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UVA-induced deleterious effect of thiopurine prodrugs including azathioprine, 6-mercaptopurine and 6-thioguanine (6-TG) increases the risk of cancer development due to the incorporation of 6-TG in patients' DNA. The catalytic mechanism by which thiobases act as a sustained oxidant producer has yet to be explored, especially through the Type I electron transfer pathway that produces superoxide radicals (O2˙-). Under Fenton-like conditions O2˙- radicals convert to extremely reactive hydroxyl radicals (˙OH), thus carrying even higher risk of biological damage than that induced by the well-studied type II reaction. By monitoring 6-TG/UVA-induced photochemistry in mass spectra and superoxide radicals (O2˙-) via nitro blue tetrazolium (NBT) reduction, this work provides two new findings: (1) in the presence of reduced glutathione (GSH), the production of O2˙-via the type I reaction is enhanced 10-fold. 6-TG thiyl radicals are identified as the primary intermediate formed in the reaction of 6-TG with O2˙-. The restoration of 6-TG and concurrent generation of O2˙- occur via a 3-step-cycle: 6-TG type I photosensitization, O2˙- oxidation and GSH reduction. (2) In the absence of GSH, 6-TG thiyl radicals undergo oxygen addition and sulfur dioxide removal to form carbon radicals (C6) which further convert to thioether by reacting with 6-TG molecules. These findings help explain not only thiol-regulation in a biological system but chemoprevention of cancer.

Selective dimension enlarging integrated with numbering-up is of great importance for microfluidics. However, its feasibility for photochemical processes remains unclear due to the strict requirements of uniform irradiation. Herein, a novel method for selective dimension enlarging in photochemical production was developed by introducing microbubbles. A membrane dispersion microreactor was employed to generate microbubbles for efficient mixing and uniform absorption of photons. With an increased channel size from 0.6 mm to 4 mm, it allowed a 41-fold increase in productivity while maintaining the microscale effect. The yield of was increased by 44−70 % with 83−86 % less side products, compared with those of the homogeneous and segmented flow systems. In addition, a theoretical method combining CFD simulation was developed to predict the change of mixing time with device scales, which could be used to assess the practicality by selective dimension enlarging for different photochemical microfluidic processes.

Thiopurines were examined for their ability to produce singlet oxygen ((1)O(2)) with UVA light. The target compounds were three thiopurine prodrugs, azathioprine (Aza), 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), and their S-methylated derivatives of 6-methylmercaptopurine (me6-MP) and 6-methylthioguanine (me6-TG). Our results showed that these thiopurines were efficient (1)O(2) sensitizers under UVA irradiation but rapidly lost their photoactivities for (1)O(2) production over time by a self-sensitized photooxidation of sulfur atoms in the presence of oxygen and UVA light. The initial quantum yields of (1)O(2) production were determined to be in the range of 0.30-0.6 in aqueous solutions. Substitution of a hydrogen atom with a nitroimidazole or methyl group at S decreased the efficacy of photosensitized (1)O(2) production as found for Aza, me6-MP and me6-TG. (1)O(2)-induced formation of 8-oxo-7,8-dihydro-2'-dexyguanosine (8-oxodGuo) was assessed by incubation of 6-methylthiopurine/UVA-treated calf thymus DNA with human repair enzyme 8-oxodGuo DNA glycosylase (hOGG1), followed by apurinic (AP) site determination. Because more 8-oxodGuo was formed in Tris D(2)O than in Tris H(2)O, (1)O(2) is implicated as a key species in the reaction. These findings provided quantitative information on the photosensitization efficacy of thiopurines and to some extent revealed the correlations between photoactivity and phototoxicity.

The incorporation of 6-thioguanine (6-TG) into DNA increases the risk of (1)O(2)-initiated skin cancer. We herein provide the first report on quantitative characterization of the photoactivity of 6-thioguanines including 6-TG and 6-thioguanosine. Time-resolved singlet oxygen luminescence was observed directly for the first time after UVA irradiation of 6-thioguanines in both CHCN(3) and aqueous solutions. Their photosensitization was characterized by the quantum yield of singlet oxygen production, showing a dramatic decrease over time from the initial 0.49-0.58 to zero. Experiments performed on both 6-TG and 6-thioguanosine did not show any significant difference in the quantum yield of singlet oxygen production, indicating that there was no potential participation of 7H- and 9H-tautomers. Our findings provide a primary basis for a better understanding of molecular events of thiopurine drugs in biological systems.

The facile synthesis and photophysical properties of three nonhydrolyzable thioglycosylated porphyrinoids are reported. Starting from meso-perfluorophenylporphyrin, the nonhydrolyzable thioglycosylated porphyrin (PGlc₄), chlorin (CGlc₄), isobacteriochlorin (IGlc₄), and bacteriochlorin (BGlc₄) can be made in 2-3 steps. The ability to append a wide range of targeting agents onto the perfluorophenyl moieties, the chemical stability, and the ability to fine-tune the photophysical properties of the chromophores make this a suitable platform for development of biochemical tags, diagnostics, or as photodynamic therapeutic agents. Compared to the porphyrin in phosphate buffered saline, CGlc₄ has a markedly greater absorbance of red light near 650 nm and a 6-fold increase in fluorescence quantum yield, whereas IGlc₄ has broad Q-bands and a 12-fold increase in fluorescence quantum yield. BGlc₄ has a similar fluorescence quantum yield to PGlc₄ (10%), but the lowest-energy absorption/emission peaks of BGlc₄ are considerably red-shifted to near 730 nm with a nearly 50-fold greater absorbance, which may allow this conjugate to be an effective PDT agent. The uptake of CGlc₄, IGlc₄, and BGlc₄ derivatives into cells such as human breast cancer cells MDA-MB-231 and K:Molv NIH 3T3 mouse fibroblast cells can be observed at nanomolar concentrations. Photobleaching under these conditions is minimal.

Singlet oxygen ( 1 O 2 ) signals observed upon illumination at 532 nm are a consequence of TiO 2 excitation in a two-photon process, and at 355 nm in a one-photon pathway. After corrections for light reflectance, the relative quantum yields of 1 0 2 production are 0.23 ± 0.01 and 0.22 ± 0.02 for 532 and 355 nm excitation, respectively. Total quenching rate constants of 1 O 2 removal by TiO 2 particles are near the diffusion-controlled rate limit. By employing 1 O 2 , as a probe, we have established an efficient and simple method to elucidate the nature of TiO 2 photoexcitation.

We suggest that singlet molecular oxygen [1O2 (1Δg)] is formed upon irradiation of indigo 1 [in air or O2-saturated DMSO and DMSO (0.5% H2SO4)] and indigo carmine 2 [in air or O2-saturated CH3OH, D2O, and 1-butyl-3-methylimidazolium tetrafluoroborate (BmIm–BF4)]. The quantum yield for production of 1O2 is estimated to be 0.6 for 1 and 0.3–0.5 for 2. The rates of reaction of 1O2 with 1 and 2 were determined by monitoring the emission of 1O2 at 1270 nm over time. Low molar absorptivities (at 532 nm) and rapid physical quenching caused by 1 and 2 limit their utility as 1O2 photosensitizers in solution. Compounds 1 and 2 degrade slowly during the photolysis due to a self-sensitized (type I or II) photooxidation reaction. Oxidative cleavage of 1 by singlet oxygen and superoxide, and 2 by superoxide has been noted before (Kuramoto, N.; Kitao, T. J. Soc. Dyers Color. 1979, 95, 257–261; Kettle, A. J.; Clark, B. M.; Winterbourn, C. C. J. Biol. Chem. 2004, 279, 18521–18525).

The chemistry of singlet oxygen with a variety of arylphosphines has been studied. Rates of singlet oxygen removal by para -substituted arylphosphines show good correlation with the Hammett σ parameter ( ρ =−1.53 in CDCl 3 ), and with the Tolman electronic parameter. The only products for the reactions of these phosphines with singlet oxygen are the corresponding phosphine oxides. Conversely, for ortho -substituted phosphines with electron-donating substituents, there are two products, namely a phosphinate formed by intramolecular insertion and phosphine oxide. Kinetic analyses demonstrate that both products are formed from the same intermediate, and this allows determination of the rate ratios for the competing pathways. Increasing the steric bulk of the phosphine leads to an increase in the amount of insertion product. VT NMR experiments show that peroxidic intermediates can only be detected for very hindered and very electron-rich arylphosphines.

We prepared the primary adduct for the reaction of singlet dioxygen ( 1 O 2 ) with an arylphosphine by using the sterically hindered arylphosphine tris( o -methoxyphenyl)phosphine. The resulting phosphadioxirane has a dioxygen molecule triangularly bound to the phosphorus atom. Olefin trapping experiments show that the phosphadioxirane can undergo nonradical oxygen atom–transfer reactions. Under protic conditions, two different intermediates are formed during the reaction of singlet dioxygen with tris( o -methoxyphenyl)phosphine, namely, the corresponding hydroperoxy arylphosphine and a hydroxy phosphorane. Experiments with other arylphosphines possessing different electronic and steric properties demonstrate that the relative stability of the tris( o -methoxyphenyl)phosphadioxirane is due to both steric and electronic effects.

Reactions of the hydrated electron, H atoms, 2-propanol, and methanol radicals with the TiO 2 nano-particles have been studied either directly or by competition kinetics. The radicals were produced by radiolysis of 2-propanol, t -butanol, or methanol aqueous solutions in acid pH's. The reactions involve electron injection to the conduction band. As expected, the t -butanol radical is inert towards TiO 2 under our conditions, while the other reducing radicals react with TiO 2 . The reactivity decreases in the order: e aq − >H>CH 3 COHCH 3 >CH 2 OH. Two TiO 2 nanocrystallite sizes, with average diameters of 1.0 and 4.7 nm were compared. For equal concentrations (in terms of TiO 2 molecules), the rate of electron injection shows relatively little dependency on particle size. The rates of interfacial electron transfer and transfer coefficient are also reported.

The yield of hydroxyl radicals has been determined by illumination of TiO 2 layers immersed in air saturated aqueous methanol solutions. This yield is equal to half the measured formaldehyde yield in the pH range 7-13. A detailed mechanism is proposed, accounting for the lack of accumulation of hydrogen peroxide. The effect of changing methanol concentration, pH and light intensity (the latter by three orders of magnitude) is in agreement with a very simple mechanism. In contrast to hydroxyl radicals, which react via hydrogen abstraction, leading to formation of HCHO, there is no sign for reaction of methanol with mobile holes. Thus, the limiting quantum yield observed at high methanol concentration is related to the maximum yield of ○OH ads under air saturated conditions at the given pH and light intensity. The effect of light intensity shows the expected inverted square root dependency. The yield of ○OH ads is nearly constant in the range 7 < pH < 12. This system may be useful for comparative tests of different TiO 2 preparations.

A triply bridged fused diporphyrin appended with six thioglucose units is reported. This new, chemically, and photochemically stable amphiphilic compound is taken up by breast cancer cells and causes cell death upon light exposure. Photophysical studies reveal absorption bands in the near IR region, and photosensitized formation of singlet oxygen in high quantum yields.

[reaction--see text] The chemistry of singlet oxygen with all three isomers of tris(methoxyphenyl)phosphine has been studied. For the severely hindered ortho isomer, intramolecular rearrangement to form phenyl diphenyl phosphinate is preferred to formation of phosphine oxide at low concentration in aprotic solvents. In protic solvents, no intramolecular reactivity is observed. A detailed kinetic analyses has been undertaken. There is no physical quenching, regardless of solvent. Mechanistic implications of these findings are discussed.

Many biomolecules contain photoactive reducing agents, such as reduced nicotinamide adenine dinucleotide (NADH) and 6-thioguanine (6-TG) incorporated into DNA through drug metabolism. These reducing agents may produce reactive oxygen species under UVA irradiation or act as electron donors in various media. The interactions of C60 fullerenes with biological reductants and light energy, especially via the Type-I electron-transfer mechanism, are not fully understood although these factors are often involved in toxicity assessments. The two reductants employed in this work were NADH for aqueous solutions and 6-TG for organic solvents. Using steady-state photolysis and electrochemical techniques, we showed that under visible light irradiation, the presence of reducing agents enhanced C60 -mediated Type-I reactions that generate superoxide anion (O2(.-)) at the expense of singlet oxygen ((1)O2) production. The quantum yield of O2(.-) production upon visible light irradiation of C60 is estimated below 0.2 in dipolar aprotic media, indicating that the majority of triplet C60 deactivate via Type-II pathway. Upon UVA irradiation, however, both C60 and NADH undergo photochemical reactions to produce O2(.-), which could lead to a possible synergistic toxicity effects. C60 photosensitization via Type-I pathway is not observed in the absence of reducing agents.

A pH-responsive, TiO2-attached sensitizer was prepared based on the adsorption of 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP) onto TiO2 nanoparticles. This colloidally dispersed TiO2-attached TCPP behaves as a single-phase colloidal sensitizer at pH 1.0-3.3 with quantum yields of singlet oxygen production (Phi(Delta)) between 0.20 and 0.25, as a heterogeneous particle sensitizer at pH 3.5-6.0 with Phi(Delta) between 0.25 and 0.50, and as homogeneous free TCPP molecules in alkaline solutions with Phi(Delta) = 0.53. The changes in Phi(Delta) are fully consistent with pH-dependent adsorption of TCPP onto the TiO2 surface. Recovery yields of 99.8% for TCPP and 98.8% for TiO2 were obtained from 1.4 mM TiO2-attached TCPP. We attribute its photosensitization ability to retaining TCPP solubility on the TiO2 surface and, hence, activity. This novel system shows a potential to bridge the gap between easily recoverable and highly efficient sensitizers.

Single-walled carbon nanotubes (SWNTs) functionalized with -COOH (along with some sulphonation and nitration), and/or modified with chitosan were prepared and tested for their singlet oxygen ((1)O(2)) production. The emission from (1)O(2) observed upon SWNT irradiation at 532 nm was due to a two-photon process, while (1)O(2) production via excitation at 355 nm occurred through a conventional one-photon pathway. The relative quantum yield of (1)O(2) production at excitation wavelength of 532 nm was found to be 0.00, 0.07-0.13 and 0.24-0.54 for highly-functionalized, partially-functionalized and non-functionalized SWNT samples respectively. The nanotube-mediated generation of (1)O(2) may find applications in both targeted destruction of tumor cells and selective degradation of drug molecules. Our research provides a practical approach to modulate the production of reactive oxygen species from SWNTs via surface functionalization/modification.

Singlet molecular oxygen [1O2 (1Deltag)] is generated cleanly in aqueous solution upon irradiation of a heterogeneous complex, meso-tetra(N-methyl-4-pyridyl)porphine (1) adsorbed onto porous Vycor glass (PVG). The cationic photosensitizer 1 tightly binds onto PVG and gives a stable material, which does not dissociate 1 into the surrounding aqueous phase. The production of 1O2 was measured by monitoring the time-resolved 1O2 (1Deltag) phosphorescence at 1270 nm. Indirect analysis of 1O2 generation was also carried out with the photooxidation of trans-2-methyl-2-pentenoate anion, which afforded the corresponding hydroperoxide. Sensitizer-1-impregnated PVG gives rise to a new singlet oxygen generator but more importantly provides a heterogeneous system for use in water.

We report the singlet oxygen sensitization properties of a series of bis-cyclometalated Ir(III) complexes (i.e., (bt)2Ir(acac), (bsn)2Ir(acac), and (pq)2Ir(acac); bt = 2-phenylbenzothiazole, bsn = 2-(1-naphthyl)benzothiazole, pq = 2-phenylquinoline, and acac = acetylacetonate). Complexes with acetylacetonate ancillary ligands give singlet oxygen quantum yields near unity (PhiDelta = (0.7-1.0) +/- 0.1), whether exciting the ligand-based state or the lowest energy excited state (MLCT + 3LC). The singlet oxygen quenching rates for these beta-diketonate complexes were found to be small [(5 +/- 2) x 105 to (6 +/- 0.2) x 106 M-1 s-1], roughly 3 orders of magnitude slower than the corresponding phosphorescence quenching rate. Similar complexes were prepared with glycine or pyridine tethered to the Ir(III) center (i.e., (bsn)2Ir(gly) and (bt)2Ir(py)Cl; gly = glycine and py = pyridine). The glycine and pyridine derivatives give high singlet oxygen yields (PhiDelta = (0.7-1.0) +/- 0.1).

Singlet oxygen reacts with Ir(I) and Rh(I) thiolato complexes to form the corresponding Ir(III) and Rh(III) peroxo thiolato complexes which do not undergo intramolecular oxidation of the thiolate moiety.

5,10,15,20-Tetrakis(N-(2-(1H-imidazol-4-yl)ethyl)benzamide)porphyrin produced twice as many singlet oxygen ((1)O(2)) molecules at pH 5.0 (quantum yield 0.53 ± 0.01) than at pH 7.4, whereas the (1)O(2) quenching rate was reduced by a factor of 2.5 for a pH change from 7.4 to 5.0.

Photophysical properties are reported for a series of cyclometalated platinum and iridium complexes that can serve as photosensitizers for singlet oxygen. The complexes have the formula (C;N)(2)Ir(O;O) or (C;N)Pt(O;O) where C;N is a monoanionic cyclometalating ligand such as 2-(phenyl)pyridyl and 2-(phenyl)quinolyl, and O;O is the ancillary ligand acetylacetonate (acac) or dipivaloylmethane (dpm). Also examined were a series of (N;N)PtMe(2) complexes where N;N is a diimine such as 2,2'-bipyridyl. In general, the cyclometalated complexes are excellent photosensitizers for the production of singlet oxygen, while the (N;N)PtMe(2) complexes were ineffective at this reaction. Quantum yields of singlet oxygen production range from 0.9-1.0 for the cyclometalated Pt complexes and 0.5-0.9 for Ir complexes. Luminescence quenching and singlet oxygen formation of the Ir complexes occurs from a combination of electron and energy transfer processes, whereas the Pt complexes only react by energy transfer. For Ir complexes with low emission energy, physical deactivation of the triplet excited state becomes competitive with energy transfer to ground state dioxygen. The rates of singlet oxygen quenching for the complexes presented here are in the range 6 x 10(6)-2 x 10(7) M(-1) s(-1) for Pt complexes and 2 x 10(5)-2 x 10(7) M(-1) s(-1) for Ir complexes, respectively. Differences in the efficiency of both forming and quenching singlet oxygen between the Ir and Pt cyclometalates are believed to come about from the more exposed coordination geometry in the latter species.