929-48-6Relevant academic research and scientific papers
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.
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.
Production of Hydroxy Acids: Selective Double Oxidation of Diols by Flavoprotein Alcohol Oxidase
Fraaije, Marco W.,Martin, Caterina,Trajkovic, Milos
supporting information, p. 4869 - 4872 (2020/02/11)
Flavoprotein oxidases can catalyze oxidations of alcohols and amines by merely using molecular oxygen as the oxidant, making this class of enzymes appealing for biocatalysis. The FAD-containing (FAD=flavin adenine dinucleotide) alcohol oxidase from P. chrysosporium facilitated double and triple oxidations for a range of aliphatic diols. Interestingly, depending on the diol substrate, these reactions result in formation of either lactones or hydroxy acids. For example, diethylene glycol could be selectively and fully converted into 2-(2-hydroxyethoxy)acetic acid. Such a facile cofactor-independent biocatalytic route towards hydroxy acids opens up new avenues for the preparation of polyester building blocks.
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.
Whole-cell microtiter plate screening assay for terminal hydroxylation of fatty acids by P450s
Weissenborn, Martin J.,Notonier, Sandra,Lang, Sarah-Luise,Otte, Konrad B.,Herter, Susanne,Turner, Nicholas J.,Flitsch, Sabine L.,Hauer, Bernhard
supporting information, p. 6158 - 6161 (2016/05/19)
A readily available galactose oxidase (GOase) variant was used to develop a whole cell screening assay. This endpoint detection system was applied in a proof-of-concept approach by screening a focussed mutant library. This led to the discovery of the thus far most active P450 Marinobacter aquaeolei mutant catalysing the terminal hydroxylation of fatty acids.
Identification of Acyl Chain Oxidation Products upon Thermal Treatment of a Mixture of Phytosteryl/-stanyl Linoleates
Wocheslander, Stefan,Eisenreich, Wolfgang,Scholz, Birgit,Lander, Vera,Engel, Karl-Heinz
, p. 9214 - 9223 (2016/12/16)
A mixture of phytosterols/-stanols, consisting of 75% β-sitosterol, 12% sitostanol, 10% campesterol, 2% campestanol, and 1% others, was esterified with linoleic acid. The resulting mixture of phytosteryl/-stanyl linoleates was subjected to thermal oxidation at 180 °C for 40 min. A silica solid-phase extraction was applied to separate a fraction containing the nonoxidized linoleates and nonpolar degradation products (heptanoates, octanoates) from polar oxidation products (oxo- and hydroxyalkanoates). In total, 15 sitosteryl, sitostanyl, and campesteryl esters, resulting from oxidation of the acyl chain, could be identified by GC-FID/MS. Synthetic routes were described for authentic reference compounds of phytosteryl/-stanyl 7-hydroxyheptanoates, 8-hydroxyoctanoates, 7-oxoheptanoates, 8-oxooctanoates, and 9-oxononanoates, which were characterized by GC-MS and two-dimensional NMR spectroscopy. The study provides data on the formation and identities of previously unreported classes of acyl chain oxidation products upon thermal treatment of phytosteryl/-stanyl fatty acid esters.
Iron Catalysis for Room-Temperature Aerobic Oxidation of Alcohols to Carboxylic Acids
Jiang, Xingguo,Zhang, Jiasheng,Ma, Shengming
supporting information, p. 8344 - 8347 (2016/07/26)
Oxidation from alcohols to carboxylic acids, a class of essential chemicals in daily life, academic laboratories, and industry, is a fundamental reaction, usually using at least a stoichiometric amount of an expensive and toxic oxidant. Here, an efficient and practical sustainable oxidation technology of alcohols to carboxylic acids using pure O2 or even O2 in air as the oxidant has been developed: utilizing a catalytic amount each of Fe(NO3)3·9H2O/TEMPO/MCl, a series of carboxylic acids were obtained from alcohols (also aldehydes) in high yields at room temperature. A 55 g-scale reaction was demonstrated using air. As a synthetic application, the first total synthesis of a naturally occurring allene, i.e., phlomic acid, was accomplished.
Intramolecular tsujitrost-type allylation of carboxylic acids: Asymmetric synthesis of highly π-allyl donative lactones
Suzuki, Yusuke,Seki, Tomoaki,Tanaka, Shinji,Kitamura, Masato
, p. 9539 - 9542 (2015/08/24)
TsujiTrost-type asymmetric allylation of carboxylic acids has been realized by using a cationic CpRu complex with an axially chiral picolinic acid-type ligand (Cl-Naph-PyCOOH: naph = naphthyl, py = pyridine). The carboxylic acid and allylic alcohol intramolecularly condense by the liberation of water without stoichiometric activation of either nucleophile or electrophile part, thereby attaining high atom- and step-economy, and low E factor. This success can be ascribed to the higher reactivity of allylic alcohols as compared with the allyl ester products in soft Ru/hard Br?nstead acid combined catalysis, which can function under slightly acidic conditions unlike the traditional Pd-catalyzed system. Detailed analysis of the stereochemical outcome of the reaction using an enantiomerically enriched D-labeled substrate provides an intriguing view of enantioselection.
ACYCLIC ALKENES VIA OZONOLYSIS OF MULTI-UNSATURATED CYCLOALKENES
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Paragraph 00157, (2015/02/02)
A method of making a compound of formula (IIa) by selective ozonolysis of a compound of formula (I) is provided, wherein A is a C6-C10 alkene chain with at least one double bond, R1 is a C1-C10 alkyl, and R3 is an oxygen-containing functional group.
