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

J Med Chem. 2023 Apr 27;66(8):5427-5438. doi: 10.1021/acs.jmedchem.2c01702. Epub 2023 Apr 11.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma*
  • Animals
  • B7-H1 Antigen / metabolism
  • Cell Line, Tumor
  • Colorectal Neoplasms*
  • Humans
  • Immunologic Factors
  • Mice
  • Mice, Inbred C57BL

Substances

  • CD274 protein, human
  • B7-H1 Antigen
  • Immunologic Factors