DYRK1A kinase inhibitors with emphasis on cancer.

Various types of cancers (including gliomas, melanomas, and esophageal, pancreas and non-small-cell lung cancers) display intrinsic resistance to pro-apoptotic stimuli, such as conventional chemotherapy and radiotherapy, and/or the activation of a multidrug resistance phenotype, which are major barriers to effective treatment and lead to poor patient prognosis. The DYRK1A kinase is directly implicated in the resistance of cancer cells to pro-apoptotic stimuli and drives several pathways that enhance proliferation, migration, and the reduction of cell death, leading to very aggressive biological behavior in cancer cell populations. The DYRK1A kinase is also implicated in neurological diseases and in neoangiogenic processes. Thus, the DYRK1A kinase is of great interest for both cancer and neuroscience research. During the last decade, numerous compounds that inhibit DYRK1A have been synthesized. The present review discusses the available molecules known to interfere with DYRK1A activity and the implications of DYRK1A in cancer and other diseases and serves as a rational analysis for researchers who aim to improve the anti-DYRK1A activity of currently available compounds.

Structure-activity relationship analyses of glycyrrhetinic acid derivatives as anticancer agents.

Cancer cell resistance to kinase inhibitors and targeted agents, acquisition of a multidrug-resistant (MDR) phenotype and/or intrinsic resistance to apoptosis prevent effective treatment in about 50% of solid cancers in adults, and the percentage is even higher in children. Glycyrrhetinic acid (GA) and some of its derivatives may offer hope in combating cancer types associated with poor prognoses. Some GA derivatives are indeed able to target both the proteasome and peroxisome proliferator-activated receptors (PPARs), two proteins that play major roles in cancer cell biology but are not related to MDR and/or apoptosis-related resistance phenotypes.

First insights into the electronic properties of a Cu(II) center embedded in the PN3 cap of a calix[6]arene-based ligand.

The first metal complex based on the calix[6]PN3 cryptand is described. The solid-state and solution studies show a 5-coordinate Cu(II) center due to its coordination to the PN3 cap and to an exchangeable guest molecule. Spectroscopic and electrochemical studies evidence surprising properties of the metal ion, which are tentatively assigned to the unusual P-Cu(II) bond enforced by the cryptand.

Reaction of cyclohexanone benzylimines with ethylidenemalonate diesters. Diphenyl 2-ethylidenemalonate: a highly electrophilic synthetic equivalent of crotonic esters.

The diastereoselective Michael alkylation of alpha-substituted and alpha,alpha'-disubstituted cyclohexanone benzylimines with ethylidenemalonate diesters was carried out for mechanistic and synthetic purposes. In the first case, an inverse regioselectivity occurred in comparison with what is generally observed since the Michael adducts resulted from alkylation of the non substituted enamine tautomer. With alpha,alpha'-disubstituted imines, in all cases, the stereochemistry of the major diastereomer was the one anticipated from a mechanism including a chairlike complex approach with a preferred exo position for the beta-methyl group of the ethylidenemalonic acid diesters. Furthermore, diphenyl 2-ethylidenemalonate 4 was found to be a highly electrophilic synthetic equivalent of crotonic esters.