Scalable Total Synthesis, IP3R Inhibitory Activity of Desmethylxestospongin B, and Effect on Mitochondrial Function and Cancer Cell Survival

Abstract

The scalable synthesis of the oxaquinolizidine marine natural product desmethylxestospongin B is based on the early application of Ireland-Claisen rearrangement, macrolactamization, and a late-stage installation of the oxaquinolizidine units by lactam reduction. The synthesis serves as the source of material to investigate calcium signaling and its effect on mitochondrial metabolism in various cell types, including cancer cells.

A Ca2+-Dependent Mechanism Boosting Glycolysis and OXPHOS by Activating Aralar-Malate-Aspartate Shuttle, upon Neuronal Stimulation

“…To study the role of ER efflux via IP3R, we used a membrane-permeable selective blocker of all types of IP3R, analog of Xestospongin B (XeB), a macrocyclic bis-1-oxaquinolizidine alkaloid originally extracted from the marine sponge Xestospongia exigua (Gafni et al, 1997;Jaimovich et al, 2005). This analog 3-dmXeB has been produced by chemical synthesis and exerts similar actions as XeB on IP3R (Podunavac et al, 2021).…”

Calcium (Ca2+) fluxes at Mitochondria-ER Contact Sites (MERCS) are a new target of senolysis in Therapy-Induced Senescence (TIS)

“…Given our observation of a decrease in Ca 2+ flux between the ER and mitochondria, we aimed to assess the essentiality of this Ca 2+ flux becomes for TIS cells. To this end, we used Desmethyl XeB (DmXeB), a competitive and selective inhibitor of IP3R, which has been reported to affect the viability of tumor cells [9].…”

“…Given our observation of a decrease in Ca 2+ flux between the ER and mitochondria, we aimed to assess the essentiality of this Ca 2+ flux becomes for TIS cells. To this end, we used Desmethyl XeB (DmXeB), a competitive and selective inhibitor of IP3R, which has been reported to affect the viability of tumor cells[9]. After confirming that DmXeB inhibits Ca 2+ release from the ER in both growing and TIS cells ( Figure 1K ), we proceeded to evaluate its effect on cell viability.…”

Copper-Catalyzed Reductive Ireland–Claisen Rearrangements of Propargylic Acrylates and Allylic Allenoates

“…The Ireland–Claisen rearrangement is a transformation that converts readily accessible ester carbon–oxygen bonds into carbon–carbon bonds with transfer of chirality, offering an alternative strategy to achieve stereoselective enolate α-alkylation. − The utility and importance of this transformation has been demonstrated by its application in many total syntheses in the past, as well as in more recent examples. − …”