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 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.