Further Probing the Properties of a Unique Sponge-derived Alkaloid Through the Isolation of a New (-)-(5E)-(8R)-(14Z)-Mycothiazole Analogue
Recommended Citation
Gerke JA, Odron SF, Kim J, Dutta N, Clarke JG, Media J, Coppage DA, Oorloff M, Alcala A, Garcia G, Kang MEF, Gerke CL, Peterson JC, Morris JD, Higuchi-Sanabria R, Valeriote FA, Crews P, and Johnson TA. Further Probing the Properties of a Unique Sponge-derived Alkaloid Through the Isolation of a New (-)-(5E)-(8R)-(14Z)-Mycothiazole Analogue. J Nat Prod 2024; 87(10):2523-2529.
Document Type
Article
Publication Date
10-25-2024
Publication Title
Journal of natural products
Abstract
Scale-up isolation of (+)-(5Z)-(8S)-(14Z)-mycothiazole (1) from Vanuatu specimens of C. mycofijiensis to semisynthesize (+)-(5Z)-(8S)-8-O-acetyl-(14Z)-mycothiazole (2) revealed a new diastereomer, (-)-(5E)-(8R)-(14Z)-mycothiazole (4). The structure of 4 was determined using HRMS, NMR, and comparing optical rotation to (-)-(5Z)-(8R)-(14Z)-mycothiazole (3) and 2. The maximum tolerated dose of 2 in mice was 0.1 mg/kg. The IC(50) of 4 in PANC-1 and HepG2 cancer cell lines was 111.6 and 115.0 nM. Evaluation of 4 in C. elegans showed similar oxygen consumption compared to 1-2, and all compounds significantly increased the lifespan. The Z orientation at Δ(5,6) is crucial for picomolar cytotoxicity but not for mitochondrial inhibition.
Medical Subject Headings
Animals; Molecular Structure; Humans; Mice; Stereoisomerism; Alkaloids; Porifera; Thiazoles; Caenorhabditis elegans; Hep G2 Cells; Drug Screening Assays, Antitumor; Antineoplastic Agents
PubMed ID
39348562
Volume
87
Issue
10
First Page
2523
Last Page
2529
