40630-84-0Relevant articles and documents
Computational chemical analysis of Ru(II)-Pheox–catalyzed highly enantioselective intramolecular cyclopropanation reactions
Nakagawa, Yoko,Nakayama, Naofumi,Goto, Hitoshi,Fujisawa, Ikuhide,Chanthamath, Soda,Shibatomi, Kazutaka,Iwasa, Seiji
, p. 52 - 61 (2019)
Computational chemical analysis of Ru(II)-Pheox–catalyzed highly enantioselective intramolecular cyclopropanation reactions was performed using density functional theory (DFT). In this study, cyclopropane ring–fused γ-lactones, which are 5.8?kcal/mol more stable than the corresponding minor enantiomer, are obtained as the major product. The results of the calculations suggest that the enantioselectivity of the Ru(II)-Pheox–catalyzed intramolecular cyclopropanation reaction is affected by the energy differences between the starting structures 5l and 5i. The reaction pathway was found to be a stepwise mechanism that proceeds through the formation of a metallacyclobutane intermediate. This is the first example of a computational chemical analysis of enantioselective control in an intramolecular carbene-transfer reaction using C1-symmetric catalysts.
Macrocyclic FKBP51 Ligands Define a Transient Binding Mode with Enhanced Selectivity
Bajaj, Thomas,Bracher, Andreas,Charalampidou, Anna,Gassen, Nils C.,Geiger, Thomas M.,Hausch, Felix,Heymann, Tim,Kolos, Jürgen,Merz, Stephanie,Meyners, Christian,Purder, Patrick L.,Taubert, Martha C.,Voll, Andreas M.,Wessig, Pablo
supporting information, p. 13257 - 13263 (2021/05/07)
Subtype selectivity represents a challenge in many drug discovery campaigns. A typical example is the FK506 binding protein 51 (FKBP51), which has emerged as an attractive drug target. The most advanced FKBP51 ligands of the SAFit class are highly selective vs. FKBP52 but poorly discriminate against the homologs and off-targets FKBP12 and FKBP12.6. During a macrocyclization pilot study, we observed that many of these macrocyclic analogs have unanticipated and unprecedented preference for FKBP51 over FKBP12 and FKBP12.6. Structural studies revealed that these macrocycles bind with a new binding mode featuring a transient conformation, which is disfavored for the small FKBPs. Using a conformation-sensitive assay we show that this binding mode occurs in solution and is characteristic for this new class of compounds. The discovered macrocycles are non-immunosuppressive, engage FKBP51 in cells, and block the cellular effect of FKBP51 on IKKα. Our findings provide a new chemical scaffold for improved FKBP51 ligands and the structural basis for enhanced selectivity.
CYANOTRIAZOLE COMPOUNDS AND USES THEREOF
-
Paragraph 00177, (2020/01/11)
The present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof: (I) wherein R1, R2, R3, and R4 are as defined herein. The present invention further provides therapeutic uses of these compounds, for example against human African typanosomiasis; pharmaceutical compositions comprising these compounds, and compositions comprising these compounds with a therapeutic co-agent.
