Uncoupling of oxidative phosphorylation by glycyrrhetic acid, fusidic acid and some related triterpenoid acids

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Abstract
Some new derivatives of 18α- and 18β-glycyrrhetic acid and oleanolic acid were tested for their ability to inhibit phosphorylation coupled to succinate oxidation in rat liver mitochondria. Glycyrrhetic acid is a potent uncoupler of oxidative phosphorylation (approaching 2,4-dinitrophenol in potency); uncoupling activity is dependent upon each of the following functional groups: 3-hydroxy, 11-oxo and 30-carboxyl groups. Inversion of the configuration at C-18 (D/E ring junction) or replacement of the 11-oxo-12-ene system in ring C by the 9(11),12-diene system in glycyrrhetic acid abolished uncoupling activity. By contrast, the hemisuccinates (3-O-carboxypropionyl derivatives) of 18α-glycyrrhetic acid and of the 18β-9,12-diene acid were moderately potent uncoupling agents but less active than 18β-glycyrrhetic acid. The uncoupling activity of these hemisuccinates could not be attributed to the carboxypropionyl group alone. Structural analogues of various glycyrrhetic acid derivatives prepared from oleanolic acid (with the carboxyl group at C-28) were less active in uncoupling oxidative phosphorylation than the corresponding compounds in the glycyrrhetic acid series (with the carboxyl group at C-30). The uncoupling activity of some derivatives of two naturally occurring tetracyclic triterpenoid acids, polyporenic acid A and fusidic acid, was also investigated and found to largely depend upon their chemical structure. The possible application of these compounds as drugs in man is discussed.