Light‐Tunable Generation of Singlet Oxygen and Nitric Oxide with a Bichromophoric Molecular Hybrid: a Bimodal Approach to Killing Cancer Cells

Abstract

The design, synthesis, photochemical properties, and biological evaluation of a novel photoactivatable bichromophoric conjugate are reported. The compound 1, [4-(4,4-difluoro-2,6-diiodo-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacen-8-yl)-N-(3-((4-nitro-3-(trifluoromethyl)phenyl)amino)propyl)butanamide] combines a 2,6-diiodo-1,3,5,7-tetramethyl BODIPY derivative as singlet oxygen ((1) O2 ) photosensitizer and 4-nitro-3-(trifluoromethyl)aniline (NOPD) as nitric oxide (NO) photodonor, joined by an alkyl spacer. These two chromogenic units absorb in distinct regions of the visible spectrum, and their individual photochemical properties are conserved in the molecular conjugate. Irradiation of the bichromophoric conjugate with green light afforded (1) O2 in high quantum yields, whereas (1) O2 production was negligible with the use of blue light; under this latter condition, NO was released. Photogeneration of NO and cytotoxic (1) O2 can therefore be regulated by appropriately tuning the excitation light wavelength and intensity. Tested on melanoma cancer cells, this resulted in amplified photomortality relative to that of a structurally correlated model compound 2 [4-(4,4-difluoro-2,6-diiodo-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacen-8-yl)-N-(3-(p-tolylamino)propyl)butanamide] deprived of the NO-release capacity. The cellular uptake of 1, evaluated by confocal fluorescence microscopy, showed that the product is localized in the cytoplasm.

BODIPY-loaded polymer nanoparticles: chemical structure of cargo defines leakage from nanocarrier in living cells

“…51,52 BODIPY dyes and their analogues have been attractive building blocks in molecular and nano-constructs for fluorescence imaging and photodynamic therapy applications. [53][54][55][56][57] Therefore, they are good candidates as a model cargo. Using the biodegradable polymer poly(lactic-co-glycolic acid) (PLGA), we prepared NPs by nanoprecipitation containing different BODIPY derivatives.…”

A Fluorescent Naphthalenediimide-Alkoxyfuroxan Photoinduced Nitric Oxide Donor

“…The quantification of 1 O2 conducted by an absorption spectroscopic analysis using 1,3diphenylisobenzofuran (DPBF), a 1 O2 scavenger, 38 revealed that three orders of magnitude more 1 O2 than NO is released. Although this result indicates that compound 6 may be a good candidate of a photodynamic therapy reagent for cancer disease because both 1 O2 and NO have anticancer capabilities, 39 the practical biological use of compound 6 as a pure NO donor is limited at present. Nevertheless, there is still a large hope that the ratio of NO to 1 O2 may be improved by taking advantage of intramolecularity of energy transfer from NDI* to the furoxan moiety in contrast to the intermolecular sensitization of molecular oxygen by NDI.…”

A Molecular Hybrid for Mitochondria‐Targeted NO Photodelivery

“…Figure3 shows the absorption spectral changes observed for as olution of 7 at different irradiationt imes, under the [16][17][18] However, small but clear spectralc hanges were also observed around the rhodamine absorption, at5 66 nm. As is more easily seen in the zoomed area in the inset of Figure 3, the rhodamine band undergoes as imultaneous hypochromic and blue-shift under violet light irradiation.…”

“…Non planar torsional conformation of the nitro group in relationt ot he aromatic ring facilitates the rearrangement. [14a, 15a] Prompted by our on-going interest in building light-controlledN Od elivering hybrid drugs, [16][17][18] and considering the limited number of studies into mitochondria-targeted NO photodelivery, [19,20] we herein report the design,s ynthesis, spectroscopic and photochemical characterization and the biological evaluation of molecular hybrid 7 (Scheme 1). It covalently binds as uitable NOPD unit, p-nitroaniline derivative 3, and rhodamine B 5,awell-known mitochondrial probe, [21] within the same molecular skeleton via an amide bridge.T he potentialo fh ybrid 7 as an antitumor drug, following its accumulationinto the mitochondriaofhuman A549 lung adenocarcinomac ells, and its capacity to release NO under the action of violet light are discussed and compared with those of suitable model compounds 8,w hich lack the NOPD framework, and 4,w hich lacks the targeting unit.…”