Inhibition of mitochondrial metabolism by (−)-jerantinine A: synthesis and biological studies in triple-negative breast cancer cells

A concise semi-synthesis of the Aspidosperma alkaloids, (−)-jerantinine A and (−)-melodinine P, and derivatives thereof, is reported. The novel compounds were shown to have potent activity against MDA-MB-231 triple-negative breast cancer cells. Furthermore, unbiased metabolomics and live cell report...

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Bibliographic Details
Published in:	RSC medicinal chemistry Vol. 14; no. 4; pp. 71 - 714
Main Authors:	Gialelis, Timothy L, Wang, Zifei, Homer, Joshua A, Yang, Wen-Hsuan, Chung, Taemoon, Hu, Qingting, Smedley, Christopher J, Pawar, Nitin J, Upadhyay, Nitinkumar S, Tuveson, David A, Lyons, Scott K, Lukey, Michael J, Moses, John E
Format:	Journal Article
Language:	English
Published:	England RSC 26-04-2023
Subjects:	Chemistry
Online Access:	Get full text
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Summary:	A concise semi-synthesis of the Aspidosperma alkaloids, (−)-jerantinine A and (−)-melodinine P, and derivatives thereof, is reported. The novel compounds were shown to have potent activity against MDA-MB-231 triple-negative breast cancer cells. Furthermore, unbiased metabolomics and live cell reporter assays reveal (−)-jerantinine A alters cellular redox metabolism and induces oxidative stress that coincides with cell cycle arrest. We report an improved 4-step semisynthesis of (−)-jerantinine A and (−)-melodinine P from (−)-tabersonine, qualify their potency against TNBC cells and confirm they induce oxidative stress. JA also acts as a potent inhibitor of nucleotide metabolism.
Bibliography:	https://doi.org/10.1039/d3md00049d Electronic supplementary information (ESI) available. See DOI ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authors contributed equally.
ISSN:	2632-8682 2632-8682
DOI:	10.1039/d3md00049d