Regioselective Synthesis and Photophysical and Electrochemical Studies of 20‐Substituted Cyanine Dye–Purpurinimide Conjugates: Incorporation of Ni^II into the Conjugate Enhances its Tumor‐Uptake and Fluorescence‐Imaging Ability

Abstract

We report herein a simple and efficient approach to the synthesis of a variety of meso-substituted purpurinimides. The reaction of meso-substituted purpurinimide with N-bromosuccinimide regioselectively introduced a bromo functionality at the 20-position, which on further reaction with a variety of boronic acids under Suzuki reaction conditions yielded the corresponding meso-substituted analogues. Interestingly, the free base and the metalated analogues showed remarkable differences in photosensitizing efficacy (PDT) and tumor-imaging ability. For example, the free-base conjugate showed significant in vitro PDT efficacy, but limited tumor avidity in mice bearing tumors, whereas the corresponding Ni(II) derivative did not produce any cell kill, but showed excellent tumor-imaging ability at a dose of 0.3 μmol kg(-1) at 24, 48, and 72 h post-injection. The limited PDT efficacy of the Ni(II) analogue could be due to its inability to produce singlet oxygen, a key cytotoxic agent required for cell kill in PDT. Based on electrochemical and spectroelectrochemical data in DMSO, the first one-electron oxidation (0.52 V vs. SCE) and the first one-electron reduction (-0.57-0.67 V vs. SCE) of both the free base and the corresponding Ni(II) conjugates are centered on the cyanine dye, whereas the second one-electron reduction (-0.81 V vs. SCE) of the two conjugates is assigned to the purpurinimide part of the molecule. Reduction of the cyanine dye unit is facile and occurs prior to reduction of the purpurinimide group, which suggests that the cyanine dye unit as an oxidant could be the driving force for quenching of the excited triplet state of the molecules. An interaction between the cyanine dye and the purpurinimide group is clearly observed in the free-base conjugate, which compares with a negligible interaction between the two functional groups in the Ni(II) conjugate. As a result, the larger HOMO-LUMO gap of the free-base conjugate and the corresponding smaller quenching constant is a reason to decrease the intramolecular quenching process and increase the production of singlet oxygen to some degree.

Palladium-Catalyzed Polyfluorophenylation of Porphyrins with Bis(polyfluorophenyl)zinc Reagents

“…We selected Pd(OAc) 2 as the palladium catalyst of choice for further investigation because of its high catalytic activity and low cost. A brief investigation of solvents found that ethereal solvents, such as THF and dioxane, were suitable reaction media (entries [14][15][16][17]. Among which, THF was the solvent of choice in terms of yield of the desired fluorinated product Zn-2a (entry 14).…”

“…The construction of porphyrins and related tetrapyrrolic macrocycles has attracted much interest [1][2][3][4][5][6] because they have a variety of important applications in many fields [7,8], including catalysis [9][10][11][12][13][14], medicine [15][16][17][18], and materials [19][20][21][22][23][24][25][26][27]. It is also well documented that the chemical, physical, and biological properties of porphyrin macrocycles can be systematically tuned by the electronic, steric and conformational environments of their peripheral substituents [7,8].…”

Tetrazine Click Chemistry for the Modification of 1‐Hydroxy‐1,1‐methylenebisphosphonic Acids: Towards Bio‐orthogonal Functionalization of Gold Nanoparticles

“…To demonstrate a broader applicability of the iEDDA approach, the as‐synthesized gold NP has also been conjugated with a tetrazine‐cyanine: 6‐methyl‐tetrazine‐sulfo‐Cy5 (TzCy5) near‐infrared dye. Indeed, cyanine 5 (Cy5) is a bright, near‐infrared (NIR) fluorescent probe currently used for biological imaging due to the low autofluorescence of biological specimens in this region of the spectrum . After removal of excess dye by a drastic washing using ultrafiltration units with a saline solution, the effective coupling of TzCy5 onto the nanoparticle surface was assessed by UV/Vis and fluorescence spectroscopies (Figure ).…”

“…Indeed, cyanine 5( Cy5) is ab right, near-infrared (NIR) fluorescent probe currently used for biological imaging due to the low autofluorescence of biological specimens in this region of the spectrum. [55][56][57] After removalo f excessd ye by ad rastic washing using ultrafiltration units with as aline solution, the effective coupling of TzCy5 onto the nanoparticle surface was assessed by UV/Vis and fluorescence spectroscopies ( Figure 5). The excitation spectrum (Figure 5a, solid lines) showst hat TzCy5 coupled Au@HMBPene NPs exhibit ap eak at 648 nm, which is in good agreement with the excitation (solid line) and the UV/Vis absorption (Figure 5a,c ircles) spectra from the free TzCy5.…”

Metalloporphyrins in Medicine: From History to Recent Trends

“…Later, the same and other groups synthesized and evaluated spectroscopic properties of the range of dyads consisting of chlorin as a donor and DOTA-chelated elements (Nd, Yb, Pd, Cu) as an acceptor. − Ethirajan and colleagues conjugated cyanine acceptor with metallochlorin donors. The researchers observed both cyanine fluorescence after irradiation of Ni-chlorin and improved dyad photostability due to singlet oxygen decomposition by Ni-chlorin . Lovell and coauthors developed new “on-line” caspase-responsive FRET system based on 5-carboxy-X-rhodamine donor and pyropheophorbide acceptor for fluorescence guiding feedback-oriented PDT and monitoring cancer cell death .…”