Studies related to antitumor antibiotics. Part XIII. Reactivity of 2- and 3-indolylcarbinyl compounds as models for mitosane action

Abstract

The base-catalyzed methanolyses of 1-methylgramine methiodide 2, 1-methylisogramine methiodide 3, and l-methylindol-2-ylmethyl N-tert-butylcarbamate 4 were studied in the temperature range 50–90 °C in order to gain information about the relative reactivity of 2- and 3-indolylcarbinyl Systems, analogous to the proposed reactive sites of the mitosane antitumor antibiotics when enzymatically reduced. The leaving groups were also analogous to those found in the mitosanes. The methanolysis of 2 proceeds with strict first-order kinetics in accord with indole nitrogen lone pair assistance of the displacement. The comparable reactions of 3 and 4 proceed with second-order kinetics in accord with a direct SN2 process and the carbamate moiety is the better leaving group by a factor of 10. Gramine methiodide 5 undergoes a very rapid elimination of the elements of [Formula: see text] followed by addition of a nucleophile such as methanol at a rate which is too rapid to follow kinetically even at −78 °C. In accord with the model for the mode of action of the mitosanes, 2.2 mM5 alkylates and cross-links DNA to the extent of 71% at pH 7 and 37 °C. The extent of cross-linking is proportional to the (G + C) content of DNA's as was found for the mitosanes and occurs at a position other than N-7 on guanine. The results suggest that in the reaction of the mitosane antibiotics with DNA the inherent greater reactivity of the 10-carbamate moiety towards nucleophilic displacement is more than offset by the rate enhancement of the 1 position due to relief of aziridine ring strain.