Permethyl analogue of the pyrrolic antibiotic distamycin A.
The synthesis of an analogue of distamycin A, a pyrrolic oligopeptide possessing antiviral and antibiotic activity, is described in which each of the three 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, however, 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.
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis*; D002478:Cells, Cultured; D004214:Distamycins / Q000138:chemical synthesis* / Q000494:pharmacology; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D010962:Plasmodium berghei; D011758:Pyrroles / Q000138:chemical synthesis*
D000962:Antimalarials; D004214:Distamycins; D011758:Pyrroles; C029122:permethyldistamycin A