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Biomimetic Synthesis of Rhytidenone A and Mode of Action of Cytotoxic Rhytidenone F.
- Source :
-
Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2020 Mar 02; Vol. 59 (10), pp. 4115-4120. Date of Electronic Publication: 2020 Jan 27. - Publication Year :
- 2020
-
Abstract
- The rhytidenone family comprises spirobisnaphthalene natural products isolated from the mangrove endophytic fungus Rhytidhysteron rufulum AS21B. The biomimetic synthesis of rhytidenone A was achieved by a Michael reaction/aldol/lactonization cascade in a single step from the proposed biosynthetic precursor rhytidenone F. Moreover, the mode of action of the highly cytotoxic rhytidenone F was investigated. The pulldown assay coupled with mass spectrometry analysis revealed the target protein PA28γ is covalently attached to rhytidenone F at the Cys92 residue. The interactions of rhytidenone F with PA28γ lead to the accumulation of p53, which is an essential tumor suppressor in humans. Consequently, the Fas-dependent signaling pathway is activated to initiate cellular apoptosis. These studies have identified the first small-molecule inhibitor targeting PA28γ, suggesting rhytidenone F may serve as a promising natural product lead for future anticancer drug development.<br /> (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Ascomycota chemistry
Biomimetic Materials chemical synthesis
Biomimetic Materials chemistry
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Naphthalenes chemical synthesis
Naphthalenes chemistry
Spiro Compounds chemical synthesis
Spiro Compounds chemistry
Antineoplastic Agents pharmacology
Biomimetic Materials pharmacology
Naphthalenes pharmacology
Spiro Compounds pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1521-3773
- Volume :
- 59
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Angewandte Chemie (International ed. in English)
- Publication Type :
- Academic Journal
- Accession number :
- 31868281
- Full Text :
- https://doi.org/10.1002/anie.201914257