ABSTRACT
A novel and straightforward synthesis of highly substituted isoquinoline-5,8-dione fused tricyclic pyrazoles is reported. The key step of the synthetic sequence is a regioselective, Ag2 CO3 promoted, 1,3-dipolar cycloaddition of C-heteroaryl-N-aryl nitrilimines and substituted isoquinoline-5,8-diones. The broad functional group tolerability and mild reaction conditions were found to be suitable for the preparation of a small library of compounds. These scaffolds were designed to interact with multiple biological residues, and two of them, after brief synthetic elaborations, were analyzed by molecular docking studies as potential anticancer drugs. In vitro studies confirmed the potent anticancer effects, showing promising IC50 values as low as 2.5â µm against three different glioblastoma cell lines. Their cytotoxic activity was finally positively correlated to their ability to inhibit PI3K/mTOR kinases, which are responsible for the regulation of diverse cellular processes in human cancer cells.
Subject(s)
Antineoplastic Agents/pharmacology , Benzoquinones/chemistry , Benzoquinones/pharmacology , Central Nervous System Neoplasms/drug therapy , Glioblastoma/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Central Nervous System Neoplasms/metabolism , Central Nervous System Neoplasms/pathology , Cycloaddition Reaction , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Glioblastoma/metabolism , Glioblastoma/pathology , Humans , Molecular Structure , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Signal Transduction/drug effects , Structure-Activity Relationship , TOR Serine-Threonine Kinases/metabolismABSTRACT
In the presence of a thiourea catalyst, ß-CF3 nitroalkenes react with Hantzsch esters in a highly enantioselective fashion, giving a broad range of ß-CF3 amine precursors with a tertiary stereocentre at the ß-position. This reaction represents the first general catalytic enantioselective approach to this important class of ß-CF3 amines.
ABSTRACT
The palladium-catalyzed desilylation-arylation of substituted vinylsilanes by p-iodoanisole in the presence of bidentate phosphine ligands is described. Apart from enhancing the rate of the reaction considerably, heteroatom-based functional groups in the vinylsilane moiety have a profound influence on the regiochemistry. A catalytic cycle for the chelation-controlled desilylation-arylation reaction involving five- and six-membered chelate rings is proposed.
