G-quadruplex (G4) are secondary DNA structures that can occur in guanine rich segments. They are formed by stacking of four strands of non-canonical DNA and are held together by Hoogsteen-like hydrogen bonds and cationic interactions. G4-DNA is evolutionary conserved and enriched at e. g. telomeres, promotor regions and ribosomal DNA. Research in the field has uncovered the importance of G4-DNA in many biological functions for example in genetic regulation, control of the latency of viruses as well as the protection of the telomere ends from degrading. G4-stabilizing molecules also have great potential as possible chemotherapeutics as the stabilization of G4-structures in tumor cells could induce apoptosis. To further understand the mechanisms of these structures we are developing new G4-stabilizing ligands with specific abilities, such as fluorescence, to be used as chemical tools. To obtain these chemical tools we are designing new synthetic routes towards completely new fluorescent molecules designed to be able to stabilize G4-structures, which initial tests have already confirmed. Our main structure is inspired by a known G4-ligand, Phen-DC3, which consists of a phenantroline backbone substituted with cationic quinoline side-chains. Our strategy is to replace the central phenantroline part in Phen-DC3 with a BODIPY-motif to obtain fluorescence. The BODIPY moiety is a very well studied structural feature that can give access to strongly fluorescent molecules in the visible region with high quantum yields. They are also known to be chemically stable and have excellent biological stability. These extended BODIPY motifs will be synthesized from commercially available indoles, through an initial acid catalyzed condensation reaction followed by attachment of the side-chains through an amide bond coupling. Finally, oxidation and coordination of boron will give access to the final ligands. These ligands will be tested in our well-established biological assay to investigate their stabilizing effect on different G4-structures.

Development of new fluorescent G-quadruplex ligands

251st National Meeting (2016)

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