The calcium-chelating capability of tetrahydrofuranic moieties modulates the cytotoxicity of annonaceous acetogenins.

Annonaceous acetogenins (AGEs) are potential phytochemicals of herbal medicines and exhibit a wide variety of biological activities. Recent work has demonstrated that AGEs have a cytotoxic potency comparable to that of Taxol. AGEs belong to a unique class of polyketides with a C35 or C37 aliphatic chain terminated by an a,b-unsaturated g-lactone group on one end and interrupted mid-chain by one or two tetrahydrofuran (THF) rings with hydroxy groups (Scheme 1). Both structural groups have been recognized as the pharmacophores that block electron transport in mitochondrial complex I. Efforts to clarify the targeting and mechanism of AGEs include altering the space between two moieties, removing either one of two critical moieties (DLac acetogenins or muricatacin), mimicking the THF moieties by ether linkage, connecting a fluorescent group at the end of the aliphatic chain or with a hydroxy group, or replacing the g-lactone moiety by a fluorescent group. Hemisynthetic and proteomic techniques to clarify the mechanism underlying the action of AGEs have suggested some cytosolic and reticulum-

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