5578-80-3Relevant articles and documents
Practical and Modular Construction of C(sp3)-Rich Alkyl Boron Compounds
Yang, Yangyang,Tsien, Jet,Ben David, Ayala,Hughes, Jonathan M. E.,Merchant, Rohan R.,Qin, Tian
supporting information, p. 471 - 480 (2021/01/13)
Alkyl boronic acids and esters play an important role in the synthesis of C(sp3)-rich medicines, agrochemicals, and material chemistry. This work describes a new type of transition-metal-free mediated transformation to enable the construction of C(sp3)-rich and sterically hindered alkyl boron reagents in a practical and modular manner. The broad generality and functional group tolerance of this method is extensively examined through a variety of substrates, including synthesis and late-stage functionalization of scaffolds relevant to medicinal chemistry. The strategic significance of this approach, with alkyl boronic acids as linchpins, is demonstrated through various downstream functionalizations of the alkyl boron compounds. This two-step concurrent cross-coupling approach, resembling formal and flexible alkyl-alkyl couplings, provides a general entry to synthetically challenging high Fsp3-containing drug-like scaffolds.
Design and characterization of the first selective and potent mechanism-based inhibitor of cytochrome p450 4z1
Kowalski, John P.,Mcdonald, Matthew G.,Pelletier, Robert D.,Hanenberg, Helmut,Wiek, Constanze,Rettie, Allan E.
, p. 4824 - 4836 (2020/06/08)
Mammary-tissue-restricted cytochrome P450 4Z1 (CYP4Z1) has garnered interest for its potential role in breast cancer progression. CYP4Z1-dependent metabolism of arachidonic acid preferentially generates 14,15-epoxyeicosatrienoic acid (14,15-EET), a metabolite known to influence cellular proliferation, migration, and angiogenesis. In this study, we developed time-dependent inhibitors of CYP4Z1 designed as fatty acid mimetics linked to the bioactivatable pharmacophore, 1-aminobenzotriazole (ABT). The most potent analogue, 8-[(1H-benzotriazol-1-yl)amino]octanoic acid (7), showed a 60-fold lower shifted-half-maximal inhibitory concentration (IC50) for CYP4Z1 compared to ABT, efficient mechanism-based inactivation of the enzyme evidenced by a KI = 2.2 μM and a kinact = 0.15 min-1, and a partition ratio of 14. Furthermore, 7 exhibited low off-target inhibition of other CYP isozymes. Finally, low micromolar concentrations of 7 inhibited 14,15-EET production in T47D breast cancer cells transfected with CYP4Z1. This first-generation, selective mechanism-based inhibitor (MBI) will be a useful molecular tool to probe the biochemical role of CYP4Z1 and its association with breast cancer.
Rational Redesign of a Regioselective Hydroformylation Catalyst for 3-Butenoic Acid by Supramolecular Substrate Orientation
Bai, Shao-Tao,Sinha, Vivek,Kluwer, Alexander M.,Linnebank, Pim R.,Abiri, Zohar,de Bruin, Bas,Reek, Joost N. H.
, p. 5322 - 5329 (2019/05/10)
Rational design of ligands for regioselective transformations is one of the long pursuing targets in the field of transition metal catalysis. In the current contribution, we report OrthoDIMphos (L2), a ligand that was designed for regioselective hydroformylation of 3-butenoic acid and its derivatives. The previously reported ParaDIMphos (L1) based hydroformylation catalyst was very selectively producing the linear aldehyde when substrates were bound in its pocket via hydrogen bonding. However, the distance between the binding site and the rhodium center was too large to also address 3-butenoic acid and its derivatives. We therefore designed OrthoDIMphos (L2) as new ligand which has a shorter distance between the DIM-receptor and the catalytic center. The OrthoDIMphos (L2) based catalyst displays high regioselectivity in the hydroformylation of 3-butenoic acid and challenging internal alkene analogue (l/b up to 84, TON up to 630), which cannot be achieved with the ParaDIMphos (L1) catalyst. Detailed studies show that the OrthoDIMphos (L2) based catalyst forms a dimeric structure, in which the two ligands coordinate to two different rhodium metals. Substrate binding to the DIM-receptor is required to break up the dimeric structure, and as only the monomeric analogue is a selective catalyst, the outcome of the reaction is dependent on substrate concentration used in catalysis.
