929-48-6Relevant articles and documents
Pharmacokinetics, metabolism and off-target effects in the rat of 8-[(1H- benzotriazol-1-yl)amino]octanoic acid, a selective inhibitor of human cytochrome P450 4Z1: β-oxidation as a potential augmenting pathway for inhibition
Kowalski, John P.,Pelletier, Robert D.,McDonald, Matthew G.,Kelly, Edward J.,Rettie, Allan E.
, p. 901 - 915 (2021)
8‐[(1H‐1,2,3‐benzotriazol‐1‐yl)amino]octanoic acid (8-BOA) was recently identified as a selective and potent mechanism-based inactivator (MBI) of breast cancer-associated CYP4Z1 and exhibited favourable inhibitory activity in vitro, thus meriting in vivo characterization. The pharmacokinetics and metabolism of 8-BOA in rats was examined after a single IV bolus dose of 10 mg/kg. A biphasic time-concentration profile resulted in relatively low clearance and a prolonged elimination half-life. The major circulating metabolites identified in plasma were products of β-oxidation; congeners losing two and four methylene groups accounted for >50% of metabolites by peak area. The –(CH2)2 product was characterized previously as a CYP4Z1 MBI and so represents an active metabolite that may contribute to the desired pharmacological effect. Ex vivo analysis of total CYP content in rat liver and kidney microsomes showed that off-target CYP inactivation was minimal; liver microsomal probe substrate metabolism also demonstrated low off-target inactivation. Standard clinical chemistries provided no indication of acute toxicity. In silico simulations using the free concentration of 8-BOA in plasma suggested that the in vivo dose used here may effectively inactivate CYP4Z1 in a xenografted tumour.
Regioselective Hydroformylation of Internal and Terminal Alkenes via Remote Supramolecular Control
Linnebank, Pim R.,Ferreira, Stephan Falc?o,Kluwer, Alexander M.,Reek, Joost N. H.
supporting information, p. 8214 - 8219 (2020/06/21)
Regioselective catalytic transformations using supramolecular directing groups are increasingly popular as it allows for control over challenging reactions that may otherwise be impossible. In most examples the reactive group and the directing group are close to each other and/or the linker between the directing group is very rigid. Achieving control over the regioselectivity using a remote directing group with a flexible linker is significantly more challenging due to the large conformational freedom of such substrates. Herein, we report the redesign of a supramolecular Rh–bisphosphite hydroformylation catalyst containing a neutral carboxylate receptor (DIM pocket) with a larger distance between the phosphite metal binding moieties and the DIM pocket. For the first time regioselective conversion of internal and terminal alkenes containing a remote carboxylate directing group is demonstrated. For carboxylate substrates that possess an internal double bond at the Δ-9 position regioselectivity is observed. As such, the catalyst was used to hydroformylate natural monounsaturated fatty acids (MUFAs) in a regioselective fashion, forming of an excess of the 10-formyl product (10-formyl/9-formyl product ratio of 2.51), which is the first report of a regioselective hydroformylation reaction of such substrates.
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.
