Chromo-pharmacophores: photochromic diarylmaleimide inhibitors for sirtuins

Abstract

Controlling the activity of sirtuins is of high biomedical relevance as the enzymes are involved in cancer, neurodegeneration and other diseases.

Emerging Targets in Photopharmacology

“…[13] Although PDT is limited to evoking cellular damage,i th as found many applications in clinical therapies and it has inspired the development of medical light-delivery systems.Photopharmacology,w hich uses light to control distinct drugtarget interactions,might provide the possibility for moreselective treatments by taking advantage of the instrumentation and technology developed for PDT. [19] Currently,p hotopharmacology is at the stage of defining and evaluating the molecular targets,supported by the results of in vitro studies on receptor binding,enzyme inhibition, and general cellular toxicity.Important breakthroughs have been made in the fields of light-controlled cancer chemotherapy, [20][21][22][23][24] neurology, [25][26][27] diabetes, [28] and antimicrobial agents, [29] among others.F uture milestones on the way to clinically applied photopharmacology will, in our opinion, include in vivo testing and extensive toxicity studies.A lso of great importance will be the evaluation of photopharmacology through molecular imaging to study the distribution of the photoactivated drugs and confirm their localized action. Optogenetics is av aluable photophysiological tool that relies on using light to modulate the activity of genetically engineered ion channels,w hich are usually derived from photoresponsive rhodopsins (Figure 1c).…”

Photochromic Materials in Biochemistry

“…A number of researchers have successfully illustrated the concept of using an existing drug scaffold and then modifying it with a photoswitch to alter the drug's ability to interact with its target [35][36][37][38][39][40][41][42][43][44]. This concept generally involves using the changes that occur to the structure and overall geometry of the photoswitch or linkage distance in the case of two binding sites to regulate activity.…”

Functionalization of photochromic dithienylmaleimides

“…[34][35][36] The synthesis of diarylmaleimides by intramolecular Perkin condensation of two independently prepared precursors gives selective access to non-symmetric diarylmaleimides. 10,37,38 Compared to diarylperfluorocyclopentenes and diarylcyclopentenes, diarylmaleimides are more hydrophilic and better water soluble, which is valuable for applications in biology and pharmacy. The absorption maxima of diarylmaleimides are shifted to higher wavelengths and thus the photoisomerization can be induced by light with lower energy reducing potential cell damage.…”

“…28 Moreover, the biocompatibility of diarylmaleimides is known from bisindolylmaleimides, for instance arcyriarubins and arcyriaflavins with antibiotic activities, several other potent protein kinase and sirtuin inhibitors. 10,[39][40][41][42][43] However, a better synthetic access to functionalized photochromic dithienylmaleimides is desirable in order to extend their applications. Herein we discuss the synthesis of functionalized dithienylmaleimides substituted on each thiophene moiety and the maleimide nitrogen atom.…”

“…To purify the chloroform for Friedel-Crafts acylations, it was washed with sulfuric acid (1 M), dried over calcium chloride, filtered through silica, subsequently refluxed with phosphorus pentoxide (5 -10 g/L) and distilled under nitrogen atmosphere. Compounds 1 10 , 2 10 , 544 , 1549 , 16 50 , 20 51 , 2210 , 25 10 , 28 10 , 2910 and 3210 were prepared according to previously reported procedures. Flash column chromatography was performed on a Biotage Isolera One automated flash purification system with UV/Vis detector using Sigma Aldrich MN silica gel 60 M (40-63 µm, 230-400 mesh) for normal phase or pre-packed Biotage SNAP cartridges (KP-C18-HS) for reversed phase chromatography.…”