查看更多>>摘要：Development of new drugs with broad-spectrum to combat RNA viruses would be beneficial to mankind but faces a great challenge. We designed and efficiently synthesized a series of quinazolin-4-amine-SCH2-coumarin conjugated compounds. Our data of the virus-cell-based assay show five new conjugates inhibit chikungunya virus with EC50 values as potent as 1.96 mu M and two conjugates inhibit hepatitis C virus with EC50 values as low as 16.6 mu M. These conjugates possess a xylene substituent at the C-4 amino group of quinazoline and a t-butyl substituent at the C-6' position of coumarin. (c) 2022 Elsevier Masson SAS. All rights reserved.
查看更多>>摘要：Hepatocellular carcinoma is one of the most common primary hepatic malignancy. Herein, a series of semisynthesized derivatives (2-30) of the natural product (+)-sclerotiorin (1) was prepared and evaluated the cytotoxic activities against six cancer cell lines. Among them, 3 and 5 were the most effective compounds against human hepatocellular carcinoma Bel-7402 cell line with IC50 values of 1.45 and 1.15 mM, respectively. Molecular mechanism study showed that 5 disrupted the mitochondrial membrane potential and induced apoptosis in a caspase-dependent manner. In addition, 5 affected AKT and ERK signaling pathways and induced AKT and ERK proteins degradation through ubiquitin-proteasome system. Furthermore, 5 displayed significant in vivo anticancer effects in the xenograft models with decreasing the tumor mass by 52.5%. The safety evaluation was confirmed by acute toxicity subchronic toxicity tests, paraffin sections of mice organ and blood routine examination. Taken together, 5 can be developed as a potential therapeutic agent for hepatocellular carcinoma. (c) 2022 Elsevier Masson SAS. All rights reserved.
查看更多>>摘要：Antibiotic resistance caused by beta-lactamases, particularly metallo-beta-lactamases, has been a major threat to public health globally. New Delhi metallo-beta-lactamase-1 (NDM-1) represents one of the most important metallo-beta-lactamases; the production of NDM-1 in bacterial pathogen significantly reduces the efficacy of beta-lactam antibiotics, including life-saving carbapenems. Herein, we have demonstrated stereochemically altered cephalosporins as potent inhibitors against NDM-1, as well as mutants of NDM. The structure and activity relationship (SAR) study on over twenty cephalosporin analogues discloses the stereochemistry and the substituents on 7-position and 30-position of cephalosporin are critical to suppress the activity of NDM-1 and the optimal compound 1u exhibited an IC50 of 0.13 mM. Furthermore, a crystal complex of NDM-1 and 1u has been obtained, suggesting this cephalosporin derivative inhibits enzyme activity by the formation of a relatively stable hydrolytic product-NDM-1 intermediate. The discovery in this study may pave the way to turn cephalosporin, a natural substrate of beta-lactamase, into an effective NDM-1 inhibitor to combat antibiotic resistance. (c) 2022 Elsevier Masson SAS. All rights reserved.
查看更多>>摘要：Glycosyl conjugation to drugs is a strategy being used to take advantage of glucose transporters (GLUT) overexpression in cancer cells in comparison with non-cancerous cells. Its extension to the conjugation of drugs to thiosugars tries to exploit their higher biostability when compared to O-glycosides. Here, we have synthesized a series of thiosugar naphthalene diimide conjugates as G-quadruplex ligands and have explored modifications of the amino sidechain comparing dimethyl amino and morpholino groups. Then, we studied their antiproliferative activity in colon cancer cells, and their antiparasitic activity in T. brucei and L. major parasites, together with their ability to bind quadruplexes and their cellular uptake and location. We observed higher toxicity for the sugar-NDI-NMe2 derivatives than for the sugar-NDI-morph compounds, both in mammalian cells and in parasites. Our experiments indicate that a less efficient binding to quadruplexes and a worse cellular uptake of the carb-NDI-morph derivatives could be the reasons for these differences. We found small variations in cytotoxicity between O-carb-NDIs and S-carb-NDIs, except against non-cancerous human fibroblasts MRC-5, where thiosugar-NDIs tend to be less toxic. This leads to a notable selectivity for b-thiomaltosyl-NDI-NMe2 12 (9.8 fold), with an IC50 of 0.3 mu M against HT-29 cells. Finally, the antiparasitic activity observed for the carb-NDI-NMe2 derivatives against T. brucei was in the nanomolar range with a good selectivity index in the range of 30-to 69-fold.(c) 2022 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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