60376-48-9Relevant articles and documents
Fragment-Based Design, Synthesis, and Biological Evaluation of 1-Substituted-indole-2-carboxylic Acids as Selective Mcl-1 Inhibitors
Wang, Ziqian,Xu, Wenjie,Song, Ting,Guo, Zongwei,Liu, Lu,Fan, Yudan,Wang, Anhui,Zhang, Zhichao
, (2017/01/11)
Based on a known selective Mcl-1 inhibitor, 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid, we applied a fragment-based approach to obtain new molecules that extended into the p1 pocket of the BH3 groove and then exhibited binding selectivity for the Mcl-1 over the Bcl-2 protein. After we deconstructed the 1H-indole-2-carboxylic acid from the parental molecule, a benzenesulfonyl was substituted at the 1-position to adopt a geometry preferred for accessing the p1 pocket according to the binding mode of the parental molecule identified by X-ray crystallography. A linear relationship between the free energy of ligand binding (ΔG) and the count of non-hydrogen heavy atoms (HAC) was maintained during the molecular growing to occupy the p1 pocket. Finally, we not only obtained compound 12 with a 7.5-fold selectivity to Mcl-1 (Ki = 0.48 μM by fluorescence polarization) over Bcl-2 (Ki = 3.6 μM), but also provided evidence that additional occupation of the p1 pocket is more favorable for Mcl-1 than for Bcl-2 binding, and contributes more to Mcl-1 inhibition than occupation of the p2 pocket. Compound 12 exhibited a selective killing ability on Mcl-1-dependent cancer cells.
A convenient access to 1,3-disubstituted furo[3,4-b]indoles by acid ion-exchange resin-catalyzed furan formation
Basset, Joan,Romero, Manel,Serra, Tha?s,Pujol, M. Dolors
experimental part, p. 356 - 362 (2012/01/06)
Efficient synthesis of furo[3,4-b]indoles starting from the corresponding indole is reported. The first route involves derivatization, protection, and deprotection steps, which stretch the syntheses. The second method provides a shorter and more efficient strategy to accessing the furoindole. The innovation starts with alkylation at C-2 of the indole presenting at the C-3 position a ketone-acetal, followed by the cycloaromatization catalyzed by polymeric ion-exchange resins. The second route represents a significant improvement over other methods previously described.