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The Chemical Cross-Linking Of Peptide Chains
Published in Roger L. Lundblad, Chemical Reagents for Protein Modification, 2020
A series of homo- and heterobifunctional reagents which form acid-labile cross-links in proteins have been reported.67 These are shown in Figure 20. The ability to be cleaved by mild acid (pH 5.0) is based on the presence of ortho ester, acetal, and ketal functional groups. Another heterobifunctional reagent which forms an acid-labile link is based on the lability of the reaction product between citraconic anhydride and lysine.68
Pharmacokinetic-Pharmacodynamic Correlations of Corticosteroids
Published in Hartmut Derendorf, Günther Hochhaus, Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
Helmut Möllmann, Stefan Baibach, Günther Hochhaus, Jürgen Barth, Hartmut Derendorf
Triamcinolone (TC) and triamcinolone acetonide (TCA), the 16α,17α-ketal of TC., are active compounds with distinct pharmacokinetics and receptor affinities. Triamcinolone has a terminal half-life of 3 h, a linear plasma protein binding of 40%, a Vd of 119 l, and a total body clearance of 29 l/h.36,104,105 No significant differences in TC plasma profiles were observed after oral administration of TC or its prodrug triamcinolone diacetate (TCD).104
Interaction of Drugs of Dependence With Receptors
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
Possible presynaptic receptor sites for ethanol are the catecholamine uptake and storage sites. It has been suggested that ethanol produces alkaloidlike compounds during its metabolism by condensation of acetaldehyde and catecholamines.175–178 Heikkilà et al.179 have shown that tetrahydroisoquinoline alkaloids (TIQ), produced by condensation of dopamine and acetaldehylde, are taken up and concentrated in the presynaptic region, and that the catecholamine uptake mechanism is inhibited by salsolinol, a TIQ condensation product of dopamine and acetal-dehyde.
Legumain/pH dual-responsive lytic peptide–paclitaxel conjugate for synergistic cancer therapy
Published in Drug Delivery, 2022
Shanshan Zheng, Yue Cai, Yulu Hong, Yubei Gong, Licheng Gao, Qingyong Li, Le Li, Xuanrong Sun
Peptide–drug conjugates (PDCs) are special drug delivery system which comprises a therapeutic peptide, a small molecule drug and a linker. Compared with single drug loaded drug delivery system, PDCs can enhance anti-tumor effect, reduce drug resistance and modified with virous linkers (Deng et al., 2021; Zhu et al., 2021). Therefore, constructing PTX/PTP-7 co-loaded polymeric nanoparticles could be a creative strategy which can overcome the above shortcomings. Given weak acidic pH is a special feature of tumor microenvironment, acid-sensitive linkages play an important role in establishing prodrugs with efficient transformation in tumor (Wang et al., 2011; Saadat et al., 2021). Li et al. utilized CDM as an acid-sensitive linkage to control prodrug release in tumor (Li et al., 2016). Moreover, Ding et al. designed a PEGylated PTX prodrug using acid-sensitive acetone-based acyclic ketal as the linkage which showed good antitumor efficacy (Mu et al., 2020). Legumain, a lysosomal/vascular cysteine protease, is strictly specific to the hydrolysis of peptide bonds with asparagine or aspartic acid (Morita et al., 2007). Legumain was demonstrated overexpressing in various cancers, such as breast cancer, colorectal cancer, and prostate cancer, whereas rarely expressed in normal tissues (Ohno et al., 2010; Haugen et al., 2015). According to the unique function and characterization of legumain, several legumain-targeted NDDS have been explored to increase drug bioavailability and minimize or eliminate side effects (Liu et al., 2003; Lin et al., 2015; He et al., 2018).
Lipid nanoparticle-based co-delivery of epirubicin and BCL-2 siRNA for enhanced intracellular drug release and reversing multidrug resistance
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Miao Yu, Shangcong Han, Zhongai Kou, Jialing Dai, Jiao Liu, Chen Wei, Yitong Li, Lutao Jiang, Yong Sun
KPAE was synthesized with KDA and diethylenetriamine via Michael addition polymerization in dry dimethyl sulfoxide. After 24 h of polymerization at 40 °C, KPAE was obtained as reddish-brown viscous liquid. The chemical structure of KPAE was identified by 1H NMR. As shown in Figure 1(A), 1H NMR in CDCl3 on a 400 MHz spectrometer: δ = 1.4 (m, OCCH3), 2.3–2.9 (m, NHCH2CH2), 3.1–3.5 (m, CH2CH2CO), 3.5–3.8 (m, OCH2CH2). The weight of KPAE copolymer was measured to be 7000–10000 Da by using gel permeation chromatography (GPC). And in acid environment, ketal groups in KPAE degraded into small molecules, and weight average molecular weight was decreased (Figure 1(B)). While in acid environment like endosomes or lysosomes (pH 5.5), ketal groups in KPAE degraded and enhanced the endosomal/lysosomal escape and release of siRNA but stable in the neutral pH of cytosol [25].
Discovery of triterpenoids as potent dual inhibitors of pancreatic lipase and human carboxylesterase 1
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Jing Zhang, Qiu-Sha Pan, Xing-Kai Qian, Xiang-Lu Zhou, Ya-Jie Wang, Rong-Jing He, Le-Tian Wang, Yan-Ran Li, Hong Huo, Cheng-Gong Sun, Lei Sun, Li-Wei Zou, Ling Yang
In summary, a series of natural triterpenoids were collected and their inhibitory effects against PL and hCES1A were assayed using 4-MUO and NLMe as substrate probe, respectively. Two natural pentacyclic triterpenoid OA and UA were found to display both good inhibitory effects on PL and hCES1A, and good selectivity over hCES2A. Thus, 14 compounds based on the UA and UA skeletons were synthesised and evaluated. Structure-activity relationship (SAR) analysis of these compounds revealed that 2-enol and 3-ketal moiety are beneficial for PL and hCES1A inhibition, and smaller 3-acetyl group is beneficial for PL inhibition, while bigger 3-O-β-carboxypropionyl group is beneficial for hCES1A. In addition, compounds 39 (OA derivative with 2-enol and 3-ketal moiety) and 41 (OA derivative with acetyl group at the C-3 site) displayed potent inhibitory effects against both PL and hCES1A. Furthermore, compounds 39 and 41 exhibited good selectivity over other human serine hydrolases including hCES2A, BChE and DPP-IV. Inhibitory kinetics and molecular docking studies demonstrated that both compounds 39 and 41 were effective mixed inhibitors of PL, while competitive inhibitors of hCES1A. Further investigations demonstrated that both compounds 39 and 41 could inhibit adipocyte adipogenesis induced by mouse preadipocytes. Collectively, our findings suggest that triterpenoids are good choices for design and development of PL and hCES1A inhibitors, while compounds 39 and 41 hold great promise for development of novel PL and hCES1A dual-target inhibitors to treat with related metabolic diseases.