Photosensitizers are reagents that produce reactive oxygen species upon light illumination and are commonly used to study oxidative stress or for photodynamic therapy. There are many available photosensitizers, but most have limitations, such as low photostability, structural instability, or a limited usable range of solvent conditions. Here, we describe a novel photosensitizer scaffold (2I-BDP) based on the unique characteristics of the BODIPY chromophore (i.e., high extinction coefficient, high photostability, and insensitivity to solvent environment). 2I-BDP shows stronger near-infrared singlet oxygen luminescence emission and higher photostability than the well-known photosensitizer, Rose Bengal. Unlike other photosensitizers, this scaffold is widely applicable under various conditions, including lipophilic and aqueous environments. HeLa cells loaded with 2I-BDP could be photosensitized by light illumination, demonstrating that 2I-BDP is potentially useful as a reagent for cell photosensitization, oxidative stress studies, or PDT.

We report the discovery of 7-oxo-2,4,5,7-tetrahydro-6 H-pyrazolo[3,4- c]pyridine derivatives as a novel class of receptor interacting protein 1 (RIP1) kinase inhibitors. On the basis of the overlay study between HTS hit 10 and GSK2982772 (6) in RIP1 kinase, we designed and synthesized a novel class of RIP1 kinase inhibitor 11 possessing moderate RIP1 kinase inhibitory activity and P-gp mediated efflux. The optimization of the core structure and the exploration of appropriate substituents utilizing SBDD approach led to the discovery of 22, a highly potent, orally available, and brain-penetrating RIP1 kinase inhibitor with excellent PK profiles. Compound 22 significantly suppressed necroptotic cell death both in mouse and human cells. Oral administration of 22 (10 mg/kg, bid) attenuated disease progression in the mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Moreover, analysis of structure-kinetic relationship (SKR) for our novel chemical series was also discussed.

Chromophore-assisted light inactivation is a promising technique to inactivate selected proteins with high spatial and temporal resolution in living cells, but its use has been limited because of the lack of a methodology to prevent nonspecific photodamage in the cell owing to reactive oxygen species generated by the photosensitizer. Here we present a design strategy for photosensitizers with an environmentsensitive off/on switch for singlet oxygen ( 1 O2) generation, which is switched on by binding to the target, to improve the specificity of protein photoinactivation. 1 O2 generation in the unbound state is quenched by photoinduced electron transfer, whereas 1 O2 generation can occur in the hydrophobic environment provided by the target protein, after specific binding. Inositol 1,4,5-trisphosphate receptor, which has been suggested to have a hydrophobic pocket around the ligand binding site, was specifically inactivated by an environmentsensitive photosensitizer-conjugated inositol 1,4,5-trisphosphate receptor ligand without 1 O2 generation in the cytosol of the target cells, despite light illumination, demonstrating the potential of environment-sensitive photosensitizers to allow high-resolution control of generation of reactive oxygen species in the cell.activatable photosensitizer ͉ boron dipyrromethene derivative ͉ electron transfer ͉ inositol 1,4,5-trisphosphate receptor C hromophore-assisted light inactivation (CALI)(1) is a technique with great potential to inactivate proteins with high spatial and temporal resolution by using an antibody to direct a suitable fluorophore specifically to the protein of interest. Illumination induces local generation of reactive oxygen species (ROS), which react chemically with the adjacent antigen and inactivate it. Although CALI is a powerful technique, its use has been limited by the complexity of the procedures (i.e., the need to deliver a labeled antibody into cells or to use a laser as the light source). Several groups have reported alternative approaches. Genetically targeted CALI is one such method, in which the target protein is tagged with a tetracysteine tag that is recognized by a membrane-permeant biarsenical chromophore (FlAsH) (2, 3), or tagged with GFP (4-6). However, these methods also cause nonspecific damage, owing to the nonspecific binding of the biarsenical chromophore to cysteine-rich proteins (3, 7) in FlAsH-mediated photoinactivation, or to the use of a relatively high-power laser in EGFP-mediated CALI (4, 5). Current implementations of the CALI technique leave much to be desired, and highly specific inactivation of a protein of interest would require a methodology to control ROS generation by the photosensitizer in the cells with high spatial resolution.We present here an approach for designing photosensitizers with an environment-controlled off/on switch for singlet oxygen ( 1 O 2 ) generation to improve the specificity of CALI. We have developed environment-sensitive photosensitizers (ESPers), which are activated by recognition of the hydrophob...