Bioactivity-Driven Synthesis of the Marine Natural Product Naamidine J and Its Derivatives as Potential Tumor Immunological Agents by Inhibiting Programmed Death-Ligand 1

The total synthesis of the marine natural product naamidine J and a rapid structure modification toward its derivatives were achieved on the basis of several rounds of structure-relationship analyses of their tumor immunological activities. These compounds were tested for programmed death-ligand 1 (...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2023-04, Vol.66 (8), p.5427-5438
Main Authors: Fu, Pan-Pan, Wang, Qun, Zhang, Qing, Jin, Yang, Liu, Jin, Chen, Kai-Xian, Guo, Yue-Wei, Liu, San-Hong, Li, Xu-Wen
Format: Article
Language:English
Subjects:
Adenocarcinoma
Animals
B7-H1 Antigen - metabolism
Cell Line, Tumor
Colorectal Neoplasms
Humans
Immunologic Factors
Mice
Mice, Inbred C57BL
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Summary:The total synthesis of the marine natural product naamidine J and a rapid structure modification toward its derivatives were achieved on the basis of several rounds of structure-relationship analyses of their tumor immunological activities. These compounds were tested for programmed death-ligand 1 (PD-L1) protein expression in human colorectal adenocarcinoma RKO cells. Among them, compound 11c was found to efficiently suppress constitutive PD-L1 expression in RKO cells with low toxicity and further exerted its antitumor effect in MC38 tumor-bearing C57BL/6 mice by reducing PD-L1 expression and enhancing tumor-infiltrating T-cell immunity. This research work may provide insight for the discovery of new marine natural product-derived tumor immunological drug leads.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.2c01702