Design and synthesis of efficient BODIPY-based photochemical tools for drug delivery and imaging

Photocages are protecting groups unmasked by the light, allowing precise spatiotemporal control over the release of a bioactive substrate in a biological environment. Most photocages use toxic ultraviolet (UV) light that has minimal penetration power inside the living tissues. The photocages that absorb in a visible or near-IR range operate with minuscule phototoxicity and higher tissue penetration capability, so the development of photocages that absorb in the biological window (600 -1000 nm) is essential. The work contained in this dissertation builds on the previously identified BODIPY photocage and rationally designs new photocages that work efficiently on living tissue. In chapter 2, a systematic study on the structure-activity relationship was done to identify structural motifs that would improve the efficiency of the photorelease on BODIPY photocages. The introduction of heavy atoms like iodine promoted the intersystem crossing rates resulting in enhanced quantum yield of release. Better leaving groups fared superior in photorelease, while meso-alkylation didn’t improve the quantum yield of release. However, alkylation at boron drastically improved the quantum yield. Alkylation was additive to halogenation resulting in a remarkable 100-fold improvement in photorelease quantum yield. This improvement makes second-generation BODIPY photocages excellent alternatives to existing other photocages. In chapter 3, newly discovered second-generation green-light absorbing BODIPY photocages were used to release cysteine cathepsin inhibitor CA-074. BODIPY-caged inhibitors were found to be cell-permeable, highly selective, and activated rapidly upon exposure to visible light. Methylated BODIPY-caged inhibitor displayed dual actions; light accelerated cysteine cathepsin inhibition and singlet oxygen production. Synergistic dual-action leads to a rapid necrotic response in the MDA-MB-231 triple-negative breast cancer cell with a high therapeutic index (>30). Photorelease of inhibitor steers cell death from apoptosis to necrosis which is a promising new way to treat the tumor. In chapter 4, previously discovered BODIPY photocages absorbing at red/near IR region were modified into highly efficient variant by inhibiting unproductive decay channels. Conformationally restricted structures were synthesized to reduced energy loss via internal conversion pathways like cis-trans isomerization, charge transfer, and “loose bolt effect.” Similarly, aryl groups were introduced at proximity to trap putatively formed carbocation and prevent ion-pair recombination. This strategy led to new highly efficient second-generation BODIPY photocages that absorb light strongly around 700 nm, a 50-fold improvement from the best known previous photocage absorbing >600 nm. In chapter 5, second-generation green-light absorbing photocages and second-generation red-light absorbing photocages were used to release various functional groups like carboxylic acid, amines, alcohol, phenol, phosphate, and halide. Both photocages release these functional groups with excellent chemical yields; however, the quantum yield of release varies based on the nature of leaving group, type of linker, and photocage itself. The plot of pKa against the quantum yield of release was linear for green-light absorbing photocages, while no correlation exists for red-light absorbing photocages. In chapter 6, a BODIPY-based photoactivable probe was designed to obtain images based on localization-based super-resolution cellular imaging. BODIPY compounds with alkyl group on boron had a massive surge in fluorescence quantum yield on photoactivation (6-fold) in both methanol and aqueous medium. This enhancement of fluorescence was successfully used in synthesizing probes that allowed to obtain in-vitro and in-vivo images of microtubes below the diffraction limit using a single low-powered laser source.