Oxidative and reductive cyclization in stiff dithienylethenes.

The electrochemical behavior of stiff dithienylethenes, undergoing double bond isomerization in addition to ring-closure, has been investigated. Electrochromism was observed in almost all cases, with the major pathway being the oxidatively induced cyclization of the open isomers. The influence of the ring size (to lock the reactive antiparallel conformation) as well as substituents (to modulate the redox potential) on the electrocyclization was examined. In the series of derivatives with 6-membered rings, both the E- and the Z-isomer convert to the closed isomer, whereas for the 7-membered rings no cyclization from the E-isomer was observed. For both stiff and normal dithienylethenes bearing benzonitrile substituents an additional and rare reductive electrocyclization was observed. The mechanism underlying both observed electrocyclization pathways has been elucidated.

Photoswitchable Inhibitors to Optically Control Specific Kinase Activity.

Potent and selective small-molecule inhibitors are valuable tools to elucidate the functions of protein kinases within complex signaling networks. Incorporation of a photoswitchable moiety into the inhibitor scaffold offers the opportunity to steer inhibitor potency with temporal precision, while the challenge of selective inhibition can often be addressed by employing a chemical genetic approach, termed the analog-sensitive method. Here, we combine the perks of these two approaches and report photoswitchable azopyrazoles to target calcium-dependent protein kinase 1 (CDPK1) from Toxoplasma gondii, a kinase naturally susceptible to analog-sensitive kinase inhibitors due to its glycine gatekeeper residue. The most promising azopyrazoles display favorable photochemical properties, thermal stability, and a substantial difference in IC50 values between both photostationary states. Consequently, the CDPK1 kinase reaction can be controlled dynamically and reversibly by applying light of different wavelengths. Inhibition of CDPK1 by the azopyrazoles drastically relies on the nature of the gatekeeper residue as a successive increase in gatekeeper size causes a concurrent loss of inhibitory activity. Furthermore, two photoswitchable inhibitors exhibit activity against T. gondii and Cryptosporidium parvum infection in a cell culture model, making them a promising addition to the toolbox for dissecting the role of CDPK1 in the infectious cycle with high temporal control. Overall, this work merges the benefits of the analog-sensitive approach and photopharmacology without compromising inhibitory potency and thus holds great promise for application to other protein kinases in the future.

Solving the Azobenzene Entropy Puzzle: Direct Evidence for Multi-State Reactivity.

A solution to the azobenzene "entropy puzzle" [ J. Phys.: Condens. Matter, 2017, 29, 314002] is provided. Previous computational studies of the thermal Z → E (back-)isomerization of azobenzene could not describe the experimentally observed large negative activation entropies. Here it is shown that the experimental results are only compatible with a more complicated multistate rotation mechanism that involves a triplet excited state. Using nonadiabatic transition state theory, close to perfect agreement is achieved between all calculated and experimental Eyring parameters. We also provide new experiments that indicate the presence of a noticeable external heavy-atom effect, which is a direct result of spin-orbit coupling effects being important in the proposed mechanism. These results suggest a reexamination of the mechanisms of related thermal double bond isomerizations in other systems in cases when an excited state of triplet (or other) multiplicity becomes thermally accessible during a rotation process.