Triggering the Directional Selectivity of a Ring‐Closure Reaction Leads to Pyridoazacarbazoles with Anticancer Properties

Abstract

We herein describe a facile and versatile synthetic route to the tetracyclic system of 6-substituted 5,6-dihydro-11H-pyrido[3,2-i]-1-azacarbazoles with promising anticancer properties. These derivatives are built up by an elegant one-step base-catalyzed synthetic procedure from commercially available building blocks. One additional step provides the corresponding skeleton hitherto unknown in the literature. The possibility to synthesize a large library of compounds with various substitution patterns utilizing this method underlines the importance of this synthetic procedure.

One‐Step Synthetic Access to Isosteric and Potent Anticancer Nitrogen Heterocycles with the Benzo[c]phenanthridine Scaffold

“…For heterocyclic classes 14 and 15 the charge density of the carbon atom next to the nitrile group is remarkably lower (1.04), which enhances its electrophilic character and is therefore responsible for the coincident formation of pyridophenanthrolines 14 and pyridoazacarbazoles 15 . In contrast, azacarbazole 10 was obtained almost exclusively when methylpyridine 9 was used . This can be verified by the charge density of the carbon atom next to the nitrile group (1.02), which is the lowest in the considered series.…”

“…(Scheme ) . We have already showed the versatility of this concept in our synthesis of the completely conjugated system of the 11 H‐ [3,2‐ i ]‐1‐azacarbazoles 10 …”

“…The 5‐ exo ‐ trig cyclization was strongly favored in this case. The corresponding 6‐ exo ‐ dig cyclization leading to the pyridophenanthroline skeleton was only observed in very small amounts . In a simplistic mechanistic picture, the influence of the ortho ‐nitrogen atom in enhancing the electrophilic character of the endocyclic carbon atom by polarization is much stronger for the pyrido[3,2‐ i ]‐1‐azacarbazoles 10 .…”

“…A new class of nitrogen heterocycle, 6‐substituted 5,6‐dihydro‐11 H ‐pyrido[3,2‐ i ]‐1‐azacarbazoles ( 10 ), were accessible from 3‐methyl‐2‐cyanopyridine ( 9 ) after optimization of the reaction conditions. Again, preliminary investigations concerning the cytotoxic activity of pyridoazacarbazoles 10 showed very promising results . A schematic of the natural‐product‐inspired development of heterocyclic structures based on the benzo[ c ]phenanthridine ring system is shown in Scheme .…”

“… a) Natural‐product‐inspired development of a one‐step synthesis of benzo[ c ]phenanthridine derivatives 3 and 4 . b) Access to two different nitrogen heterocycles, pyrido[3,4‐ c ][1,9]phenanthrolines 8 and pyrido[3,2‐ i ]‐1‐azacarbazoles 10 , by the established synthetic route …”