704-65-4Relevant articles and documents
Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor
Szlavik, Zoltan,Csekei, Marton,Paczal, Attila,Szabo, Zoltan B.,Sipos, Szabolcs,Radics, Gabor,Proszenyak, Agnes,Balint, Balazs,Murray, James,Davidson, James,Chen, Ijen,Dokurno, Pawel,Surgenor, Allan E,Daniels, Zoe Marie,Hubbard, Roderick E.,Le Toumelin-Braizat, Ga?tane,Claperon, Audrey,Lysiak-Auvity, Ga?lle,Girard, Anne-Marie,Bruno, Alain,Chanrion, Maia,Colland, Frédéric,Maragno, Ana-Leticia,Demarles, Didier,Geneste, Olivier,Kotschy, Andras
, p. 13762 - 13795 (2020/12/02)
Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report the discovery of our clinical candidate S64315, a selective small molecule inhibitor of Mcl-1. Starting from a fragment derived lead compound, we have conducted structure guided optimization that has led to a significant (3 log) improvement of target affinity as well as cellular potency. The presence of hindered rotation along a biaryl axis has conferred high selectivity to the compounds against other members of the Bcl-2 family. During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials.
Method for preparing multi-target small-molecule compounds S63845
-
Paragraph 0017; 0019; 0027, (2018/03/26)
The invention discloses a method for preparing multi-target small-molecule compounds S63845, and relates to the technical field of chemical synthesis. The method has the advantages that routes for synthesizing the multi-target small-molecule compounds S63
Electrochemical polymerization of iron(III) polypyridyl complexes through C-C coupling of redox non-innocent phenolato ligands
Unjaroen, Duenpen,Swart, Marcel,Browne, Wesley R.
supporting information, p. 470 - 479 (2017/01/11)
Phenolato moieties impart redox flexibility to metal complexes due their accessible (oxidative) redox chemistry and have been proposed as functional ligand moieties in redox non-innocent ligand based transition metal catalysis. Here, the electro- and spectroelectrochemistry of phenolato based μ-oxodiiron(III) complexes [(L1)Fe(μ-O)Fe(L1)]2+ (1) and [(L2)Fe-(μ-O)Fe(L2)]2+ (2), where L1 = 2-(((di(pyridin-2-yl)methyl)-(pyridin-2-ylmethyl)amino)methyl)phenol and L2 = 3, 5-di-tert-butyl-2-(((di(pyridin-2-yl)methyl)(pyridin-2-ylmethyl)amino)-methyl)phenol, is described. The electrochemical oxidation of 1 in dichloromethane results in aryl C-C coupling of phenoxyl radical ligand moieties to form tetra nuclear complexes, which undergo subsequent oxidation to form iron(III) phenolato based polymers (poly-1). The coupling is blocked by placing tert-butyl groups at para and ortho positions of phenol units (i.e., 2). Poly-1 shows two fully reversible redox processes in monomer free solution. Assignment of species observed during the electrochemical and chemical {(NH4)2[CeIV(NO3)6]} oxidation of 1 in acetonitrile is made by comparison with the UV-vis-NIR absorption and resonance micro-Raman spectroelectrochemistry of poly-1, and by DFT calculations, which confirms that oxidative coupling occurs in acetonitrile also. However, in contrast to that observed in dichloromethane, in acetonitrile, the oligomers formed are degraded in terms of a loss of the Fe(III)-O-Fe(III) bridge by protonation. The oxidative redox behavior of 1 and 2 is, therefore, dominated by the formation and reactivity of Fe(III) bound phenoxyl radicals, which considerably holds implications in regard to the design of phenolato based complexes for oxidation catalysis.
NEW HYDROXYESTER DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
-
Page/Page column 28-29, (2017/01/09)
Compounds of formula (1) wherein R1, R2, R3, R4, R5, R6, R7, R13, Ra, Rb, A and n are as defined in the description. Medicaments containing them
NEW HYDROXYACID DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
-
Page/Page column 33; 34, (2017/01/09)
Compounds of formula (I): wherein R1, R2, R3, R4, R5, R6, R7, R8, R14, A and n are as defined in the description. Medicaments.
NEW BICYCLIC DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
-
Page/Page column 42, (2017/05/12)
Compounds of formula (I); wherein R1, R2, R3, R4, R5, R6, R7, R8, R14, W, A and n are as defined in the description. Medicaments.
NEW THIENOPYRIMIDINE DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
-
Page/Page column 43, (2015/07/15)
Compounds of formula (I): wherein R1, R2, R3, R4, R5, R6, R7, R12, X, A and n are as defined in the description.
A novel photochemical Wittig reaction for the synthesis of 2-aryl/alkylbenzofurans
Ghosh, Somnath,Das, Jhantu
scheme or table, p. 1112 - 1116 (2011/03/22)
The synthesis of 2-aryl/alkylbenzofurans has been achieved in high yields under photochemical conditions from readily accessible and suitably substituted phosphonium bromides by an intramolecular photochemical Wittig reaction onto aryloxycarbonyl groups.
Stereoselective synthesis of benzannulated spiroketals: Influence of the aromatic ring on reactivity and conformation
Liu, Guodong,Wurst, Jacqueline M.,Tan, Derek S.
supporting information; experimental part, p. 3670 - 3673 (2011/03/18)
Image Presented A systematic stereocontrolled synthesis of benzannulated spiroketals has been developed, using kinetic spirocyclization reactions of glycal epoxides, leading to a new AcOH-induced cyclization and valuable insights into the reactivity and c
