919295-79-7Relevant academic research and scientific papers
Discovery of aryl-substituted indole and indoline derivatives as RORγt agonists
Zhu, Yan,Sun, Nannan,Yu, Mingcheng,Guo, Huimin,Xie,Wang, Yonghui
, (2019)
A series of aryl-substituted indole and indoline derivatives were discovered as novel RORγt agonists by a scaffold-based hybridization of the reported RORγt agonists 1 and 2. SAR studies on the core structures, the RHS hydrophilic side chains and the LHS hydrophobic aryl groups of a hybrid compound 3 led to the identification of potent RORγt agonists with improved drug-like properties. Compound 14 represented a high potency lead with an EC50 of 20.8 ± 1.5 nM, the (S)-enantiomer (EC50 = 16.1 ± 4.5 nM) of which was 17 times more potent than the (R) counterpart (EC50 = 286 ± 30.4 nM) in RORγ dual FRET assay. The cell-based GAL4 reporter gene assay also suggested 14 as the most active compound which exhibited an EC50 of 247 ± 33.1 nM and a maximum activation percentage of 133%. Moreover, 14 showed high metabolic stability (t1/2 = 113 min) in mouse liver microsome and had improved aqueous solubility at pH 7.4 compared to the parent compounds. Furthermore, 14 was found to be orally bioavailable and demonstrated excellent in vivo pharmacokinetics in mice. Present studies indicate that 14 deserves further investigation in tumor animal models as a potential candidate of RORγt agonist for cancer immunotherapy.
Directed Evolution of a Cytochrome P450 Carbene Transferase for Selective Functionalization of Cyclic Compounds
Brandenberg, Oliver F.,Chen, Kai,Arnold, Frances H.
supporting information, p. 8989 - 8995 (2019/06/13)
Transfers of carbene moieties to heterocycles or cyclic alkenes to obtain C(sp2)-H alkylation or cyclopropane products are valuable transformations for synthesis of pharmacophores and chemical building blocks. Through their readily tunable active-site geometries, hemoprotein "carbene transferases" could provide an alternative to traditional transition metal catalysts by enabling heterocycle functionalizations with high chemo-, regio-, and stereocontrol. However, carbene transferases accepting heterocyclic substrates are scarce; the few enzymes capable of heterocycle or cyclic internal alkene functionalization described to date are characterized by low turnovers or depend on artificially introduced, costly iridium-porphyrin cofactors. We addressed this challenge by evolving a cytochrome P450 for highly efficient carbene transfer to indoles, pyrroles, and cyclic alkenes. We first developed a spectrophotometric high-throughput screening assay based on 1-methylindole C3-alkylation that enabled rapid analysis of thousands of P450 variants and comprehensive directed evolution via random and targeted mutagenesis. This effort yielded a P450 variant with 11 amino acid substitutions and a large deletion of the non-catalytic P450 reductase domain, which chemoselectively C3-alkylates indoles with up to 470 turnovers per minute and 18000 total turnovers. We subsequently used this optimized alkylation variant for parallel evolution toward more challenging heterocycle carbene functionalizations, including C2/C3 regioselective pyrrole alkylation, enantioselective indole alkylation with ethyl 2-diazopropanoate, and cyclic internal alkene cyclopropanation. The resulting set of efficient biocatalysts showcases the tunability of hemoproteins for highly selective functionalization of cyclic targets and the power of directed evolution to enhance the scope of new-to-nature enzyme catalysts.
Discovery and refinement of a new structural class of potent peptide deformylase inhibitors
Boularot, Adrien,Giglione, Carmela,Petit, Sylvain,Duroc, Yann,De Sousa, Rodolphe Alves,Larue, Valéry,Cresteil, Thierry,Dardel, Frédéric,Artaud, Isabelle,Meinnel, Thierry
, p. 10 - 20 (2007/10/03)
New classes of antibiotics are urgently needed to counter increasing levels of pathogen resistance. Peptide deformylase (PDF) was originally selected as a specific bacterial target, but a human homologue, the inhibition of which causes cell death, was rec
