Lactic acid-based polymers in depth
Yoshinobu Onuma, Patrick W.J.C. Serruys in Bioresorbable Scaffolds, 2017
The hydrolysis of a polyester chain depends on the local concentration in water and also on the presence of catalysts such as bases or acids. The cleavage of ester bonds generates more and more acidic and alcoholic chain ends. As a result, the matrix is more and more hydrophilic and the rate of ester cleavage increases according to a phenomenon named “autocatalysis.” Typically, once a device made of a lactic acid-based polymer is in contact with an aqueous medium, water penetrates more or less rapidly and the hydrolytic cleavage of ester bonds starts. The local acidity increases in the bulk and hydrolysis speeds up. For a time, the partially degraded macromolecules remain insoluble in the outer medium and thus stay entrapped in the matrix. There is no mass loss. However, as soon as partially degraded macromolecules become soluble, diffusion starts from the surface to the outer aqueous phase.
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
Chemical Carcinogenesis in Skin: Causation, Mechanism, and Role of Oncogenes
Rhoda G. M. Wang, James B. Knaak, Howard I. Maibach in Health Risk Assessment, 2017
Structure-activity relationships within the phorbol ester series indicate a distinct linkage between promoting potency and chemical structure, and thereby reflect the interaction of phorbol esters with a specific cellular binding site.21 The two-stage initiation-promotion protocol in mouse skin yields mainly reversibly growing benign papillomas,22,23 which are known to be of monoclonal origin.24,25 In the course of the initiation-promotion regimen carcinomas arise directly from the papillomas by the process known as malignant progression.26 However, the development of carcinoma does not occur in initiated skin without promotion indicating that promotion has to be regarded as a prerequisite for malignant progression. Recently Aldaz et al.27 provided evidence that the majority of the papillomas produced by initiation-promotion protocol are promoter independent. This study further supported the hypothesis that the large number of papillomas developed by two-stage initiation-promotion regimens in SENCAR mice may have the potential to progress towards malignancy.
Liposome–ligand conjugates: a review on the current state of art
Published in Journal of Drug Targeting, 2020
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.
Construction of pH-sensitive targeted micelle system co-delivery with curcumin and dasatinib and evaluation of anti-liver cancer
Published in Drug Delivery, 2022
Xiangle Zeng, Yawen Zhang, Xue Xu, Zhuo Chen, Lanlan Ma, Yushuai Wang, Xuliang Guo, Jianchun Li, Xiu Wang
In addition, a large number of tumor microenvironment-responsive nanoparticles were developed to further enhance the intracellular delivery of drugs and control the release of encapsulated drugs into tumor cells (Liu et al., 2014, 2016; Rao et al., 2014; Ye et al., 2016). Currently, the combination of active targeting of the micelle system and an intracellular pH-sensitive targeting strategy in cancer treatment is helpful to trigger the activation of nanosystems, thereby improving tumor targeting and intracellular drug delivery. This new approach provides an effective strategy to improve the therapeutic effect (Lai et al., 2021). Among them, ester bonds () are a kind of pH-triggered chemical structure, which is widely used to construct stimuli-responsive carriers (Wang et al., 2021; Zhang et al., 2021).
Discovering a new class of antifungal agents that selectively inhibits microbial carbonic anhydrases
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Giannamaria Annunziato, Laura Giovati, Andrea Angeli, Marialaura Pavone, Sonia Del Prete, Marco Pieroni, Clemente Capasso, Agostino Bruno, Stefania Conti, Walter Magliani, Claudiu T. Supuran, Gabriele Costantino
In a previous work10, we reported the identification of a new chemotype as prototype of new selective inhibitors for microbial CAs. The reported compounds relied on the presence of N-oxide pyridine ring as new potential ZCG, showing an encouraging activity, in the low µM range, and combining an interesting selectivity profile toward the human isoforms. The identified compounds represented excellent hits to be further optimised in classical medicinal chemistry optimisation cycles. Prompted by these encouraging results, we decided to start a hit-to-lead campaign aimed at improving the activity profile of our class of inhibitors, while preserving the selectivity profile toward the human CA isoforms. The main sites of scaffold modifications, reported in Figure 2, can be summarised as follow: (i) retention of the 2-amino N-oxide-pyridine core as main scaffold of most of synthesised compounds; (ii) modification of the ester moiety in position R with a more metabolically stable functional group; (iii) introduction of alkyl or aromatic groups of different nature in position R1; (iv) introduction of alkyl in position R2 and R3; (v) introduction of a nitrogen atom in position 4 (X), since the 1-N-oxide pyrazine ring is a scaffold described in several approved drugs (e.g. Minoxidil36, Acipimox37).
Related Knowledge Centers
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