Inhibition of Very-Long-Chain Fatty Acid Formation by Indanofan, 2-[2-(3-Chlorophenyl)oxiran-2-ylmethyl]-2-ethylindan-1,3-dione, and Its Relatives

Abstract

Indanofan and its analogs inhibited the elongation of stearoyl- or arachidoyl-CoA by [2-14C]-malonyl-CoA in leek microsomes from Allium porrum. Although the precise mode of interaction of indanofan at the molecular level is not completely clarified by the present study, it is concluded that indanofan and analogs act as inhibitor of the elongase enzyme involved in de novo biosynthesis of fatty acids with an alkyl chain longer than C18, called very-long-chain fatty acids (VLCFAs). For a strong inhibition of VLCFA formation chloro substituents at the benzene ring and the oxirane group were necessary. Furthermore, the greenhouse test showed strong activity for indanofan and its analogs, and the scores coincided with cell-free elongation inhibition. The cell-free assay, however, failed to indicate any activity for an analog having a methylene instead of the oxirane group, while both Digitaria ciliaris and Echinochloa oryzicola were killed with 1 kg a.i./ha. This finding cannot be discussed because the applied use rate of 1 kg a.i./ha is too high to allow for a score differentiation. For high concentrations of this compound additional unknown inhibitory effects may be involved besides fatty acid elongation.

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.…”

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

“…Iso values of 10-7 to 10-6 M. However, inhibitory activity by the old type of thiolcarbamates, such as EPTC or prosulfocarb, was found rather weak, indicating an Iso value higher than 10-5 M (see Table 1 and Fig. 1: Couderchet et al 1998;Matthes et al 1998;Takahashi et al 2001aTakahashi et al ,b, 2002.…”

“…The herbicides affecting acetolactate synthase, protoporphyrinogen oxidase, or photosynthetic electron transport do not inhibit oleic acid incorporation into VLCFAs present in a sporopollenin fraction of Scenedesmus acutus cells. 1\vo correlations, phytotoxicity indicated by growth inhibition or chlorophyll decrease vs. inhibition of oleate incor- poration into sporopollenin of Scenedesmus cells, can be significantly calculated (data for calculation, see Table 2: Couderchet et al 1998;Takahashi et al 2002).…”

“…These compounds inhibit incorporation of [2-14C]-malonyl-CoA into arachidoyl-CoA (Table 8; Takahashi et al 2002). Both indanofan 2 and tridiphane 7 exhibit a ca.…”

Target sites for herbicides: entering the 21st century

“…Herbicides inhibiting ACCase, aryloxyphenoxys and cyclohexanediones, have been successful in controlling monocotyledonous weeds for 20 years. Herbicides including completely different structures, such as cafenstrole, indanofan, chloroacetamides and oxyacetamides, have been recently confirmed as cytosolic elongase inhibitors in very‐long‐chain fatty‐acid biosynthesis 23–30…”