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To gain further insights into the importance of the unsaturated 1,4-ketoaldehyde moiety of ophiobolin A (OpA) for the potency and selectivity observed toward cancer stem cells, several derivatives were synthesized through controlled reduction and oxidations of the unsaturated aldehyde and ketone moieties. Structure elucidation of these new OpA derivatives was achieved through detailed NMR studies and comparison to OpA and known isolated congeners possessing variations in these regions. The relative stereochemistry of the newly generated stereocenters was determined by coupling constants in conjunction with conformational analyses (DFT) of the synthetic derivatives. The cytotoxicity of these derivatives was studied against breast cancer and glioblastoma cell lines possessing stem-cell like properties. In addition, the comparative activity toward HMLE and HMLE-TWIST mammary epithelial cells was studied, with the latter cell line representing an epithelial mesenchymal transition positive (EMT + ) cell line., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Ltd.)