Inhibition of sterol biosynthesis and accumulation of 2,3-oxidosqualene in bramble cell suspension cultures treated with 2-aza-2,3-dihydro-squalene and 2-aza-2,3-dihydrosqualene-N-oxide

Add time:08/07/2019    Source:sciencedirect.com

2-Aza-2,3-dihydrosqualene (1), 2-aza-2,3-dihydro-squalene-N-oxide (2) and derivatives are new compounds designed to inhibit the 2,3-oxidosqualene-cycloartenol (lanosterol) cyclase. The effects of these compounds were studied on sterol biosynthesis in suspension cultures of bramble cells. Both 1 and 2 inhibited the growth of cells with an IC50 of 11 μM for 1 and 21 μM for 2. When the cells grown in the presence of the two drugs were analysed, accumulation of squalene and 2,3-oxidosqualene was observed but no significant decrease of the total sterol content per g of dry weight of cells was noticed. Pulse experiments with [2-14C]acetate on 15-day-old cells treated with 1 resulted in a strong decrease of the incorporation of radioactivity into the 4-desmethyl sterol fraction. An IC50 of 7.5 μM was determined when the cells were preincubated for a period of two hr with 1 or 2. This inhibition was correlated with an accumulation of [14C]-2,3-oxidosqualene and of [14C]-squalene. No [14C]-2,3:22(23)-dioxidosqualene was detectable in these conditions. Derivatives of 1 and 2 or similar compounds were also assayed; N-lauryl-dimethylamino-N-oxide (LDAO) was shown to be particularly effective and produced accumulation of enormous amounts of [14C]-2,3-oxidosqualene. Compound 1 (but not 2 or LDAO) leads also to the accumulation of a red pigment identified as lycopene. Our work confirms studies with enzymatic systems in demonstrating that 1, 2 and LDAO inhibit the 2,3-oxidosqualene-cycloartenol cyclase and provides evidence that the squalene synthetase and the Δ8 → Δ7-sterol isomerase are also inhibited.

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