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Design of Bioresponsive Polymers
Published in Deepa H. Patel, Bioresponsive Polymers, 2020
Anita Patel, Jayvadan K. Patel, Deepa H. Patel
In ROMP reaction, various metals used as the catalysts like simple ruthenium trichloride/alcohol mix to Grubbs’ catalysts [40, 41]. The ROMP reaction is catalyzed mostly during the development of metal-carbene complexes when initially stated by Nobel Prize winner Yve Chauvin and Jean-Louis Hérisson [42, 43] even though a hydride system has as well described [40]. A beginning of the carbene species takes place in the course of various pathways; co-catalysts, substituent interactions, as well as solvent interactions, each, and everyone can give to the manufacture of the reactive catalytic species [40, 44, 45].
Affinity Modification — Organic Chemistry
Published in Dmitri G. Knorre, Valentin V. Vlassov, Affinity Modification of Biopolymers, 1989
Dmitri G. Knorre, Valentin V. Vlassov
Carbenes were shown to react with any bipolymer residue. Thus, when membrane-embedded proteolipid of the Fo part of ATP synthase in mitochondria and chloroplasts was labeled with carbenes generated from 3-[trifluoromethyl-3(m-[125I]phenyl)]diazirine, modification of methionine, valine, leucine, serine, threonine, isoleucine, and phenylalanine residues was observed.127 However, products of the modification were not chemically characterized as in almost all cases of photoaffinity modification.
The Modification Of Carboxyl Groups
Published in Roger L. Lundblad, Chemical Reagents for Protein Modification, 2020
Diazo compounds have proved useful for some time in the esterification of the carboxyl groups of proteins. This is particularly true of diazomethane. The use of this compound was reviewed 20 years ago by the late Philip Wilcox,1,2 and we are not aware of the extensive use of this compound during the past decade. Various α-keto diazo derivatives have proved particularly fruitful in the study of acid proteinases. Rajagopalan, Stein, and Moore3 demonstrated that pepsin was inactivated by diazoacetyl-l-norleucine methyl ester. During the course of these studies, it was observed that cupric ions greatly enhanced both the rate and specificity of the modification. Originally it was suggested that cupric ions blocked nonspecific reaction with carboxyl groups not at the active site. Subsequently it was shown that cupric ions and diazoacetyl-norleucine methyl ester formed a highly reactive species, presumably a copper-complexed carbene, which then reacted with a specific protonated carboxyl group at the active site of pepsin.4,5 The modification of carboxyl groups in a variety of acid proteinases with a variety of α-keto diazo compounds is shown in Table 1. These diazo compounds are by no means specific for carboxyl group modification in protein. Benzyloxycarbonyl-phenylalanyldiazomethylketone has been shown to modify cathepsin B1, presumably by reaction with the active-site sulfhydryl group.6 Other possible side reactions of α-keto diazo compounds have been reviewed by Widner and Viswanatha.7 These side reactions result primarily from the oxidative modification of tryptophan, methionine, tyrosine, and cystine. These side reactions can be virtually obviated by vigorous exclusion of oxygen from the reaction and the addition of an oxygen scavenger (e.g., Na2S204). These compounds are also precursors of carbenes via photoactivation (see Chapter 16).
Replacing the phthalimide core in thalidomide with benzotriazole
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Mikhail Krasavin, Andrey Bubyrev, Alexander Kazantsev, Christopher Heim, Samuel Maiwald, Daniil Zhukovsky, Dmitry Dar’in, Marcus D. Hartmann, Alexander Bunev
The synthesis of the benzotriazole analogue 2 of thalidomide was achieved as detailed below. Commercially available glutarimide 3 was (dimethylamino)methylenated at the α-position using the Brederick’s reagent (4)8. The resulting derivative 5 readily entered the Regitz diazo transfer reaction9 with 4-nitrophenylsulfonyl azide (NsN3) to give hitherto undescribed 3-diazopiperidine-2,6-dione (6) in excellent yield. α-Diazocarbonyl compounds were recently established to regioselectively alkylate benzotriazoles at N2 when activated as Rh(II) carbenes10. Indeed, when α-diazoglutarimide (6) was activated by Rh(II) espionate (bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)]) (1 mol%) and reacted with benzotriazole, desired ‘benzotriazolo thalidomide’ 2 was obtained in excellent yield and complete regioselectivity (Scheme 1).
N-heterocyclic carbene metal complexes as therapeutic agents: a patent review
Published in Expert Opinion on Therapeutic Patents, 2022
Kostiantyn O. Marichev, Siddappa A. Patil, Shivaputra A. Patil, Hector M. Heras Martinez, Alejandro Bugarin
N-Heterocyclic carbenes (NHC) are a class of compounds known for their inherited reactivity and excellent ligands to form stable metal complexes [1–3]. Traditionally, the applications of these complexes cover the fields of organometallic chemistry [4], material science [5], homogeneous and heterogeneous catalysis [6,7]. Despite similar donor properties of NHCs with classic nitrogen or phosphorus containing ligands, the remarkable catalytic activities of NHC metal complexes often exceed those of P- or N-metal complexes due to their unique electronic properties [8,9]. While NHCs in their free-form are commonly air- and/or moisture sensitive, their complexes with transition metals are often very stable and suitable for catalysis even in aqueous and/or aerobic media [10,11], which makes them an ideal class of compounds for catalytic and therapeutic use in biological systems. Their use as therapeutic agents has been extensively studied in the past decade [12–15]. In particular, silver [16–18], gold [19–21], platinum [22], and palladium [23] NHC complexes have demonstrated excellent antimicrobial and anticancer properties.
Mechanism-based inactivation of cytochrome P450 enzymes by natural products based on metabolic activation
Published in Drug Metabolism Reviews, 2020
Tingting Zhang, Jinqiu Rao, Wei Li, Kai Wang, Feng Qiu
It has been clarified that a reactive carbene intermediate derived from MDP is involved in the inactivation of P450 enzymes (Franklin 1971; Philpot and Hodgson 1971; Murray 2000; Kamel and Harriman 2013). Savinin (Table 3), a methylenedioxyphenyl lignan isolated from Acanthopanax chiisanensis, has been proven to be a mechanism-based inactivator of CYP3A4. It was speculated that the mechanism of inactivation of CYP3A4 by savinin was attributed to the formation of a reactive carbene intermediate. Specifically, hydrogen atom abstraction from the methylene carbon followed by hydroxylation at the bridging methylene group results in the formation of an unstable intermediate. On one hand, the resulting intermediate can undergo ring opening, hydrolysis and the subsequent loss of formic acid (HCOOH) to form a catechol (Figure 4, pathway A), which may further be oxidized to the reactive ortho-quinone metabolic intermediate, leading to covalent modification of the active sites of the enzyme. On the other hand, elimination of a water molecule from the intermediate should produce an acidic oxonium ion (Figure 4, pathway B) that upon deprotonation gives a carbene intermediate. This carbene species can coordinate with the heme iron of P450 enzymes, resulting in the formation of a carbene-iron complex (Kamel and Harriman 2013).