BODIPY‐Appended 2‐(2‐Pyridyl)benzimidazole Platinum(II) Catecholates for Mitochondria‐Targeted Photocytotoxicity

Abstract

Platinum(II) complexes of the type [Pt(L)(cat)] (1 and 2), in which H2 cat is catechol and L represents two 2-(2-pyridyl)benzimidazole ligands with 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) pendants, were synthesized to achieve mitochondria-targeted photocytotoxicity. The complexes showed strong absorptions in the range λ=510-540 nm. Complex 1 exhibited intense emission at λ=525 nm in 1 % DMSO/water solution (fluorescence quantum yield of 0.06). Nanosecond transient absorption spectral features indicated an enhanced population of the triplet excited state in di-iodinated complex 2. The generation of singlet oxygen by complex 2 upon exposure to visible light, as evidenced from experiments with 1,3-diphenylisobenzofuran, is suitable for photodynamic therapy because of the remarkable photosensitizing ability. The complexes resulted in excellent photocytotoxicity in HaCaT cells (half maximal inhibitory concentration IC50 ≈3 μm, λ=400-700 nm, light dose=10 J cm(-2) ), but they remained non-toxic in the dark (IC50 >100 μm). Confocal microscopy images of 1 and Pt estimation from isolated mitochondria showed colocalization of the complexes in the mitochondria. Complex 2 displayed generation of reactive oxygen species induced by visible light, disruption of the mitochondrial membrane potential, and apoptosis.

Cytotoxic performances of new anionic cyclometalated Pt(II) complexes bearing chelated O^O ligands

“…Following such an approach, Mitra et al . synthesized the catecholate containing Pt(II) neutral complexes [(N^N)Pt(O^O)] (Chart 2d) based on carboplatin and oxaliplatin archetypes (Chart 1b,c), and by performing time‐dependent UV–visible spectral studies they demonstrated the breakage of the Pt‐O bond in the presence of an excess of glutathione, which can be the basis for the observed activity triggered by the generated free coordinating site.…”

Development of a novel carboplatin like cytoplasmic trackable near infrared fluorophore conjugate via strain-promoted azide alkyne cycloaddition

“…[14] Specifically a number of Pt(II) anticancer type compounds have been reported where boron-fluorescent dipyrromethene (BODIPY) moieties have been tethered to Pt centres via prior direct covalent modification of the ammine carrier ligands. For instance Miller et al developed BODIPY tethered Pt complexes for high resolution of cancer in vivo, [15] Hall and coworkers to monitor the fate of cisplatin analogues, [16] [16,17] Furthermore a number of Pt complexes which offer a general synthetic approach to the functionalization of Pt centres have been developed, including those that possess reactive azide handles that facilitate click reactions, Figure 3 (a-c). [6,18] The 6-azidohexanoato ligands in 3 (c) were clicked with azadibenzocyclooctyne (ADIBO, Figure 3d) derivatives for example including the near-infrared fluorescent reporter, Cy5.5, which was used to visualize the cellular uptake of Pt in live prostate cancer cells.…”

Photosensitization and controlled photosensitization with BODIPY dyes

“…Instead of ER or nucleus, mitochondria regulating oxidative stress, metabolic energy and apoptotic machinery serves as a better target since mitochondrial integrity is essential for viability of cells. Compound 42 was prepared by Chakravarty and coworkers for a combinatory effect of PDT and chemotherapy such that mitochondria localized complex was expected to operate in such a way that release Pt from the complex is capable of inhibiting replication of mt-DNA (mitochondrial DNA) and BODIPY moiety embedded into the complex produces singlet oxygen for oxidative damage [111]. Further analysis on HaCaT human skin keratinocyte Fig.…”