1128077-17-7Relevant 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.
Preparation of sulfenyl pyrroles
Gillis, H. Martin,Greene, Lana,Thompson, Alison
experimental part, p. 112 - 116 (2009/06/18)
Sulfenyl groups are attracting interest as masking/protecting groups for pyrroles. A facile one-step synthesis of sulfenyl pyrroles, involving the reaction of pyrroles with N-(aryl- and alkylthio)phthalimides in the presence of MgBr2, is reported and the methodology extends to include sulfinyl pyrroles. The one-step procedure gives good yields and is more efficient and practical than current multistep protocols to sulfenyl pyrroles that involve thiocyanato pyrrolic intermediates. A convenient procedure for the synthesis of N-(aryl- and alkylthio)phthalimides is also reported. Georg Thieme Verlag Stuttgart.
