699-04-7Relevant articles and documents
Discovery of novel small-molecule inhibitors of BRD4 using structure-based virtual screening
Vidler, Lewis R.,Filippakopoulos, Panagis,Fedorov, Oleg,Picaud, Sarah,Martin, Sarah,Tomsett, Michael,Woodward, Hannah,Brown, Nathan,Knapp, Stefan,Hoelder, Swen
, p. 8073 - 8088 (2013)
Bromodomains (BRDs) are epigenetic readers that recognize acetylated-lysine (KAc) on proteins and are implicated in a number of diseases. We describe a virtual screening approach to identify BRD inhibitors. Key elements of this approach are the extensive design and use of substructure queries to compile a set of commercially available compounds featuring novel putative KAc mimetics and docking this set for final compound selection. We describe the validation of this approach by applying it to the first BRD of BRD4. The selection and testing of 143 compounds lead to the discovery of six novel hits, including four unprecedented KAc mimetics. We solved the crystal structure of four hits, determined their binding mode, and improved their potency through synthesis and the purchase of derivatives. This work provides a validated virtual screening approach that is applicable to other BRDs and describes novel KAc mimetics that can be further explored to design more potent inhibitors.
Selective Monomethylation of Amines with Methanol as the C1 Source
Choi, Geunho,Hong, Soon Hyeok
supporting information, p. 6166 - 6170 (2018/04/30)
The N-monomethyl functionality is a common motif in a variety of synthetic and natural compounds. However, facile access to such compounds remains a fundamental challenge in organic synthesis owing to selectivity issues caused by overmethylation. To address this issue, we have developed a method for the selective, catalytic monomethylation of various structurally and functionally diverse amines, including typically problematic primary aliphatic amines, using methanol as the methylating agent, which is a sustainable chemical feedstock. Kinetic control of the aliphatic amine monomethylation was achieved by using a readily available ruthenium catalyst at an adequate temperature under hydrogen pressure. Various substrates including bio-related molecules and pharmaceuticals were selectively monomethylated, demonstrating the general utility of the developed method.
Tandem C(sp3)?H Arylation/Oxidation and Arylation/Allylic Substitution of Isoindolinones
Jiménez, Jacqueline,Kim, Byeong-Seon,Walsh, Patrick J.
supporting information, p. 2829 - 2837 (2016/09/13)
Isoindolinones comprise an important class of medicinally active compounds. Herein we report a straightforward functionalization of isoindolinones with aryl bromides (22 examples) using a palladium(II) acetate/NIXANTPHOS-based catalyst system. Additionally 3-aryl-3-hydroxyisoindolinone derivatives, which exhibit anti-tumor activity, can be accessed via a tandem reaction. Thus, when the arylation product is exposed to air under basic conditions, in situ oxidation takes place to install the 3-hydroxy group. Furthermore, a tandem arylation/allylic substitution reaction is advanced in which both the arylation and allylic substitution are catalyzed by the same palladium catalyst. Finally, a tandem arylation/alkylation procedure is presented. These tandem reactions enable the synthesis of a variety of structurally diverse isoindolinone derivatives from common starting materials. (Figure presented.).