3814-19-5Relevant articles and documents
Discovery of 3,5-Dimethyl-4-Sulfonyl-1 H-Pyrrole-Based Myeloid Cell Leukemia 1 Inhibitors with High Affinity, Selectivity, and Oral Bioavailability
Zhu, Peng-Ju,Yu, Ze-Zhou,Lv, Yi-Fei,Zhao, Jing-Long,Tong, Yuan-Yuan,You, Qi-Dong,Jiang, Zheng-Yu
, p. 11330 - 11353 (2021/08/24)
Myeloid cell leukemia 1 (Mcl-1) protein is a key negative regulator of apoptosis, and developing Mcl-1 inhibitors has been an attractive strategy for cancer therapy. Herein, we describe the rational design, synthesis, and structure-activity relationship study of 3,5-dimethyl-4-sulfonyl-1H-pyrrole-based compounds as Mcl-1 inhibitors. Stepwise optimizations of hit compound 11 with primary Mcl-1 inhibition (52%@30 μM) led to the discovery of the most potent compound 40 with high affinity (Kd = 0.23 nM) and superior selectivity over other Bcl-2 family proteins (>40,000 folds). Mechanistic studies revealed that 40 could activate the apoptosis signal pathway in an Mcl-1-dependent manner. 40 exhibited favorable physicochemical properties and pharmacokinetic profiles (F% = 41.3%). Furthermore, oral administration of 40 was well tolerated to effectively inhibit tumor growth (T/C = 37.3%) in MV4-11 xenograft models. Collectively, these findings implicate that compound 40 is a promising antitumor agent that deserves further preclinical evaluations.
Synthesis and structure-activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis
Pesce, Emanuela,Bellotti, Marta,Liessi, Nara,Guariento, Sara,Damonte, Gianluca,Cichero, Elena,Galatini, Andrea,Salis, Annalisa,Gianotti, Ambra,Pedemonte, Nicoletta,Zegarra-Moran, Olga,Fossa, Paola,Galietta, Luis J.V.,Millo, Enrico
, p. 14 - 35 (2015/06/08)
Abstract The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel present in the membrane of epithelial cells. Mutations affecting the CFTR gene cause cystic fibrosis (CF), a multi-organ severe disease. The most common CF mutation, F508del, impairs the processing and activity (gating) of CFTR protein. Other mutations, like G551D, only cause a gating defect. Processing and gating defects can be targeted by small molecules called generically correctors and potentiators, respectively. Aminoarylthiazoles (AATs) represent an interesting class of compounds that includes molecules with dual activity, as correctors and potentiators. With the aim to improve the activity profile of AATs, we have now designed and synthesized a library of novel compounds in order to establish an initial SAR that may provide indications about the chemical groups that are beneficial or detrimental for rescue activity. The new compounds were tested as correctors and potentiators in CFBE41o-expressing F508del-CFTR using a functional assay. A dual active compound, AAT-4a, characterized by improved efficacy and marked synergy when combined with the corrector VX-809 has been identified. Moreover, by computational methods, a possible binding site for AATs in nucleotide binding domain NBD1 has been detected. These results will direct the synthesis of new analogues with possibly improved activity.
Regioselective C-H activation of cyclometalated bis-tridentate ruthenium complexes
Muise, Stacy S. R.,Severin, Holly A.,Koivisto, Bryan D.,Robson, Kiyoshi C. D.,Schott, Eduardo,Berlinguette, Curtis P.
experimental part, p. 6628 - 6635 (2012/02/05)
A series of bis-tridentate Ru(II) complexes consisting of trimethyl-4,4′,4″-tricarboxylate-2,2′:6′, 2″-terpyridine (Me3tctpy) and derivatized 6-phenyl-2,2′- bipyridine (pbpy) ligands are reported. Each complex is attached to a terminal tripheny
