Molecular hybridization used to design and synthesize neo-tanshinlactone derivatives as PD-1/PD-L1 inhibitors.

Abstract

Four series of molecular hybrids (37 final products) of neo-tanshinlactone, a natural product extracted from Salvia miltiorrhiza Bunge, and known PD-1/PD-L1 interaction inhibitors were prepared as possible chemotherapeutic agents against triple negative breast cancer. Screening using a homogenous time-resolved fluorescence method resulted in three lead compounds (MZ52 IC50 74 ± 4 nM; MZ58 IC50 134 ± 17 nM; MZ61 IC50 225 ± 19 nM). With less T cell cytotoxicity and effects in activating CD8+ T cells in a T cell proliferation assay and a functionality experiment, MZ58 was selected as the best candidate for animal experiments. MZ58 exhibited antitumor effects in a subcutaneous transplantation tumor model as well as effects in reducing T cell exhaustion. In conclusion, after in vivo and in vitro experiments, we successfully acquired an effective candidate (MZ58) showing antitumor effects with low cytotoxicity toward T cells as well as the ability to activate CD8+ T cells and reduce T cell exhaustion.

• Authors: Menghan Zhang, Jianmin Liu, Yue Wang, Ping Wang, Susan Morris-Natschke, Kuo-Hsiung Lee
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 54 Pg. 116579 (01 15 2022) ISSN: 1464-3391 [Electronic] England
• PMID: 34954618 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Ltd.

Chemical References

• Antineoplastic Agents
• B7-H1 Antigen
• CD274 protein, human
• Furans
• Immune Checkpoint Inhibitors
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Pyrones
• neotanshinlactone

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• B7-H1 Antigen (antagonists & inhibitors, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Design
• Drug Screening Assays, Antitumor
• Furans (chemical synthesis, chemistry, pharmacology)
• Humans
• Immune Checkpoint Inhibitors (chemical synthesis, chemistry, pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Molecular Structure
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, metabolism)
• Pyrones (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship