RESUMO
An efficient and straightforward one-pot tandem synthesis of 3-arylindan-1-ones was consummated through silver nitrate-promoted C-C coupling of simple indane-1,3-dione with arylboronic acid via 1,3-indanedione monotosylhydrazone under microwave conditions. The resulting series of 3-arylindan-1-ones exhibited impressive yields, surpassing those achievable with traditional methods and requiring a shorter time frame. This innovative approach significantly accelerated the synthesis of biologically active compounds such as (+)-indatraline (Lu 19-005) and several other industrially relevant substances.
RESUMO
A straightforward and feasible palladium-catalyzed direct α-arylation of indane-1,3-dione to 2-substituted aryl/heteroaryl indene-1,3-diones has been disclosed for the first time. Optimization of reaction conditions identified tBu-XPhos as a preferred ligand for the bis(acetonitrile)dichloropalladium(II) catalyst. A broad spectrum of aryl iodides and aryl triflates containing electron-donating, electron-withdrawing, and sterically hindered substituents gave an excellent yield for the quick access α-arylated 1,3-diones library.
Assuntos
Indenos , Paládio , Catálise , Iodetos , Estrutura MolecularRESUMO
Aurora B plays critical role in the process of chromosome condensation and chromosome orientation during the regulation of mitosis. The overexpression of Aurora B has been observed in several tumor types. As a part of our ongoing effort to develop Aurora B inhibitors, herein, we described the design, synthesis and evaluation of phenyl/pyridine diazepine analogs. The diazepane aniline pyrimidine (4a) was identified as an initial hit (Aurora B IC50 6.9 µM). Molecular modeling guided SAR optimization lead to the identification of 8-fluorobenzodiazepine (6c) with single digit nM potency (Aurora B IC50 8 nM). In the antiproliferation assay 6c showed activity across the cell lines with IC50 of 0.57, 0.42, and 0.69 µM for MCF-7, MDA-MB 231, and SkoV3 respectively. In the in vivo PK profile. 6c has shown higher bioavailability (73%) along with good exposure (AUC of 1360 ng.h/mL).
Assuntos
Antineoplásicos/farmacologia , Aurora Quinase B/antagonistas & inibidores , Azepinas/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Aurora Quinase B/metabolismo , Azepinas/síntese química , Azepinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
A sensitive, specific, selective and rapid LC-ESI-MS/MS method has been developed and validated for the quantification of defactinib in mice plasma using 13C3,15N-tofacitinib as an internal standard (I.S.). Sample preparation was accomplished through a liquid-liquid extraction process. Baseline chromatographic resolution of defactinib and the I.S. was achieved on an Atlantis dC18 column using an isocratic mobile phase comprising 0.2% formic acid in water and acetonitrile (25:75, v/v) delivered at a flow rate of 0.5mL/min. Defactinib and the I.S. eluted at â¼1.59 and 0.99min, respectively. The total chromatographic run time was 2.50min. A linear response function was established in the concentration range of 0.13-106 ng/mL. Method validation was performed as per regulatory guidelines and the results met the acceptance criteria. The intra- and inter-day accuracy and precision were in the range of 5.57-13.3 and 8.63-12.1%, respectively. Defactinib was found to be stable under various stability conditions. This novel method has been applied to a pharmacokinetic study in mice.