Photochromic Indolyl Fulgimides as Chromo-pharmacophores Targeting Sirtuins

Abstract

Sirtuins are involved in epigenetic regulation, the pathogenesis of cancer, and several metabolic and neurodegenerative diseases. Despite being a promising drug target, only one small molecule passed class II clinical trials to date. Deriving a better mechanistic understanding is hence crucial to find new modulators. We previously reported on a series of dithienyl maleimides as photochromic tool compounds. However, their photochromic behavior was limited. To improve the interconversion and stability of both photoisomers, we replaced the dithienyl maleimide with a fulgimide as a photochromic core to result in biologically active compounds reversibly addressable with purple and orange light. We characterize the obtained compounds regarding their spectroscopic properties, their photostability, and binding characteristics toward sirtuins resulting in a fully remote-controllable Sirtuin modulator using visible light as the external stimulant.

Photoresponsive molecular tools for emerging applications of light in medicine

“…Photoswitches that could full all those requirements are Ptype diarylethenes and fulgimides, 27 which show absorbance in the 450-700 nm region, but the geometrical changes that can be obtained upon isomerization are limited, which renders the design of diarylethene-containing photocontrolled tools for biomedical application challenging. 13,28 Tetra-substituted azobenzenes could also be a possible candidate for this scenario, as they show absorbance in the green light region of the spectrum and half-lives in the days regime.…”

Fulgimides as Light‐Activated Tools in Biological Investigations

“…Simeth et al successfully improved dithienylmaleimide-modified sirtuin inhibitors by introducing N-alkylated indolyl fulgimides into the inhibitor scaffold. [16] While the dithienylmaleimidemodified compounds did not photoisomerize in aqueous solution, the indolyl fulgimide derivatives offered enhanced photophysical properties. In addition, different substitution patterns on the heteroaromatic moiety influenced both the synthesis yields and the photochemical properties.…”

“…Fulgimides are imide derivatives of fulgides that have mainly been used in optical data storage, molecular computing and photomechanical materials . The use of fulgimides for biological investigations has not been greatly explored despite the advantageous photophysical properties of this photoswitch , , . This minireview summarizes the chemical properties of fulgimides, as well as their application in biological investigations over the last 30 years.…”

“…[15] The use of fulgimides for biological investigations has not been greatly explored despite the advantageous photophysical properties of this photoswitch. [10,12,16] This minireview summarizes the chemical properties of fulgimides, as well as their application in biological investigations over the last 30 years.…”

Fulgazepam: A Fulgimide-Based Potentiator of GABAA Receptors

“…[20,43] Recently, few examples using fulgi(mi)des in a biological context are reported. [44][45][46] The transformation of a known ligand into a photoresponsive molecule is typically achieved by either extending the pharmacophore with a photoswitch or via incorporation of the photochromic scaffold as part of the drug's chemical structure. Once introduced, ideally one isomeric state is biologically active whereas the other loses its required interactions.…”