4385-79-9Relevant academic research and scientific papers
Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors
Weber, Csaba,Sipos, Melinda,Paczal, Attila,Balint, Balazs,Kun, Vilibald,Foloppe, Nicolas,Dokurno, Pawel,Massey, Andrew J.,Walmsley, David Lee,Hubbard, Roderick E.,Murray, James,Benwell, Karen,Edmonds, Thomas,Demarles, Didier,Bruno, Alain,Burbridge, Mike,Cruzalegui, Francisco,Kotschy, Andras
, p. 6745 - 6764 (2021/05/29)
The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and in vivo and demonstrated drug-like properties. The inhibition of DYRK1A in vivo translated into dose-dependent tumor growth inhibition in a model of ovarian carcinoma.
ZnMe2-Mediated, Direct Alkylation of Electron-Deficient N-Heteroarenes with 1,1-Diborylalkanes: Scope and Mechanism
Jo, Woohyun,Baek, Seung-Yeol,Hwang, Chiwon,Heo, Joon,Baik, Mu-Hyun,Cho, Seung Hwan
supporting information, p. 13235 - 13245 (2020/09/01)
The regioselective, direct alkylation of electron-deficient N-heteroarenes is, in principle, a powerful and efficient way of accessing alkylated N-heteroarenes that are important core structures of many biologically active compounds and pharmaceutical agents. Herein, we report a ZnMe2-promoted, direct C2- or C4-selective primary and secondary alkylation of pyridines and quinolines using 1,1-diborylalkanes as alkylation sources. While substituted pyridines and quinolines exclusively afford C2-alkylated products, simple pyridine delivers C4-alkylated pyridine with excellent regioselectivity. The reaction scope is remarkably broad, and a range of C2- or C4-alkylated electron-deficient N-heteroarenes are obtained in good yields. Experimental and computational mechanistic studies imply that ZnMe2 serves not only as an activator of 1,1-diborylalkanes to generate (α-borylalkyl)methylalkoxy zincate, which acts as a Lewis acid to bind to the nitrogen atom of the heterocycles and controls the regioselectivity, but also as an oxidant for rearomatizing the dihydro-N-heteroarene intermediates to release the product.
