830-03-5Relevant articles and documents
Simple Design of an Enzyme-Inspired Supported Catalyst Based on a Catalytic Triad
Nothling, Mitchell D.,Ganesan, Aravindhan,Condic-Jurkic, Karmen,Pressly, Eric,Davalos, Ashley,Gotrik, Michael R.,Xiao, Zeyun,Khoshdel, Ezat,Hawker, Craig J.,O'Mara, Megan L.,Coote, Michelle L.,Connal, Luke A.
, p. 732 - 745 (2017)
Enzyme active sites afford an intricate interplay of functional groups to mediate complex organic and inorganic reactions. Many hydrolytic enzymes use a catalytic triad comprising three different functional residues—(Ser(-OH), Hist(-imidazole), Asp(-CO2H))—that catalyze the hydrolysis of numerous unique substrates. Inspired by this design, we have developed a simple one-step synthesis for preparing a new supported catalytic system in which the three reactive groups of the catalytic triad (alcohol, imidazole, and carboxylate) are incorporated into a single functional unit. These artificial active sites can be coupled to a solid-phase support (Merrifield resin) by copper(I)-catalyzed azide-alkyne cycloaddition “click chemistry,” and their effectiveness as esterolysis catalysts was demonstrated. Furthermore, tuning the local hydrophobicity of the resin particles with an approach analogous to the native enzyme hydrophobic pocket increased the catalytic efficiency. Quantum mechanics and molecular dynamics computational modeling were used to probe the catalytic effect and suggested a concerted two-step mechanism and hydrophobic nanoenvironment similar to that of hydrolytic enzymes.
Protonic Reorganization in Catalysis by Serine Proteases: Acylation by Small Substrates
Quinn, Daniel M.,Elrod, James P.,Ardis, Robert,Friesen, Paul,Schowen, Richard L.
, p. 5358 - 5365 (1980)
The pH (pD)-rate profiles for acylation of α-lytic protease in protium and deuterium oxides by p-nitrophenyl acetate show pK values of 5.92 and 6.60, well below the enzyme ionization pK values of 6.70 and 7.35.This is attributed to a pH-induced change in the rate-determining step.The data are consistent with an initial acylation of active-site histidine (protolytically assisted, kH/kD = 2.4), followed by an intramolecular N -> O acyl shift to active-site serine by parallel specific-acid-catalyzed (kH/kD = 0.5) and general-acid-catalyzed (kH/kD = 2) routes.The magnitude of pK(D2O) - pK(H2O) and a proton inventory of the general-acid-catalyzed N -> O acyl shift both suggest that deprotonation of α-lytic protease generates an unusual protonic site with a "loosely bound" proton.The β-deuterium isotope effect, k3H/k3D = 0.98, for the same step confirms nucleophilic interaction at carbonyl in the transition state.An abbreviated proton inventory for acylation of α-chymotrypsin by p-nitrophenyl acetate is consistent with a "loosely bound" proton there also.A proton inventory for acylation of elastase by N-(carbobenzyloxy)-L-alanine p-nitrophenyl ester is linear, suggesting one-proton catalysis and indicating that if "loosely bound" reactant-state protons are present, they are catalytically silent.The general picture, from this work and that of others, is that the catalytic response of serine proteases to small, "unnatural" substrates is highly variable, both in site of nucleophilic attack and involvement of protolytic catalysis.Probably mutual transition-state interactions over an extended region of both enzyme and natural-substrate structure are required to bring into active function the full catalytic capability with which the serine proteases have been endowed by biological evolution.
Palladium-catalyzed aryl group transfer from triarylphosphines to arylboronic acids
Enright, Dale R.,Gogate, Akash R.,Smoliakova, Irina P.,Vasireddy, Purna C. R.
, (2021/11/11)
A study of Pd-catalyzed arylation of arylboronic acids with triarylphosphines is presented. Various parameters of this transformation, such as the oxygen presence, choice of solvent, temperature, palladium source, bases and oxidants, were tested and the optimal conditions of the aryl transfer were determined. The effect of electron-withdrawing and electron-donating substituents on the aryl groups of both reactants was also investigated. The unusual transfer of the acetate group from Pd(OAc)2 to p-nitrophenylboronic acid in the presence of PAr3 is reported. A plausible mechanism of the Pd-catalyzed aryl group transfer from PAr3 to the arylboronic acid is proposed.
Efficient Assay for the Detection of Hydrogen Peroxide by Estimating Enzyme Promiscuous Activity in the Perhydrolysis Reaction
Wilk, Monika,Ostaszewski, Ryszard
, p. 1464 - 1469 (2021/02/01)
Hydrogen peroxide is an ideal oxidant in view of its availability, atom economy, or green aspects. Furthermore, it is produced by the cell mitochondria and plays a meaningful role in controlling physiological processes, but its unregulated production leads to the destruction of organs. Due to its diverse roles, a fast and selective method for hydrogen peroxide detection is the major limitation to preventing the negative effects caused by its excess. Therefore, we aimed to develop an efficient assay for the detection of H2O2. For this purpose, we combined the enzymatic method for the detection of hydrogen peroxide with the estimation of the promiscuity of various enzymes. We estimated the activity of an enzyme in the reaction of p-nitrophenyl esters with hydrogen peroxide resulting in the formation of peracid. To our knowledge, there is no example of a simple, multi-sensor demonstrating the promiscuous activity of an enzyme and detecting hydrogen peroxide in aqueous media.
Prodrug compound and application ofprodrug compound in treatment of cancer
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Paragraph 0181-0182, (2021/03/06)
The present invention provides a compound indicated by a formula (I), pharmaceutically acceptable salts or esters thereof, a pharmaceutical composition of the compound, and application of the compoundand the pharmaceutical composition in the inhibition or regulation of the activity of tyrosine kinase and treating disease symptoms or symptoms including cancer mediated by tyrosine kinase.
PRODRUGS OF THE TYROSINE KINASE INHIBITOR FOR TREATING CANCER
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Paragraph 00144-00145, (2021/03/05)
There are provided compounds of Formula (I), and pharmaceutically acceptable salts and esters thereof, and pharmaceutical compositions thereof, useful for inhibition or modulation of the activity of tyrosine kinases and treatment of disease states or conditions mediated by tyrosine kinases, including cancers. (I)
Tropolonate salts as acyl-transfer catalysts under thermal and photochemical conditions: Reaction scope and mechanistic insights
Mai, Binh Khanh,Koenigs, Rene M.,Nguyen, Thanh Vinh,Lyons, Demelza J.M.,Empel, Claire,Pace, Domenic P.,Dinh, An H.
, p. 12596 - 12606 (2020/11/18)
Acyl-transfer catalysis is a frequently used tool to promote the formation of carboxylic acid derivatives, which are important synthetic precursors and target compounds in organic synthesis. However, there have been only a few structural motifs known to efficiently catalyze the acyl-transfer reaction. Herein, we introduce a different acyl-transfer catalytic paradigm based on the tropolone framework. We show that tropolonate salts, due to their strong nucleophilicity and photochemical activity, can promote the coupling reaction between alcohols and carboxylic acid anhydrides or chlorides to give products under thermal or blue light photochemical conditions. Kinetic studies and density functional theory calculations suggest interesting mechanistic insights for reactions promoted by this acyl-transfer catalytic system.
Organocatalytic Control over a Fuel-Driven Transient-Esterification Network**
Eelkema, Rienk,Fan, Bowen,Macchione, Mariano,Mendes, Eduardo,Wang, Chang-Lin,van der Helm, Michelle P.
supporting information, p. 20604 - 20611 (2020/09/07)
Signal transduction in living systems is the conversion of information into a chemical change, and is the principal process by which cells communicate. In nature, these functions are encoded in non-equilibrium (bio)chemical reaction networks (CRNs) controlled by enzymes. However, man-made catalytically controlled networks are rare. We incorporated catalysis into an artificial fuel-driven out-of-equilibrium CRN, where the forward (ester formation) and backward (ester hydrolysis) reactions are controlled by varying the ratio of two organocatalysts: pyridine and imidazole. This catalytic regulation enables full control over ester yield and lifetime. This fuel-driven strategy was expanded to a responsive polymer system, where transient polymer conformation and aggregation are controlled through fuel and catalyst levels. Altogether, we show that organocatalysis can be used to control a man-made fuel-driven system and induce a change in a macromolecular superstructure, as in natural non-equilibrium systems.
Divergent Late-Stage (Hetero)aryl C?H Amination by the Pyridinium Radical Cation
Ham, Won Seok,Hillenbrand, Julius,Jacq, Jér?me,Genicot, Christophe,Ritter, Tobias
supporting information, p. 532 - 536 (2019/01/04)
(Hetero)arylamines constitute some of the most prevalent functional molecules, especially as pharmaceuticals. However, structurally complex aromatics currently cannot be converted into arylamines, so instead, each product isomer must be assembled through a multistep synthesis from simpler building blocks. Herein, we describe a late-stage aryl C?H amination reaction for the synthesis of complex primary arylamines that other reactions cannot access directly. We show and rationalize through a mechanistic analysis the reasons for the wide substrate scope and the constitutional diversity of the reaction, which gives access to molecules that would not have been readily available otherwise.
Stereodivergent Protein Engineering of a Lipase to Access All Possible Stereoisomers of Chiral Esters with Two Stereocenters
Xu, Jian,Cen, Yixin,Singh, Warispreet,Fan, Jiajie,Wu, Lian,Lin, Xianfu,Zhou, Jiahai,Huang, Meilan,Reetz, Manfred T.,Wu, Qi
supporting information, p. 7934 - 7945 (2019/05/22)
Enzymatic stereodivergent synthesis to access all possible product stereoisomers bearing multiple stereocenters is relatively undeveloped, although enzymes are being increasingly used in both academic and industrial areas. When two stereocenters and thus four stereoisomeric products are involved, obtaining stereodivergent enzyme mutants for individually accessing all four stereoisomers would be ideal. Although significant success has been achieved in directed evolution of enzymes in general, stereodivergent engineering of one enzyme into four highly stereocomplementary variants for obtaining the full complement of stereoisomers bearing multiple stereocenters remains a challenge. Using Candida antarctica lipase B (CALB) as a model, we report the protein engineering of this enzyme into four highly stereocomplementary variants needed for obtaining all four stereoisomers in transesterification reactions between racemic acids and racemic alcohols in organic solvents. By generating and screening less than 25 variants of each isomer, we achieved >90% selectivity for all of the four possible stereoisomers in the model reaction. This difficult feat was accomplished by developing a strategy dubbed "focused rational iterative site-specific mutagenesis" (FRISM) at sites lining the enzyme's binding pocket. The accumulation of single mutations by iterative site-specific mutagenesis using a restricted set of rationally chosen amino acids allows the formation of ultrasmall mutant libraries requiring minimal screening for stereoselectivity. The crystal structure of all stereodivergent CALB variants, flanked by MD simulations, uncovered the source of selectivity.
