Structure-activity relationships and the cytotoxic effects of novel diterpenoid alkaloid derivatives against A549 human lung carcinoma cells.
The cytotoxicity of three alkaloids from the roots of Aconitum yesoense var. macroyesoense as well as 36 semi-synthetic C(20)-diterpenoid atisine-type alkaloid derivatives against A549 human lung carcinoma cells was examined. Ten acylated alkaloid derivatives, pseudokobusine 11-veratroate (9), 11-anisoate (12), 6,11-dianisoate (14), 11-p-nitrobenzoate (18), 11,15-di-p-nitrobenzoate (22), 11-cinnamate (25) and 11-m-trifluoromethylbenzoate (27), and kobusine 11-p-trifluoromethylbenzoate (35), 11-m-trifluoromethylbenzoate (36) and 11,15-di-p-nitrobenzoate (39), exhibited cytotoxic activity, and 11,15-dianisoylpseudokobusine (16) was found to be the most potent cytotoxic agent. Their IC(50) values against A549 cells ranged from 1.72 to 5.44 μM. In the occurrence of cytotoxic effects of atisine-type alkaloids, replacement by an acyl group at both C-11 and C-15 resulted in the enhancement of activity of the parent alkaloids compared to that from having hydroxy groups at this position, and the presence of a hydroxy group at the C-6 position was required for the cytotoxic effects. These acylated alkaloid derivatives inhibit cell growth through G1 arrest.
Wada
Koji
K
School of Pharmacy, Hokkaido Pharmaceutical University, 7-1 Katsuraoka-cho, Otaru, Hokkaido 047-0264, Japan. kowada@hokuyakudai.ac.jp
Hazawa
Masaharu
M
Takahashi
Kenji
K
Mori
Takao
T
Kawahara
Norio
N
Kashiwakura
Ikuo
I
D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004224:Diterpenes / Q000737:chemistry* / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D015394:Molecular Structure; D010616:Phenanthrenes / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000470:Alkaloids; D001952:Bridged-Ring Compounds; D004224:Diterpenes; D010616:Phenanthrenes; C111428:kobusine; C111430:pseudokobusine