Abstract
Here, we report on the synthesis of libraries of new 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones 3 (twenty-two compounds) and new 2-amino-5-arylidene-1,3-thiazol-4(5H)-ones 5 (twenty-four compounds) with stereo controlled Z-geometry under microwave irradiation. The 46 designed final compounds were tested in order to determine their activity against four representative protein kinases (DYR1A, CK1, CDK5/p25, and GSK3α/β). Among these 1,3-thiazolidin-4-ones, the molecules (5Z) 5-(4-hydroxybenzylidene)-2-thioxo-1,3-thiazolidin-4-one 3e (IC50 0.028 μM) and (5Z)-5-benzo[1,3]dioxol-5-ylmethylene-2-(pyridin-2-yl)amino-1,3-thiazol-4(5H)-one 5s (IC50 0.033 μM) were identified as lead compounds and as new nanomolar DYRK1A inhibitors. Some of these compounds in the two libraries have been also evaluated for their in vitro inhibition of cell proliferation (Huh7 D12, Caco2, MDA-MB 231, HCT 116, PC3, and NCI-H2 tumor cell lines). These results will enable us to use the 1,3-thiazolidin-4-one core as pharmacophores to develop potent treatment for neurological or oncological disorders in which DYRK1A is fully involved.
Highlights
Protein kinases represent an important class of enzymes that play an important role in the regulation of various cellular processes
Continuing in the effort to identify new DYRK1A inhibitors, we decided to explore the synthesis of new 5-arylidene-5H-thiazol-4-ones and new 5-arylidene-2-thioxo-1,3thiazolidin-4-ones. We studied their effects on some protein kinases (DYRK1A, CK1, CDK5-p25, and GSK-3α/β) and on six representative tumor cell lines
All the data presented in this study demonstrate the interest and the potential of the 1,3-thiazolidin-4-one core in inhibition of the protein kinase DYRK1A
Summary
Protein kinases represent an important class of enzymes that play an important role in the regulation of various cellular processes These enzymes catalyze proteinphosphorylation on serine, threonine, and tyrosine residues, which are frequently deregulated in human diseases. Drug discovery has consisted of the empirical approach of random screening of large synthetic molecule libraries (or derivative of natural products) using high-throughput cell-based cytotoxicity assays to screening against clinical validated molecular targets. This approach has been successful in the area of oncology with small-molecule inhibitors of kinases, in cancer progression and metastasis [2]. Among the 538 human kinases, DYRKs (dual-specificity tyrosine phosphorylation regulated kinases, 5 members) are a family of eukaryotic kinases that belong to a larger
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