Very-Long-Chain Fatty Acid Biosynthesis is Inhibited by Cafenstrole, N,N-Diethyl-3-mesitylsulfonyl-1H-1,2,4-triazole-1-carboxamide and Its Analogs

Abstract

The rice herbicide cafenstrole and its analogs inhibited the incorporation of [l-1 4 C]-oleate and [2-1 4 C]-malonate into very-long-chain fatty acids (VLCFAs), using Scenedesmus cells and leek microsomes from Allium porrum. Although the precise mode of interaction of cafenstrole at the molecular level is not completely clarified by the present study, it is con cluded that cafenstrole acts as a specific inhibitor of the microsomal elongase enzyme in volved in the biosynthesis of fatty acids with alkyl chains longer than C18. For a strong VLCFA biosynthesis inhibition an -S 0 2-linkage of the 1,2,4-triazole-l-carboxamides was required. Furthermore, /V,./V-dialkyl substitution of the carbamoyl nitrogen and electron-donating groups such as methyl at the benzene ring of 1,2,4-triazole-l-carboxamides produced a strong inhibition of VLCFA formation. A correlation was found between the phytotoxic effect against barnyardgrass (Echinochloa oryzicola) and impaired VLCFA formation.

5,5-Dimethyl-3-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-1-phenyl-3-(trifluoromethyl)-3,5,6,7-tetrahydro-1H-indole-2,4-dione, a Potent Inhibitor for Mammalian Elongase of Long-Chain Fatty Acids Family 6: Examination of Its Potential Utility as a Pharmacological Tool

“…With regard to inhibitors for de novo fatty acid synthesis, FAS inhibitors such as C75 have been reported and are shown to suppress lipid synthesis and feeding behavior in vivo (Loftus et al, 2000). However, cafenstrole, indanofan, and chloroacetamides have been reported as inhibitors of the long-chain fatty acid elongases, with micromolar potency for plant very long-chain fatty acid elongase (Takahashi et al, 2001(Takahashi et al, , 2002Götz and Böger, 2004). However, no inhibitor for mammalian long-chain fatty acid elongases has been identified.…”

Effect of fentrazamide on the growth, morphology and anatomy of Echinochloa crus-galli and Echinochloa oryzicola

“…Fentrazamide inhibited the biosynthesis of very long chain fatty acids as well as chloroacetamides, oxyacetamides, including mefenacet, cafenstrole and thenylchlor. [4][5][6][7][8] Fedtke and Hess et al reported that the morphological effect of mefenacet on green algal cells was similar to that observed for thiocarbamates and chloroacetamides. 9) The macroscopic symptoms of mefenacet on E. oryzicola were dark green coloration, stunting of leaves, and strong growth inhibition of plants.…”

Structure-Activity Correlation of Very Long-Chain Fatty Acid Biosynthesis Inhibitors

“…Its phytotoxic symptoms, namely impaired seedling emergence and stunting, have been reported as quite similar to those of chloroacetamide herbicides like alachlor or butachlor (Fukazawa et al 1995). A strong inhibition ofVLCFA biosynthesis by cafenstrole has been found in unicellular Scenedesmus cells (Couderchet et al 1998) and in cucumber cotyledons , and furthermore, in a cell-free preparation from leek seedlings (Takahashi et al 2001b). Incorporation of exogenously applied p4C]-oleate into a sporopollenin fraction of Scenedesmus acutus cells was drastically decreased by the herbicide.…”

“…The two herbicides structurally belong to the carbamoylated five-membered nitrogenheterocycles, bearing a dialkylcarbamoyl group as a common feature. Recently, a relationship between the structure of cafenstrole and its analogs and inhibition of VLCFA biosynthesis has been discussed using data obtained with Scenedesmus and leek microsomal assays (Takahashi et al 2001b). …”