27549-93-5Relevant articles and documents
Selective α-Deuteration of Cinnamonitriles using D2O as Deuterium Source
Guo, Beibei,de Vries, Johannes G.,Otten, Edwin
supporting information, p. 179 - 186 (2021/10/12)
The selective α-deuteration of α,β-unsaturated nitriles using the strong base tBuOK or a metal-ligand cooperative Ru pincer catalyst is described. With D2O as deuterium source and glyme as solvent at 70 °C, tBuOK is an efficient catalyst for deuteration at the α-C(sp2) position of cinnamonitriles, providing access to a broad range of deuterated derivatives in good to excellent yields and with very high levels of deuterium incorporation. While the tBuOK-catalysed protocol does not tolerate base-sensitive functional groups, cinnamonitrile derivatives containing a benzylic bromide or ester moiety were deuterated in excellent yields using Milstein's ruthenium PNN pincer catalyst. Moreover, the activity for H/D exchange of the metal-ligand cooperative Ru catalyst is found to be significantly higher than that of tBuOK, allowing reactions to proceed well even at room temperature. A mechanistic proposal is put forward that involves deprotonation of the cinnamonitrile α-CH position when using tBuOK as catalyst, whereas H/D exchange catalysis with the Ru PNN pincer likely proceeds via (reversible) oxa-Michael addition of D2O. (Figure presented.).
Pd(II)-Catalyzed CC Bond Cleavage by a Formal Group-Exchange Reaction
Ye, Runyou,Zhu, Maoshuai,Yan, Xufei,Long, Yang,Xia, Ying,Zhou, Xiangge
, p. 8678 - 8683 (2021/07/26)
A chelation-assisted palladium-catalyzed CC bond cleavage of α, β-unsaturated ketone to form alkenyl nitrile in the presence of nitrile is disclosed on the basis of a formal group-exchange reaction formulated as C1C2 + C3 → C1C3 + C2, differing from normal alkene oxidative cleavage and metathesis type. The isolated key active Pd(II) complex as well as deuterium-labeled experiment revealed the necessity of the chelation group, and a plausible catalytic pathway was proposed.
Comprehensive structure-activity-relationship of azaindoles as highly potent FLT3 inhibitors
Grimm, Sebastian H.,Gagestein, Berend,Keijzer, Jordi F.,Liu, Nora,Wijdeven, Ruud H.,Lenselink, Eelke B.,Tuin, Adriaan W.,van den Nieuwendijk, Adrianus M.C.H.,van Westen, Gerard J.P.,van Boeckel, Constant A.A.,Overkleeft, Herman S.,Neefjes, Jacques,van der Stelt, Mario
supporting information, p. 692 - 699 (2019/01/22)
Acute myeloid leukemia (AML) is characterized by fast progression and low survival rates, in which Fms-like tyrosine kinase 3 (FLT3) receptor mutations have been identified as a driver mutation in cancer progression in a subgroup of AML patients. Clinical trials have shown emergence of drug resistant mutants, emphasizing the ongoing need for new chemical matter to enable the treatment of this disease. Here, we present the discovery and topological structure-activity relationship (SAR) study of analogs of isoquinolinesulfonamide H-89, a well-known PKA inhibitor, as FLT3 inhibitors. Surprisingly, we found that the SAR was not consistent with the observed binding mode of H-89 in PKA. Matched molecular pair analysis resulted in the identification of highly active sub-nanomolar azaindoles as novel FLT3-inhibitors. Structure based modelling using the FLT3 crystal structure suggested an alternative, flipped binding orientation of the new inhibitors.
