Hemisynthesis and antiproliferative properties of mono-[O-(14-benzoylaconine-8-yl)]esters and bis-[O-(14-benzoylaconine-8-yl)]esters.
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 (IC(50) > 60 μM). 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 μM. 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).
Université Bordeaux Segalen, Institut Bergonié, 229 cours de l'Argonne, 33076 Bordeaux, France.
Ainura
A
Chodoeva
Jean-Jacques
JJ
Bosc
Jean
J
Guillon
Pierre
P
Costet
Alain
A
Decendit
Jean-Michel
JM
Mérillon
Jean-Michel
JM
Léger
Christian
C
Jarry
Jacques
J
Robert
D000157:Aconitine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004952:Esters; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D023041:Xenograft Model Antitumor Assays
D004952:Esters; C047307:benzoylaconine; D000157:Aconitine