Hemisynthesis and antiproliferative properties of mono-[O-(14-benzoylaconine-8-yl)]esters and bis-[O-(14-benzoylaconine-8-yl)]esters

作者：Chodoeva Ainura; Bosc Jean Jacques; Guillon Jean; Costet Pierre; Decendit Alain; Merillon Jean Michel; Leger Jean Michel; Jarry Christian; Robert Jacques^*

来源：European Journal of Medicinal Chemistry, 2012, 54: 343-351.

DOI：10.1016/j.ejmech.2012.05.015

• Aconitum alkaloids
• Antiproliferative activity
• Tumour models

A series of mono- and bifunctional acyl compounds, build from the 8-O-azeloyl-14-benzoylaconine scaffold and differing by the length of the alkyl linker chain, were synthesised and evaluated against a panel of human tumour cell lines, A-549 (lung cancer), MCF-7 (breast cancer) and HCT-15 (colon cancer). None of the mono-[O-(14-benzoylaconine-8-yl)]esters displayed in vitro activity against tumour cells (IC50 > 60 mu M). However, three bis-[O-(14-benzoylaconine-8-yl)]esters presented a noticeable in vitro cytotoxic activity, those bearing 7, 8 and 9 carbon atoms between the two aconitine moieties, with IC(50)s ranging between 4 and 28 mu M. The most active, bis[O-(14-benzoylaconine-8-yl)]suberate, was then evaluated in vivo in immunodeficient mice bearing human tumour xenografts originating from MCF-7 and HCT-15 cells. For MCF-7 cells, administration of five doses every 4 days, and weekly administration of 4 doses resulted in T/C percent values of 36% (p = 0.001) and 56% (p = 0.02) on day 45, respectively. For HCT-15 cells, administration of five doses every 3 days resulted in 49% tumour regression on the 25th day (p = 0.00001).

• 出版日期2012-8