A series of natural and synthetic colchicine derivatives was examined for their potency in the lymphocytic leukemia P388 screen in mice, for their toxicity in mice, and for their binding to microtubule protein. The natural alkaloids cornigerine and colchifoline and several N,O-substituted analogues of colchifoline were found to be as potent and as toxic as colchicine in the P388 screen with good affinity for tubulin. The 1,2-(methylenedioxy)-substituted isomer of cornigerine was considerably less potent in vivo than could have been anticipated from the in vitro tubulin binding data. Several N-acyl and N-aroyl derivatives prepared from deacetylcolchicine showed high potency in the in vitro and in vivo screens. Colchicide was found to be highly potent in vivo, and N-carbethoxydeacetylcolchicine, a synthetic analogue of colchicine with a N-carbethoxy instead of an N-acetyl function, showed interesting biological properties.
This paper is dedicated to Prof. Raymond U . Lemieux on the occasion of his 60th birthday MARIA A. IORIO, MARISA MOLINARI, and ARNOLD BROSSI. Can. J. Chem. 59,283 (1981). Treatment of a mixture of deacetylcolchicine and deacetylisocolchicine, obtained by diazomethane methylation of deacetylcolchiceine, with trifluoroacetylglycolyl chloride in pyridine, afforded directly colchifoline and isocolchifoline. The two ether isomers could be separated by chromatography and the material eluted first proved to be identical with colchifoline isolated from commercial samples of colchicine.MARIA A. IORIO, MARISA MOLINARI et ARNOLD BROSSI. Can. J. Chem. 59,283 (1981). Un melange de deac0tylcolchicine et de dtacttylisocolchicine, obtenu par la methylation de la deac6tylcolchiceine par le diazomethane, reagit avec le chlorure de trifluoroacetylglycolyle dans la pyridine et conduit directement a la colchifoline et a I'isocolchifoline. On peut stparer les deux ethers isomeres par chromatographie. Le premier produit elut est identique a la colchifoline que I'on a isole a partir d'un echantillon commercial de colchicine.[Traduit par le journal]Colchifoline (5) the N-acetyl group of colchicine. We now would like to report a synthesis of colchifoline (5) from deacetylcolchiceine (g), readily available from colchicine (3) (3).A mixture of 1 and 2 was obtained from deacetylcolchiceine (8) HCl into colchifoleine (9), glycolyl a h~d r o x~a c e t~l a t i n g illustrated with the same arrangements of the oxyagent, was prepared glycolic acid by treat-gen functionalities in ring C as in colchiceine (10) ment with trifluoroacetic anhydride and treatment of the acid with refluxing thionyl chloride in the (5). form of a colorless liquid (see Experimental). The Structure Assignments reaction mixture obtained after usual work-up wasThe colchicine-like nature of ring C in colseparated by chromatography over silica gel. The chifoline (5) and the iso structure of isocolchifoline first eluted material was identical with colchifoline (6) were evident from a comparison of their IH nmr (5), a minor contaminant of commercial colchicine spectra (aromatic protons) with those of reference (1). The second compound, obtained in at least substances (3, 4) reported recently (6-8). Mass equal amounts, was assigned the structure of spectra of colchifoline (5) and isocolchifoline (6) isocolchifoline (6). The two ethers 5 and 6 are con-showed the same fragmentation pattern with the
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