1110272-22-4Relevant articles and documents
Small molecule microarray identifies inhibitors of tyrosyl-DNA phosphodiesterase 1 that simultaneously access the catalytic pocket and two substrate binding sites
Zhao, Xue Zhi,Kiselev, Evgeny,Lountos, George T.,Wang, Wenjie,Tropea, Joseph E.,Needle, Danielle,Hilimire, Thomas A.,Schneekloth, John S.,Waugh, David S.,Pommier, Yves,Burke, Terrence R.
, p. 3876 - 3884 (2021)
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a member of the phospholipase D family of enzymes, which catalyzes the removal of both 3′- and 5′-DNA phosphodiester adducts. Importantly, it is capable of reducing the anticancer effects of type I topoisomerase (TOP1) inhibitors by repairing the stalled covalent complexes of TOP1 with DNA. It achieves this by promoting the hydrolysis of the phosphodiester bond between the Y723 residue of human TOP1 and the 3′-phosphate of its DNA substrate. Blocking TDP1 function is an attractive means of enhancing the efficacy of TOP1 inhibitors and overcoming drug resistance. Previously, we reported the use of an X-ray crystallographic screen of more than 600 fragments to identify small molecule variations on phthalic acid and hydroxyquinoline motifs that bind within the TDP1 catalytic pocket. Yet, the majority of these compounds showed limited (millimolar) TDP1 inhibitory potencies. We now report examining a 21?000-member library of drug-like Small Molecules in Microarray (SMM) format for their ability to bind Alexa Fluor 647 (AF647)-labeled TDP1. The screen identified structurally similarN,2-diphenylimidazo[1,2-a]pyrazin-3-amines as TDP1 binders and catalytic inhibitors. We then explored the core heterocycle skeleton using one-pot Groebke-Blackburn-Bienayme multicomponent reactions and arrived at analogs having higher inhibitory potencies. Solving TDP1 co-crystal structures of a subset of compounds showed their binding at the TDP1 catalytic site, while mimicking substrate interactions. Although our original fragment screen differed significantly from the current microarray protocol, both methods identified ligand-protein interactions containing highly similar elements. Importantly inhibitors identified through the SMM approach show competitive inhibition against TDP1 and access the catalytic phosphate-binding pocket, while simultaneously providing extensions into both the substrate DNA and peptide-binding channels. As such, they represent a platform for further elaboration of trivalent ligands, that could serve as a new genre of potent TDP1 inhibitors.
Zinc Iodide Catalyzed Synthesis of 3-Aminoimidazo[1,2- a ]pyridines from 2-Aminopyridines and α-Amino Carbonyl Compounds
Han, Xu,Ma, Chaowei,Wu, Zhaoyang,Huang, Guosheng
, p. 351 - 356 (2016)
A concise approach to 3-aminoimidazo[1,2-a]pyridines is developed via the zinc iodide catalyzed reaction of 2-aminopyridines and α-amino carbonyl compounds in the presence of oxygen. This novel and user-friendly protocol employing diverse and easily avail
HETERO-CYCLIC COMPOUND AND ORGANIC LIGHT EMITTING DEVICE USING THE SAME
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, (2016/10/08)
The present specification relates to a novel heterocyclic compound and an organic light-emitting device using the same. According to one embodiment of the present specification, provided is a compound in chemical formula 1. The compound of the present specification can be used as an organic matter layer material of an organic light-emitting device.COPYRIGHT KIPO 2016
