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| Main Authors: | , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Marine drugs
2024
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/39728112/ |
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Table of Contents:
- Structure-Activity Relationship Study of Majusculamide D: Overcoming Metabolic Instability and Severe Toxicity with a Fluoro Analogue. Zhao, Xiuhe Xi, Xiaonan Zhang, Mingxiao Lv, Mengxue Zhang, Xiang Lu, Yaxin Wang, Liang Chen, Yue Animals Humans Mice Structure-Activity Relationship Antineoplastic Agents Cell Line, Tumor Cyanobacteria Cell Proliferation Xenograft Model Antitumor Assays Pancreatic Neoplasms Aquatic Organisms Oligopeptides Cell Movement Majusculamide D, isolated from the marine cyanobacterium , is an anticancer lipopentapeptide consisting of fatty acid, tripeptide, and pyrrolyl proline moieties. In this work, by utilizing a convergent synthetic approach, late-stage modification, and bioisostere strategy, 26 majusculamide D analogues were synthesized, and two ( and ) demonstrated IC values < 1 nM against PANC-1 cancer cells. The results summarized a preliminary structure-activity relationship mainly at the C23, C4, C34, and C10 sites. A series of in vitro assays, including wound healing, transwell, clone formation, EdU, and western blot, confirmed that majusculamide D inhibited the migration, invasion, and proliferation of pancreatic cancer cells. The optimized fluorinated analogue demonstrated a notable enhancement in stability during the mouse plasma assay (>50% left after 24 h), exhibited tumor-suppressive effects (51.5% at a dosage of 5 mg/kg), and successfully mitigated the severe toxicity (no mouse dead) observed in the group treated with majusculamide D (3 mice dead) in a xenografted mouse model.