Effect of antineoplastic and cytotoxic Mannich Bases derived from conjugated styryl ketones on mitochondrial respiration in rat liver cells.
Five cytotoxic Mannich bases (5-dimethylamino-1-substituted phenyl-1-penten-3-ones), three having antineoplastic activity, were evaluated for respiratory-inhibiting properties in rat liver mitochondria in the presence of four substrates: succinate, glutamate, 3-hydroxybutyrate, and palmitylcarnitine. Four compounds (Ib--Ie) showed significant inhibiting properties which, on occasion, were reversed partially by coenzyme Q10. Evaluation of the spectra of the mitochondrial cytochromes indicated that Ib--Ie blocked the electron transport chain prior to the sequence of cytochromes. Since inhibition occurred when different substrates were used, a common site of action for Ib--Ie is likely; competition of Ib--Ie with coenzyme Q10 probably occurs. Compounds Ia--Ie inhibited RNA polymerase from Swiss mouse kidney cells but were virtually bereft of activity versus RNA polymerase from L-1210 leukemia cells. Polarography of the Mannich bases and the related styryl ketones showed that antineoplastic activity was associated with higher half-wave potentials.
D000588:Amines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D007659:Ketones / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology; D007939:Leukemia L1210 / Q000201:enzymology; D008297:Male; D008352:Mannich Bases / Q000494:pharmacology*; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D011048:Polarography; D051381:Rats
D000588:Amines; D000970:Antineoplastic Agents; D007659:Ketones; D008352:Mannich Bases; D012321:DNA-Directed RNA Polymerases