Novel antileukemic sterol glycosides from Ajuga salicifolia

Abstract

Two novel and three new sterol glycosides were isolated from the MeOH ext. of the aerial parts of Ajuga salicifolia (L.) Schreber. The structures of the compds. were elucidated as (3R,16S,17S,20R,22S,23S,24S,25S)-16,23:16,27:22,25-triepoxy-3-(beta -D-glucopyranosyloxy)coprostigmast-7-en-17-ol (I), (3R,16S,17S,20R,22S,23S,24S,25S)-16,23:16,27:22,25-triepoxy-3-coprostigmast-7-en-17-ol (II), (3R,16S,17R,20S,22R,24S,25S)-22,25-epoxy-3,27-bis(beta -D-glucopyranosyloxy)coprostigmast-7-en-16-ol (III), (3R,16S,17R,20S,22R,24S,25S)-22,25-epoxy-3--27-(beta -D-glucopyranosyloxy)coprostigmast-7-en-16-ol (IV), and (3R,16R,17S,20R,22S,23S,24S,25S)-22,25-epoxy-3-(beta -D-glucopyranosyloxy)coprostigmast-7-ene-16,17,23,27-tetrol 27-acetate (V) by means of 1D and 2D NMR spectroscopy and HR-MALDI mass spectrometry. The novel compds. which consist of three addnl. ring systems at the coprostigmastane skeleton, were named ajugasalicioside A (I) and B (II), and the new compds. C (III), D (IV) and E (V). In cytotoxicity assays (HeLa cells, Jurkat T cells, and peripheral mononuclear blood cells), ajugasaliciosides A-D specifically inhibited the viability and growth of Jurkat T-leukemia cells at concns. below 10 micro M. Ajugasalicioside A (I; IC50 = 6 micro m) and C (III: IC50 = 3 micro M) were the most active compds. I induced cell-cell contact, inhibited Jurkat T cell proliferation. and up-regulated mRNA levels of the cell-cycle regulator cyclin D1, which might be an indication for cell differentiation. Furthermore, I down-regulated the mRNA levels of the NF-kB subunit p65 in a concn.-dependent manner. These effects were not found for ajugasalicioside B (II), which has an addnl. glucose unit, and the onset of cytotoxicity of II (IC50 = 10 micro M) was delayed by 24 h.