| Autor: |
Boyé, O., Brossi, A., Yeh, H. J. C., Hamel, E., Wegrzynski, B., Toome, V. |
| Zdroj: |
Canadian Journal of Chemistry; May 1992, Vol. 70 Issue: 5 p1237-1249, 13p |
| Abstrakt: |
Trimethoxy-substituted dihydrodibenzocycloheptenes 4–7, required for a structure–activity study measuring the inhibition of tubulin polymerization in vitro, were synthesized by four different routes: (1) Synthesis of 4was achieved from 2,3-dimethoxybenzaldehyde via biphenyl aldehyde 17, chain lengthening to propionic acid 20, acid-catalyzed cyclization toward ketone 21, and removal of the carbonyl group. (2) Compound 5was obtained by eliminating the sterically most hindered methoxy group in 25or 26by metal reduction in alcohol. (3) Compound 6was prepared from biphenyl aldehyde 34obtained by Grignard reaction on oxazoline 32. (4) Compound 7was obtained by reductive deoxygenation of the tetrazolyl ether derivative of N-acetylcolchinol 41. The key role of the aromatic oxygen atoms in colchicine and allo congeners as points of interaction with the colchicine binding site on tubulin was demonstrated by the lack of inhibitory activity of compounds 4–7. Optically active 5-acetamide 8a,bisomers of N-acetylcolchinyl methyl ether 2were obtained after chemical resolution of amine 47. The absolute configuration of the optical isomers 47a,band 8a,bwas determined by 1H NMR and CD measurements. These compounds were found inactive as inhibitors of tubulin polymerization. |
| Databáze: |
Supplemental Index |
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