Biological effects of modified colchicines. 2. Evaluation of catecholic colchicines, colchifolines, colchicide, and novel N-acyl- and N-aroyldeacetylcolchicines.

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.