Methods of Protein Iodination
Erwin Regoeczi in Iodine-Labeled Plasma Proteins, 2019
An acyl group is the univalent group, , where R is any organic group attached to one bond of the bivalent carbonyl group ,. The alkyl group has already been defined in Section C.1.a. An aryl group is an organic group derived from an aromatic hydrocarbon by the removal of a hydrogen (e.g., the phenyl group, C6H5-, derived from benzene, C6H6). Amines are organic derivatives of ammonia (NH3) formed by the replacement of one, two, or three of the hydrogen atoms by an alkyl or aryl group; correspondingly, the resulting aliphatic and aromatic (and other) amines are classified as primary (RNH2), secondary (R2NH), or tertiary (R3N) amines. Amides are carboxylic acid derivatives obtained by the replacement of the OH group of an acid by an amino group (NH2). Azo compounds are organic compounds which contain the group, -N:N-, attached to two alkyl or aryl groups (e.g., azobenzene, C6H5-N:N-C6H5). In contrast, only one of the two N atoms bonded together in diazo compounds is attached to a carbon of an organic structure (RN=N, see further below). Imines, containing the grouping, -CH=N-, arise from the condensation of primary amines with aldehydes (or ketones) through the loss of H2O. Imides are nitrogen analogs of anhydrides:
Biocatalysts: The Different Classes and Applications for Synthesis of APIs
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
The aldolase-catalyzed reaction proceeds via two different mechanisms, a Schiff base formation (class I aldolases) or by Zn2+ activation (class II aldolases), as depicted in the opposite scheme for DHAP-dependent enzymes. The mechanism of class I aldolases (a) is characterized by the formation of an imine between the terminal amino group of a Lys residue and the carbonyl oxygen atom of the substrate DAHP. The imine may rearrange to an enamine that attacks nucleophilicly the aldehyde carbonyl carbon. Subsequent hydrolysis gives the new aldol and the free enzyme. The first steps in the reaction mechanism of the class II aldolases such as tagatose-1,6-diphosphate aldolase or fructose-1,6-diphosphate aldolase (b) are the binding of DAHP and the abstraction of a proton from the activated C1 by a functional group of the active site. The following steps (not shown), are glyceraldehyde-3-phosphate binding with subsequent C–C bond formation, and proton transfer.
Molecular Aspects of the Activity and Inhibition of the FAD-Containing Monoamine Oxidases
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
The reaction catalysed by MAO removes two hydrogen atoms from the amine forming an imine, and reduces FAD. The reduced FAD is then reoxidized by oxygen to form hydrogen peroxide. The imine product is hydrolysed by water giving the corresponding aldehyde and ammonia (Fig. 10.2). This chapter will consider the structure of the enzyme and the redox reaction with the cofactor and before turning to the substrate specificity, kinetics and mechanism that are important for drug design. MAO A and MAO B show broad specificity for both substrates and inhibitors, yet can display exquisite selectivity as will be discussed in the last section on inhibitors.
Synthesis of thiazolidin-4-ones and thiazinan-4-ones from 1-(2-aminoethyl)pyrrolidine as acetylcholinesterase inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Adriana M. das Neves, Gabriele A. Berwaldt, Cinara T. Avila, Taís B. Goulart, Bruna C. Moreira, Taís P. Ferreira, Mayara S. P. Soares, Nathalia S. Pedra, Luiza Spohr, Anita A. A. dE Souza, Roselia M. Spanevello, Wilson Cunico
Both thiazolidin-4-ones and thiazinan-4-ones have similar syntheses strategy. The main synthetic route involves three components (an aldehyde or ketone, a primary amine, and carboxylic acid). The reactions proceed by initial formation of an imine followed by intramolecular cyclisation and elimination of water. Moreover, these methods can be applied in two-steps, one step multicomponent (all reactants together at the beginning of reaction) or one-step one-pot reactions, under catalysis or not22. We have been studying these classes of heterocycles in a few years23–26 and in continuation of our research programme, this work aims to synthesise novel thiazolidin-4-ones and thiazinan-4-ones from a specific amine, the 1–(2-aminoethyl)pyrrolidine, affording compounds structurally similar to AChE that could act as AChE inhibitors (Figure 1). The same strategy was used in previous work with good results27. Another goal is the AChE inhibitory activity and cytotoxicity of synthesised compounds, contributing to the search for new compounds that can be used for the AD treatment.
Antibody-drug conjugates: Design and development for therapy and imaging in and beyond cancer, LabEx MAbImprove industrial workshop, July 27–28, 2017, Tours, France
Published in mAbs, 2018
Camille Martin, Claire Kizlik-Masson, André Pèlegrin, Hervé Watier, Marie-Claude Viaud-Massuard, Nicolas Joubert
Even though maytansinoids have proven to be effective in ADCs, payloads with new mechanisms of action and increased potency compared to classical tubulin inhibitors are needed. Dr. Chari presented a new class of payload, indolinobenzodiazepines (termed IGNs), displaying better potencies against some tumor cell lines compared to maytansinoids. Chemical investigations on the core showed that switching one imine for an amine changed the crosslinking character of the di-imine into the alkylating character of the mono-imine. This resulted in reduced toxicity observed in vivo while conserving an equivalent potency (pM range) for the mono-imine IGN compared to the di-imine IGN.4 Combining a sulfonic cleavable linker to this new deoxyribonucleic acid (DNA)-alkylating IGN, the ADC obtained had an improved therapeutic window and demonstrated bystander killing effect. Using this molecular construction on an anti-CD33 mAb, the resulting ADC IMGN779 showed promising activity in models with high and moderate expression of the antigen. It has now entered a Phase 1 study for patients with acute myeloid leukemia. A question from the audience highlighted the problems of mAb choice when making an ADC. Dr. Chari explained that the key parameter is its ability to deliver the payload efficiently.
Assessment of the antiproliferative and apoptotic roles of sulfonamide carbonic anhydrase IX inhibitors in HeLa cancer cell line
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Ismail Koyuncu, Ataman Gonel, Mustafa Durgun, Abdurrahim Kocyigit, Ozgur Yuksekdag, Claudiu T. Supuran
The aromatic sulfonamides used in this study were reported in our previous study13. Briefly, the imine compound derivatives (A1-A3) were synthesised through the reaction of 4–(2-aminoethyl)benzenesulfonamide with substituted aromatic aldehydes with catalytic amounts of formic acid in methanol at the refluxing temperature for 3–5 h. The secondary amine derivatives (B1-B3) were prepared by reduction of the imine compounds (A1-A3) with NaBH4 in methanol. All the derivatives of imine and amine were characterised with both analytical and spectral data. The aromatic aldehydes used in the synthesis were 5-chloro-2-hydroxybenzaldehyde (A1,B1), 3,5-dichloro-2-hydroxybenzaldehyde (A2, B2), and 2-hydroxybenzaldehyde (A3, B3). These CA inhibitors have been shown to induce a moderately effective, reversible inhibition of the membrane-bound isozyme CA IX compared with traditional inhibitors. The KIs of the CA inhibitors and the chemical structures of the inhibitors tested are shown in Table 113.