Activation of Sirtuin 2 Inhibitors Employing Photoswitchable Geometry and Aqueous Solubility

Abstract

Because isoenzymes of the experimentally and therapeutically extremely relevant sirtuin family show high similarity, addressing the unique selectivity pocket of sirtuin 2 is a promising strategy towards selective inhibitors. An unrelated approach towards selective inhibition of isoenzymes with varied tissue distribution is targeted drug delivery or spatiotemporal activation by photochemical activation. Azologization of two nicotinamide‐mimicking lead structures was undertaken to combine both approaches and yielded a set of 33 azobenzenes and azopyridines that have been evaluated for their photochemical behaviour and bioactivity. For some compounds, inhibitory activity reached the sub‐micromolar range in their thermodynamically favoured E form and could be decreased by photoisomerization to the metastable Z form. Besides, derivatization with long‐chain fatty acids yielded potent sirtuin 2 inhibitors, featuring another intriguing aspect of azo‐based photoswitches. In these compounds, switching to the Z isomer increased aqueous solubility and thereby enhanced biological activity by up to a factor of 21. The biological activity of two compounds was confirmed by hyperacetylation of sirtuin specific histone proteins in a cell‐based activity assay.

Molecular photoswitches in aqueous environments

“…Most of the compounds of the library had the required photophysical properties in water and long thermal half-lives of the metastable Z isomers (4300 h). 625 However, phenyl azopyridines carrying a hydroxy or amino group (such as 4.25a and 4.25b) exhibited shortened half-lives due to tautomerization (see Section 3.2.3). 626,627 The respective azopyridines were consequently modified by methylation of the aniline (example 4.25d) or introduction of methyl groups in the ortho positions (example 4.25c) as attempt to increase the thermal halflives.…”

“…636 A similar phenomenon regarding the solubility was also observed for some azopyridines discussed in Section 4.1.3 (vide supra). 625 The planarity in photoswitches can also be affected by attaching suitable substituents to the photoswitchable core. In this way, a library of hemithioindigo inhibitors (Fig.…”

Diarylethen‐basierte lichtschaltbare Inhibitoren von Serinproteasen

“…Diese Strategie eignet sich gut für das Design von niedermolekularen Konstrukten. Viele lichtschaltbare, meist von Azobenzol abgeleitete Inhibitoren [5a–d] dieser Art wurden beschrieben, wobei auch andere Arten von Photoschaltern verwendet wurden [5e–h] . Der zweite erfolgreiche Ansatz besteht in der Entwicklung so genannter “zweiarmiger” Inhibitoren, bei denen die Photoschalter‐Einheit zwei Inhibitor‐Bausteine verbindet (Abbildung 1 B).…”

Resveratrol isoforms and conjugates: A review from biosynthesis in plants to elimination from the human body

“…[8] RESV is able to activate and regulate the group of NAD +dependent enzymes known as sirtuins (SIRT). According to Grathwol et al, [9] SIRT2 inhibition is thermodynamically favored by E-isomers insofar as the Z-isomers are metastable forms with decreased biological effects due to the photoisomerization by UV radiation (similar Abbreviations: CR, cis-resveratrol; HPLC, high-performance liquid chromatography; HPLC-DAD, high-performance liquid chromatography with diode array detector; LC-MS/MS, liquid chromatography-mass spectrometry; RESV, resveratrol; TR, trans-resveratrol.…”

“…RESV is able to activate and regulate the group of NAD + ‐dependent enzymes known as sirtuins (SIRT). According to Grathwol et al, [ 9 ] SIRT2 inhibition is thermodynamically favored by E ‐isomers insofar as the Z ‐isomers are metastable forms with decreased biological effects due to the photoisomerization by UV radiation (similar to what happens to the potency of TR that decreases when it turns into CR).…”