4392-11-4Relevant academic research and scientific papers
Design, synthesis, cytotoxic activity, and apoptosis inducing effects of 4- And N-substituted benzoyltaurinamide derivatives
Akgül, ?zlem,Erdo?an, Mümin Alper,Birim, Dervi?,Kayaba?i, ?a?la,Gündüz, Cumhur,Arma?an, Güliz
, p. 1674 - 1693 (2021/01/05)
In this study, a group of 4-substituted benzoyltaurinamide derivatives were designed, synthesized, and investigated for their anticancer activity against three cancer cell lines and one nontumorigenic cell line by MTT assay. Among the final compounds, methoxyphenyl derivatives 14, 15, 16 were found to be effective against all the tested cancerous cell lines with promising selectivity. The most active compounds were further evaluated to determine the molecular mechanism of their anticancer activity by using western blot assay and the Annexin V-FITC/PI test. Compound 14 (in SH-SY5Y and MDA-MB-231 cell lines) and 15 (in SH-SY5Y cell line) were found to induce intrinsic apoptotic pathway by upregulating BAX, caspase-3, and caspase-9, while downregulating Bcl-2 and Bcl-xL expression levels. According to mechanistic studies, compounds displayed their anticancer activity via three different mechanisms: a. caspase-dependent, b. caspase-independent, and c. caspase-dependent pathway that excluded caspase-9 activation. As a result, this study provides interesting data which can be used to design new taurine-based anticancer derivatives.
Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods
Pelz, Nicholas F.,Bian, Zhiguo,Zhao, Bin,Shaw, Subrata,Tarr, James C.,Belmar, Johannes,Gregg, Claire,Camper, DeMarco V.,Goodwin, Craig M.,Arnold, Allison L.,Sensintaffar, John L.,Friberg, Anders,Rossanese, Olivia W.,Lee, Taekyu,Olejniczak, Edward T.,Fesik, Stephen W.
supporting information, p. 2054 - 2066 (2016/03/22)
Myeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family of proteins responsible for the regulation of programmed cell death. Amplification of Mcl-1 is a common genetic aberration in human cancer whose overexpression contributes to the evasion of apoptosis and is one of the major resistance mechanisms for many chemotherapies. Mcl-1 mediates its effects primarily through interactions with pro-apoptotic BH3 containing proteins that achieve high affinity for the target by utilizing four hydrophobic pockets in its binding groove. Here we describe the discovery of Mcl-1 inhibitors using fragment-based methods and structure-based design. These novel inhibitors exhibit low nanomolar binding affinities to Mcl-1 and >500-fold selectivity over Bcl-xL. X-ray structures of lead Mcl-1 inhibitors when complexed to Mcl-1 provided detailed information on how these small-molecules bind to the target and were used extensively to guide compound optimization.
