Formation of Peptide Bonds — Proteases as “Activating Systems”
Willi Kullmann in Enzymatic Peptide Synthesis, 1987
The principle of carboxyl activation is ubiquitious in the field of peptide or protein synthesis both in vivo and in vitro. A typical species of an activated acyl group donor is the so-called active ester of the form RCOO—R′ (R′ = alkyl, acyl, aryl). In ribosomal protein synthesis the peptidyl-t-RNA represents an active peptide ribosyl ester which exhibits strong acylating power, and, as a consequence, is readily aminolyzed by an incoming amino acyl-t-RNA.3This ester type activation is also widely used in the field of chemical peptide synthesis. (For a comprehensive review see Reference 4). Carboxyl activation is not only accomplished via active oxygen-based esters; thus during nonribosomal peptide biosynthesis of microbial antibiotics, which is mediated by a multienzyme complex, and to a minor extent during the chemosynthesis of peptides, thioesters play the role of an energy-rich acyl-group donor.4,5
Hydrolytic Enzymes for the Synthesis of Pharmaceuticals
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
In the previous section, the action of water as nucleophile in hydrolytic reactions of different organic compounds have been illustrated, here the role of other nucleophiles will be deeply analysed. For instance, the esterification of carboxylic acids with alcohols is well known, and this has allowed the formation of esters in non-selective and selective fashions. For instance, the reaction of substituted benzoic acids with alcohols and (N,N)-disubstituted amino alcohols has allowed the synthesis of interesting alkyl esters, some of them key intermediates in the synthesis of benzocaine, chloroprocaine and procaine anaesthetics (Giunta et al., 2013). The reaction with CAL-B and equimolecular amounts of a determined (amino) alcohol led to complete conversions in many cases by using cyclohexane as solvent, yielding the desired esters in quantitative yields after a simple work-up by filtration and solvent distillation (Scheme 9.19). Esterification of benzoic acids with alcohols in the presence of CAL-B.
Monographs of Topical Drugs that Have Caused Contact Allergy/Allergic Contact Dermatitis
Anton C. de Groot in Monographs in Contact Allergy, 2021
General aspects of corticosteroids used on the skin and mucous membranes are discussed in Chapter 2.4. A practical guideline for diagnosing allergic reactions to corticosteroids is presented in ref. 2. Methylprednisolone base is used in oral forms only. Esters used in other applications include methylprednisolone acetate (Chapter 3.119), methylpredni- solone hemisuccinate (Chapter 3.220), and methylprednisolone aceponate (Chapter 3.218). As methylprednisolone base is used as tablet only, this implies that by far most allergic reactions to ‘methylprednisolone’ have in fact been the result of sensitization to an ester of methylprednisolone or of cross-reactivity to another corticosteroid. It is also likely that there has been confusion in some publications on the correct forms of the drugs used, e.g. that methylprednisolone was mentioned where in fact an ester form should have been mentioned (1,3).
Liposome–ligand conjugates: a review on the current state of art
Published in Journal of Drug Targeting, 2020
İpek Eroğlu, Mamudu İbrahim
This is the most frequently used linkage in terms of engineering liposome conjugates. Ester bond is formed when hydroxyl group of a molecule reacts (sometimes with the help of succinic acid as linkers) with carboxylic acid group of the liposomes or vice versa [100]. Because of the unreactive nature of carboxyl groups (due to low nucleophilic property), reactants such as carbonyl diimidazole are used to modify these carboxyl groups to make room for ester linkages. Carbonyl diimidazole is an active carbonylating agent consisting of two acylimidazole-leaving groups that react with carboxylic acids to generate N-acylimidazoles of high reactivity. The active carboxylate resulting from this reaction is then positioned to bond with hydroxyl groups through ester linkages [64]. This bond is usually meant to be broken by esterase enzymes through the process of hydrolysis; but then several factors including adjacent groups (e.g. bromide) and spacers may influence the cleavage process [101,102]. Guo and Szoka [103] utilised diortho ester to successfully synthesise low pH-sensitive PEG-diortho ester-distearoyl glycerol conjugate (POD). Distearoyl glycerol containing two saturated hydrocarbon side chains is coupled to the diortho ester (3,9-diethyl-2,4,8,10-tetraoxaspiro[5]undecane) in order to facilitate the anchoring of PEG2000 into lipid bilayers. The formed liposome conjugate was found to be stable up to 12 h at neutral pH, but degraded at pH 5 to release the payload, and thus found to be suitable for application in tumour targeting.
MCL-1 inhibitors – where are we now (2019)?
Published in Expert Opinion on Therapeutic Patents, 2019
Steven Fletcher
A patent application (WO2017027845) from Memorial Sloan Kettering Cancer Center was recently filed describing phenylsulfonamide-benzofurans as inhibitors of members of the BCL-2 family, wherein some compounds exhibited selectivity for MCL-1-dependent cell lines over BCL-2- and BCL-xL-dependent cell lines [29]. The generic structures are described by formulae 11 and 12 (Figure 9) in which the non-R2 groups may be hydrogen, alkyl, cycloalkyl, halogen, and so on. The R2 group may be hydrogen, alkyl, cycoalkyl, as well as OR and NR2 to encompass esters and tertiary amides, respectively. The lead compound 10, dubbed MCLin, induced apoptosis (as measured by an Annexin-V assay) with EC50 values of 667 nM and 336 nM, respectively, in MCL-1 addicted H23 and H82 lung cancer cells. Significantly, MCLin exhibited limited impact on apoptosis in BCL-2 (DMS53) and BCL-xL (SW1417) addicted cell lines. It must be noted that no in vitro data was provided, so there is no evidence that these compounds induce apoptosis in H23 and H82 cells through the direct inhibition of MCL-1. Furthermore, since MCL-1 inhibitors usually possess a carboxylic acid or appropriate bioisostere, we speculate that if, indeed, MCLin does act on-target then it may be a pro-drug, with the active inhibitor actually the corresponding carboxylic acid metabolite.
Phenolic benzotriazoles: a class comparison of toxicokinetics of ultraviolet-light absorbers in male rats
Published in Xenobiotica, 2021
Suramya Waidyanatha, Esra Mutlu, Seth Gibbs, Jessica Pierfelice, Jeremy P. Smith, Brian Burback, Chad T. Blystone
We used a method, utilizing protein precipitaion followed by LC-MS/MS, to quantitate phenolic benzotriazoles. The use of protein precipitation for sample cleanup and incorporation of 96-well format increased the efficiency of the method and sample throughput. For all compounds, except the ester, the parent concentrations were quantified. For the ester, the corresponding acid, tBuPrA-BZT, was used. Analytical method qualification data for the quantitation of analytes are summarized in Table 3. Standard curves were linear over the concentration ranges evaluated with coefficients of determination >0.98 for all analytes. Estimated LOD values ranged from 0.166 to 1.16 ng/mL depending on the analyte (Table 3). The %RE values estimated based on calibration standards were ≤ ±18.9 and QC samples were ≤ ±22.7. The %RSD values were ≤13.7 for all except for octrizole which was ≤24.5 Taken collectively, the data show that the method is suitable for the quantitation of analytes in plasma from the investigation on TK behaviour of the class.