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 straightforward and efficient method has been demonstrated for the oxidative coupling of terminal alkynes using a simple Cu3(BTC)2-metal organic framework as a sustainable heterogeneous copper catalyst. A series of symmetrical 1,3-diynes bearing diverse functional groups have been synthesized in moderate to excellent yields via a Cu3(BTC)2 catalyzed Glaser-Hay reaction. The presence of the coordinatively unsaturated open CuII sites in Cu3(BTC)2 catalyzes the homocoupling in the presence of air, as an environment friendly oxidant without the use of external oxidants, ligands or any additives. The present methodology avoids stoichiometric reagents and harsher or special reaction conditions, and shows good functional group tolerance. The as-prepared catalyst could be separated easily by simple filtration and reused several times without any notable loss in activity. The hot filtration test has investigated the true heterogeneity of the catalyst. Additionally, the powder X-ray diffraction pattern of the reused catalyst revealed the high stability of the catalyst.
RESUMO
A highly efficient enantioselective Henry reaction has been carried out using per-6-ABCD as a supramolecular chiral host and promoter to give the corresponding adduct with high yield (up to 99%) and enantiomeric excess (up to 99%). Per-6-ABCD also promotes the diastereoselective Henry reaction in a syn-selective manner to give the adduct up to 99% yield with 99:1 syn/anti selectivity. The enantiomeric excess of the syn-adduct is 99%. The catalyst is recovered and reused without loss in its activity.
Assuntos
beta-Ciclodextrinas/química , Aldeídos/química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
Per-6-amino-beta-cyclodextrin (per-6-ABCD), acting simultaneously as a supramolecular ligand for CuI and host for aryl bromides, catalyzes N-arylation of imidazole with aryl bromides under mild conditions. This simple method proceeds with excellent yield for the coupling of imidazole with various substituted aryl bromides demonstrating good tolerance of other functionalities.