40480-99-7Relevant academic research and scientific papers
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.
THE REACTION OF β-AMINOENONES WITH α-AMINO DERIVATIVES. SYNTHESIS OF 2-FUNCTIONALIZED PYRROLES
Alberola, Angel,Andres, Jose M.,Gonzalez, Alfonso,Pedrosa, Rafael,Vicente, Martina
, p. 1049 - 1058 (2007/10/02)
β-Aminoenones react with ethyl glycinate, α-aminoacetonitrile and α-aminoacetamide hydrochlorides leading to 2-fuctionalized pyrroles.Although the trans-amination is a high-yield process, the transformation of the intermediate, in both basic or thermally
ELECTROPHILIC HETEROAROMATIC SUBSTITUTIONS. X. UNEXPECTED RESULTS IN THE α-SIDE-CHAIN CHLORINATION OF A SERIES OF ETHYL 3,4,5-TRIALKYLPYRROLE-2-CARBOXYLATES
Scarsella, Marco,Sleiter, Giancarlo
, p. 757 - 762 (2007/10/02)
The reaction of a series of 3,4,5-trialkyl-substituted ethyl pyrrole-2-carboxylates with an excess of sulphuryl chloride followed by solvolysis has been investigated in several solvents and under different experimental conditions.In all cases, beside the expected α-side-chain substituted product, substantial amounts of derivatives functionalised also in a β-side chain have been isolated and identified.The process turned out to be electrophilic in nature and to involve allylic migration of the halogen from the α-sigma adduct to the adjacent β-side chain.Virtually identical results have been obtained when elemental chlorine was used.
