Photopharmacology is an attractive approach for achieving targeted drug action with the use of light. In photopharmacology, molecular photoswitches are introduced into the structure of biologically active small molecules to allow for the optical control of their potency. Going beyond trial and error, photopharmacology has progressively applied rational drug design methodologies to devise light-controlled bioactive ligands. In this review, we categorize photopharmacological efforts from the standpoint of medicinal chemistry strategies, focusing on diffusible photochromic ligands modified with photoswitches that operate through E-Z bond isomerization. In the vast majority of cases, photoswitchable ligands are designed as analogs of existing compounds, through a variety of approaches. By analyzing in detail a comprehensive list of instructive examples, we describe the state of the art and discuss future opportunities for rational design in photopharmacology.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/anie.202300681

Rational Design in Photopharmacology with Molecular Photoswitches.

Water, water, everywhere… It's time to stop and think

In total, 47,500,000 people worldwide are affected by dementia and this number is estimated to double by 2030 and triple within 2050 resulting in a huge burden on public health. Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia, accounting for 60–70% of all the cases. The cause of AD is still poorly understood but several brain abnormalities (e.g., loss of neuronal connections and neuronal death) have been identified in affected patients. In addition to the accumulation of β-amyloid plaques in the brain tissue, aberrant phosphorylation of tau proteins has proved to increase neuronal death. DYRK1A phosphorylates tau on 11 different Ser/Thr residues, resulting in the formation of aggregates called ‘neurofibrillary tangles’ which, together with amyloid plaques, could be responsible for dementia, neuronal degeneration and cell death. Small molecule inhibition of DYRK1A could thus represent an interesting approach toward the treatment of Alzheimer’s and ot...

DYRK1A inhibition as potential treatment for Alzheimer’s disease

Aromatic units tethered with an azo (-N=N-) functionality comprise a unique class of compounds, known as molecular photoswitches, exhibiting a reversible transformation between their E- and Z-isomers in response to photo-irradiation. Photoswitches have been explored extensively in the recent past to prepare dynamic self-assembled materials, optoelectronic devices, responsive biomaterials, and more. Most of such materials involve azobenzenes as the molecular photoswitch and to date, SciFinder lists more than 7000 articles and 1000 patents. Subsequently, a great deal of effort has been invested to improve the photo-isomerization efficiency and related mesoscopic properties of azobenzenes. Recently, azoheteroarenes and cyclic azobenzenes, such as arylazopyrazoles, arylazoisoxazoles, arylazopyridines, and diazocines, have emerged as second generation molecular photoswitches beyond conventional azobenzenes. These photoswitches offer distinct photoswitching behavior and responsive properties which make them highly promising candidates for multifaceted applications ranging from photoresponsive materials to photopharmacophores. In this mini-review, we introduce the structural refinement and photoresponsive properties of azoheteroarenes and diazocines and summarize the state-of-the-art on utilizing these photoswitches as responsive building blocks in supramolecular assembly, material science and photopharmacology, highlighting their versatile photochemical behavior, enhanced functionality, and latest applications.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/anie.202304437

Azoheteroarene and Diazocine Molecular Photoswitches: Self-Assembly, Responsive Materials and Photopharmacology.

Targeting the PDGF-B/PDGFR-β Interface with Destruxin A5 to Selectively Block PDGF-BB/PDGFR-ββ Signaling and Attenuate Liver Fibrosis

In this study we report on the hit optimization of substituted 3,5-diaryl-pyrazin-2(1H)-ones toward potent and effective platelet-derived growth factor receptor (PDGF-R) β-inhibitors. Originally, the 3,5-diaryl-pyrazin-2-one core was derived from the marine sponge alkaloid family of hamacanthins. In our first series compound 2 was discovered as a promising hit showing strong activity against PDGF-Rβ in the kinase assay (IC50 = 0.5 μM). Furthermore, 2 was shown to be selective for PDGF-Rβ in a panel of 24 therapeutically relevant protein kinases. Molecular modeling studies on a PDGF-Rβ homology model using prediction of water thermodynamics suggested an optimization strategy for the 3,5-diaryl-pyrazin-2-ones as DFG-in binders by using a phenolic OH function to replace a structural water molecule in the ATP binding site. Indeed, we identified compound 38 as a highly potent inhibitor with an IC50 value of 0.02 μM in a PDGF-Rβ enzymatic assay also showing activity against PDGF-R dependent cancer cells.

Optimization of potent DFG-in inhibitors of platelet derived growth factor receptorβ (PDGF-Rβ) guided by water thermodynamics.

In this study, we report on the modification of a 3,4-diaryl-isoxazole-based CK1 inhibitor with chiral pyrrolidine scaffolds to develop potent and selective CK1 inhibitors. The pharmacophore of the lead structure was extended towards the ribose pocket of the adenosine triphosphate (ATP) binding site driven by structure-based drug design. For an upscale compatible multigram synthesis of the functionalized pyrrolidine scaffolds, we used a chiral pool synthetic route starting from methionine. Biological evaluation of key compounds in kinase and cellular assays revealed significant effects of the scaffolds towards activity and selectivity, however, the absolute configuration of the chiral moieties only exhibited a limited effect on inhibitory activity. X-ray crystallographic analysis of ligand-CK1δ complexes confirmed the expected binding mode of the 3,4-diaryl-isoxazole inhibitors. Surprisingly, the original compounds underwent spontaneous Pictet-Spengler cyclization with traces of formaldehyde during the co-crystallization process to form highly potent new ligands. Our data suggests chiral “ribose-like” pyrrolidine scaffolds have interesting potential for modifications of pharmacologically active compounds.

Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine Scaffolds

Effective synthesis of 3,5-diaryl-(1H)-pyrazin-2-ones via microwave mediated ring closure

Pyrazin-2-ones (II) (24 examples), present as scaffold in a number of biologically active compounds, are prepared via ring closure of diketoamides (I).

Effective Synthesis of 3,5-Diaryl-(1H)-pyrazin-2-ones via Microwave Mediated Ring Closure.

Highly Regio‐ and syn‐Diastereoselective Synthesis of 4‐Hydroxy‐1,2‐alkadienylcarbamates from α‐Titanated 2‐Alkynylcarbamates and Aldehydes.

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