Photoswitchable DNA-Intercalators for targeted regulation of transcription

• Applicants: Professor Dr. Heiko Ihmels; Professor Dr. Jochen Mattay; Professor Dr. Norbert Sewald
• Subject Area: Biological and Biomimetic Chemistry ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 255999580

Photochromic compounds display high potential for the external stimulation of chemical and biochemical regognition processes. Photoswitchable intercalators will be synthesized employing different molecular photoswitches (azobenzenes, diarylethenes, spiropyrans/-oxazins) and characterized with respect to structure and function regarding their interaction with DNA. The bicyclic depsipeptide triostin A and especially its correlate TANDEM are considered as prototype targets that will be modified by photoswitchable groups. The DNA- bisintercalators triostin A and TANDEM belong to the family of quinoxaline antibiotics. Both quinoxaline moieties are bound across an amide bond to a bicyclic octadepsipeptide containing D-serine, L-alanine, N-methyl-L-cystein, and N-methyl-L-valine, with a disulfide bond between the two Cys residues. TANDEM does not contain any N-methyl amino acids. Triostin A displays antibiotic activity against gram-positive bacteria that is caused by intercalation of the quinoxaline residues into the minor groove of DNA. This causes structural changes in DNA blocking DNA- and RNA-polymerase.Azo-bridged TANDEM derivatives were shown in own preliminary experiments to be interesting bistable switches that isomerize only very slowly in the dark from the cis- to the trans-configuration. Consequently, such TANDEM derivatives will be geometrically optimized to display, besides improved water solubility, better binding properties to DNA. According to a different strategy to obtain photoswitchable intercalators, the quinoxaline moieties in TANDEM derivatives will be replaced by photoswitchable spiropyrans and spirooxazins that are able to intercalate when present in the merocyanine form. In addition, DNA-binding heterocyclic polyamides will be conjugated with photoswitchable spiropyrans. These modifications will allow to influence the ability of binding to DNA by an external stimulus (light). Photochemical switching will allow to synchronize the biochemical processes replication and transcription in vitro or within a cell population and to trigger or control them.

• DFG Programme: Research Grants