Synthetic Development of New 3-(4-Arylmethylamino)butyl-5-arylidene-rhodanines under Microwave Irradiation and Their Effects on Tumor Cell Lines and against Protein Kinases

摘要

A new route to 3-(4-arylmethylamino)butyl-5-arylidene-2-thioxo-1,3-thiazolidine-4-one >9 was developed in six steps from commercial 1,4-diaminobutane >1 as starting material. The key step of this multi-step synthesis involved a solution phase “one-pot two-steps” approach assisted by microwave dielectric from N-(arylmethyl)butane-1,4-diamine hydrochloride >6a–>f (as source of the first point diversity) and commercial bis-(carboxymethyl)-trithiocarbonate reagent >7 for construction of the rhodanine platform. This platform was immediately functionalized by Knoevenagel condensation under microwave irradiation with a series of aromatic aldehydes >3 as second point of diversity. These new compounds were prepared in moderate to good yields and the fourteen synthetic products >9a–>n have been obtained with a Z-geometry about their exocyclic double bond. These new 5-arylidene rhodanines derivatives >9a–>n were tested for their kinase inhibitory potencies against four protein kinases: Human cyclin-dependent kinase 5-p25, HsCDK5-p25; porcine Glycogen Synthase Kinase-3, GSK-3α/β; porcine Casein Kinase 1, SsCK1 and human HsHaspin. They have also been evaluated for their in vitro inhibition of cell proliferation (HuH7 D12, Caco 2, MDA-MB 231, HCT 116, PC3, NCI-H727, HaCat and fibroblasts). Among of all these compounds, >9j presented selective micromolar inhibition activity on SsCK1 and >9i exhibited antitumor activities in the HuH7 D12, MDA-MBD231 cell lines.