Permethyl analog of the pyrrolic antibiotic distamycin A

Abstract

The synthesis of an analogue of distamycin A, a pyrrolic oligopeptide possessing antiviral and antibiotic activity, is described in which each of the 3 pyrrole rings is fully methylated. This structural modification results in pyrrole rings which are extraordinarily electron rich and required the development of a new synthetic approach to these polypyrrolic amides. The key reactions involved development of a general method for the synthesis of 3-aminopyrroles and for formation of an amide bond between a pyrrole-2-carboxylic acid and these 3-aminopyrroles. Since the acid is hindered, a poor electrophile, and acid sensitive, while the amine is unstable and a hindered, weak nucleophile, amide bond formation under the usual conditions was poor. A very efficient method was developed involving the isolation of 1-hydroxybenzotriazole active ester prepared in situ from another active ester. Neither the mono-, di- nor tripyrrolic permethyl analogues were effective antimalarials and none showed anticancer activity.