Figure 3.

Structure–activity relationships of betulin derivatives for [³H]TC transport inhibition and [³H]preS1 binding inhibition. Chemical modifications at the lupane skeleton of betulin revealed clear structure–activity relationships for the potency (pot., IC₅₀ of [³H]preS1 binding inhibition) and virus selectivity index (sel. ind., ratio IC₅₀ [³H]TC transport inhibition / IC₅₀ [³H]preS1 binding inhibition). (a) 3,28-di-O-acetylation (shown in orange), additional C₂₉-hydroxylation (shown in purple), 3-O-modification with caffeoyl (shown in light-blue), 28-oxime generation (shown in red), and C₃₀ saturation (shown in green) of the betulin core structure improve the potency and/or selectivity index of the respective compounds. The respective inhibition pattern are illustrated by bar graphs for [³H]TC uptake (shown in dark-blue) and [³H]preS1 peptide binding (shown in red), respectively, in the presence or absence of a fix concentration (100 µM) of the respective betulin derivative. Graphs show means ± SD of quadruplicate determinations. *Significantly different with p < 0.01 (two-way ANOVA with Sidak's multiple comparison test); ns, not significant. (b) The diagram shows all IC₅₀ values for [³H]TC uptake inhibition and [³H]preS1 binding inhibition of the respective compounds. Effects (IC₅₀ shifts) of the structural modifications are illustrated by arrows, starting from the core structure betulin (compound 1). Compounds can be divided into three groups regarding their potency to inhibit [³H]preS1 binding: potent inhibitors (IC₅₀ ≤ 10 µM), less potent inhibitors (10 µM < IC₅₀ < 100 µM) and poor inhibitors (IC₅₀ ≥ 100 µM). Compounds with a selectivity index of > 10 are classified as selective inhibitors.