Efficient Synthesis of Oligo-N-methylpyrrolecarboxamides and Relateed Compounds

Abstract

1-Methyl-4-nitro-2-rrichloroacetylpyrrol I , a new precursor for the syntheses of oligo-N-methylpyrrolecarboxamide antibiotics and their analogues, was prepared with facility.The versatility of 2 was demonstrated by the syntheses of oligopeptides 16-19.1-Methyl-4-nitro-2-triehlor~a~etylimidazole 5 was also prepared for a precursor of oligo-N-methylimidae01ecarboxamidds. 1 2 Netropsin 1 and distamycin 2 that contain N-methylpyrrolecarboxamides belong to a well k n o w class of oligopeptide antitumor antibiotics called "Lexitropsins".Preferential binding of these peprides in the minor groove of double-helical DNA at specific AT-rich regions in a non-intercalarive fashion has been the subject of X-ray crystal log rap hi^^'^ and physico-chemical3s5 investigations.In the pasc decade.Dervan and co-workers have demonstrated that higher numbers of Nm e t h y l p y r r o l e ~a r b o ~~i n i d e s in synthetic oligopeptides fit the natural twist of the B-DNA helix with increased sequence specif~city.~'~Recently, Dickerson and co-workers examined the structural requirements for the molecular recognition of the peptides and predicted that the replacement of one or more pyrrole rings by imidazole or other appropriate heterocycle, should result in a rational alteration of base recognition from AT to GC.' Lown and eo-workers have synthesized these novel oligopeptide analogues and confirmed the prediction.'