New procedure for the synthesis of indolo[3,2-b]quinoline derivatives with DNA G-quadruplex stabilization capacity

G-quadruplexes (G4s) DNA structures in oncogenic promoter regions (of c-MYC and KRAS oncogenes, for example) and telomeres are potential targets for cancer therapy. Small molecules could serve as DNA G4 stabilizers and down-regulate the targeted gene expression leading to induction of programmed cell death by apoptosis.

Indolo[3,2-b]quinoline derivatives were previously reported as stabilizers of G4 DNA structures. Structures with a carboxylate group at position 7 and three alkylamine side chains (IQ3A) were discovered to be promising selective anticancer leads, as these compounds are able to preferentially target the G4 motifs in the KRAS promoter and inhibit the transcription and translation of this oncogene, inducing apoptosis of KRAS-dependent colon cancer cells. The synthetic methods for these derivatives have been described before. Herein we describe an alternative experimental procedure for the synthesis of IQ3As. The major improvement lies in the synthesis of one of the intermediates, in which the use of a microwave oven to irradiate the reaction mixture at 300 W, 140ºC, was required previously. It is shown that, instead, a pressure tube can be used to carry the reaction, at the same temperature, simplifying the overall procedure and eliminating the requirement of a microwave apparatus.