepared in good to excellent yields by sequential Buchwald-Hartwig and Fischer indole reactions. The methods feature mild reaction conditions and good functional group tolerance.
RESUMO
Amination of C-H bonds activated by ether oxygen atoms is facile with chloramine-T as nitrene source and copper(I) chloride in acetonitrile as catalyst. For cyclic ethers the hemiaminal products are generally stable and can be isolated pure. For acyclic ethers, the hemiaminal products, as expected, fragment with elimination of alcohol to yield imines. When activation of benzylic positions is remote through a conjugated system, stable benzylamine derivatives are isolated. Mechanistic studies are consistent with concerted insertion of an electrophilic nitrenoid into the C-H bond in the rate-determining step, though in an asynchronous manner with a more activated substrate.
Assuntos
Cloraminas/química , Cobre/química , Éteres/síntese química , Compostos de Tosil/química , Aminação , Catálise , Éteres/química , Estrutura Molecular , EstereoisomerismoRESUMO
Investigation of weak screening hits led to the identification of N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-2-phenylacetamides and N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-N'-benzylureas as potent, selective ligands for the human CCR5 chemokine receptor.