Macrophilones from the Marine Hydroid Macrorhynchia philippina Can Inhibit ERK Cascade Signaling
| Autor: | Kirk R. Gustafson, John S. Schneekloth, Daniel A. Ritt, Deborah K. Morrison, Heidi R. Bokesch, William C. Reinhold, Katherine Zlotkowski, Pengcheng Yan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway MAP Kinase Signaling System Metabolite Pharmaceutical Science Peptide Antineoplastic Agents 01 natural sciences Article Analytical Chemistry 03 medical and health sciences chemistry.chemical_compound Cell Line Tumor Drug Discovery Animals Humans Cytotoxicity Hydroid (botany) Pyrroloiminoquinones Pharmacology chemistry.chemical_classification Molecular Structure 010405 organic chemistry Chemistry Kinase Organic Chemistry Sumoylation 0104 chemical sciences 030104 developmental biology Enzyme Hydrozoa Complementary and alternative medicine Biochemistry Cell culture Molecular Medicine Drug Screening Assays Antitumor |
| Popis: | Six new macrophilone-type pyrroloiminoquines were isolated and identified from an extract of the marine hydroid Macrorhynchia philippina. The proton-deficient and heteroatom-rich structures of macrophilones B-G (2-7) were elucidated by spectroscopic analysis and comparison of their data with those of the previously reported metabolite macrophilone A (1). Compounds 1-7 are the first pyrroloiminoquines to be reported from a hydroid. The macrophilones were shown to inhibit the enzymatic conjugation of SUMO to peptide substrates, and macrophilones A (1) and C (3) exhibit potent and selective cytotoxic properties in the NCI-60 anticancer screen. Bioinformatic analysis revealed a close association of the cytotoxicity profiles of 1 and 3 with two known B-Raf kinase inhibitory drugs. While compounds 1 and 3 showed no kinase inhibitory activity, they resulted in a dramatic decrease in cellular protein levels of selected components of the ERK signal cascade. As such, the chemical scaffold of the macrophilones could provide small-molecule therapeutic leads that target the ERK signal transduction pathway. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|