Further Probing the Properties of a Unique Sponge-derived Alkaloid Through the Isolation of a New (-)-(5E)-(8R)-(14Z)-Mycothiazole Analogue

Joe A. Gerke; Sophia F. Odron; Juri Kim; Naibedya Dutta; Jacqueline G. Clarke; Joseph Media; David A. Coppage; Maria Oorloff; Athena Alcala; Gilberto Garcia; Marissa E. F. Kang; Cy L. Gerke; Jacob C. Peterson; Joseph D. Morris; Ryo Higuchi-Sanabria; Frederick A. Valeriote; Phillip Crews; Tyler Johnson

doi:10.1021/acs.jnatprod.4c00691

Further Probing the Properties of a Unique Sponge-derived Alkaloid Through the Isolation of a New (-)-(5E)-(8R)-(14Z)-Mycothiazole Analogue

Joe A. Gerke, Sophia F. Odron, Juri Kim, Naibedya Dutta, Jacqueline G. Clarke, Joseph Media, David A. Coppage, Maria Oorloff, Athena Alcala, Gilberto Garcia, Marissa E. F. Kang, Cy L. Gerke, Jacob C. Peterson, Joseph D. Morris, Ryo Higuchi-Sanabria, Frederick A. Valeriote, Phillip Crews, Tyler Johnson

Department of Natural Sciences and Mathematics

Research output: Contribution to journal › Article › peer-review

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 IC50 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 Δ5,6 is crucial for picomolar cytotoxicity but not for mitochondrial inhibition.

Original language	American English
Pages (from-to)	2523–2529
Journal	Journal of Natural Products
Volume	87
Issue number	10
DOIs	https://doi.org/10.1021/acs.jnatprod.4c00691
State	Published - Sep 30 2024

Keywords

Anatomy
Cells
Isolation
Mitochondria
Rodent Models

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Gerke, J. A., Odron, S. F., Kim, J., Dutta, N., Clarke, J. G., Media, J., Coppage, D. A., Oorloff, M., Alcala, A., Garcia, G., Kang, M. E. F., Gerke, C. L., Peterson, J. C., Morris, J. D., Higuchi-Sanabria, R., Valeriote, F. A., Crews, P., & Johnson, T. (2024). Further Probing the Properties of a Unique Sponge-derived Alkaloid Through the Isolation of a New (-)-(5E)-(8R)-(14Z)-Mycothiazole Analogue. Journal of Natural Products, 87(10), 2523–2529. https://doi.org/10.1021/acs.jnatprod.4c00691

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 & Johnson, T 2024, 'Further Probing the Properties of a Unique Sponge-derived Alkaloid Through the Isolation of a New (-)-(5E)-(8R)-(14Z)-Mycothiazole Analogue', Journal of Natural Products, vol. 87, no. 10, pp. 2523–2529. https://doi.org/10.1021/acs.jnatprod.4c00691

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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 IC50 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 Δ5,6 is crucial for picomolar cytotoxicity but not for mitochondrial inhibition.",

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AU - Kim, Juri

AU - Dutta, Naibedya

AU - Clarke, Jacqueline G.

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AU - Coppage, David A.

AU - Oorloff, Maria

AU - Alcala, Athena

AU - Garcia, Gilberto

AU - Kang, Marissa E. F.

AU - Gerke, Cy L.

AU - Peterson, Jacob C.

AU - Morris, Joseph D.

AU - Higuchi-Sanabria, Ryo

AU - Valeriote, Frederick A.

AU - Crews, Phillip

AU - Johnson, Tyler

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