Dibenzothiophene S-oxide Research Articles

Photochemistry of N-aryl and N-alkyl dibenzothiophene sulfoximines.

N-phenyl dibenzothiophene sulfoximine has been demonstrated to produce phenyl nitrene and dibenzothiophene S-oxide upon irradiation with UV-A light, and dibenzothiophene S-oxide upon further irradiation releases triplet atomic oxygen. Thus, N-phenyl dibenzothiophene sulfoximine exhibits a rare dual-release capability in its photochemistry. In this work, N-substituted dibenzothiophene sulfoximine derivatives are irradiated with UV-A light to compare their photochemistry and quantum yield of dibenzothiophene S-oxide production with that of N-phenyl dibenzothiophene sulfoximine. Both N-aryl and N-alkyl derivatives of dibenzothiophene sulfoximine are examined to observe their effects on the quantum yield of the photolysis reaction. Adding electron withdrawing N-aryl substituents is shown to increase the quantum yield of dibenzothiophene S-oxide production, while adding electron donating N-aryl substituents is shown to decrease the quantum yield. The quantum yield was slightly lowered or not increased by most N-alkyl substituents. Furthermore, the quantum yield was not augmented by branching and steric hindrance effects associated with the N-alkyl substituents. These results suggest that electronic modulation of the sulfoximine bonds affects the observed photolysis reaction.

Insights into the Mechanism of O(3P)-Mediated Oxidation of Alkenes through Kinetic Isotope Effects and Computational Modeling.

Photodeoxygenation of aryl sulfoxides, such as dibenzothiophene S-oxide (DBTO), produces atomic oxygen [O(3P)] in solution. The mechanism of alkene oxidation with O(3P) remains uncertain. To address this, the current study utilized kinetic isotope effects (KIEs) and computational approaches to study the reaction of O(3P) with styrene and its isotopologues. Notably, the 2° CH/D KIE at the internal and terminal carbons of the reactive π-bond was ∼1.00 and ∼0.87, respectively. These findings indicate a terminal addition of O(3P) to the π-bond, supporting a stepwise oxidation pathway. Both epoxide and aldehyde products go through the same rate-determining transition state and then diverge based on the intermediate conformation. The O-C-C-C dihedral angle (φ) on the triplet surface dictates the product distribution, where φ = 50° or 310° leads to epoxide formation and φ = 180° leads to aldehyde formation. Computational modeling suggests that the epoxide is formed through rapid ring closure upon intersystem crossing from the triplet to the singlet ground state. Similarly, the aldehyde is generated via a 1,2-H shift immediately following intersystem crossing. This study integrates experimental and computational methods to understand the O(3P)-mediated oxidation of alkenes, providing supporting evidence for a stepwise addition mechanism.

Effects of photodeoxygenation on cell biology using dibenzothiophene S-oxide derivatives as O(3P)-precursors.

Photodeoxygenation of dibenzothiophene S-oxide and its derivatives have been used to generate atomic oxygen [O(3P)] to examine its effect on proteins, nucleic acids, and lipids. The unique reactivity and selectivity of O(3P) have shown distinct oxidation products and outcomes in biomolecules and cell-based studies. To understand the scope of its global impact on the cell, we treated MDA-MB-231 cells with 2,8-diacetoxymethyldibenzothiophene S-oxide and UV-A light to produce O(3P) without targeting a specific cell organelle. Cellular responses to O(3P)-release were analyzed using cell viability and cell cycle phase determination assays. Cell death was observed when cells were treated with higher concentrations of sulfoxides and UV-A light. However, significant differences in cell cycle phases due to UV-A irradiation of the sulfoxide were not observed. We further performed RNA-Seq analysis to study the underlying biological processes at play, and while UV-irradiation itself influenced gene expression, there were 9 upregulated and 8 downregulated genes that could be attributed to photodeoxygenation.

Photochemistry of N-Phenyl Dibenzothiophene Sulfoximine.

Sulfoximines are popular scaffolds in drug discovery due to their hydrogen bonding properties and chemical stability. In recent years, the role of reactive intermediates such as nitrenes has been studied in the synthesis and degradation of sulfoximines. In this work, the photochemistry of N-phenyl dibenzothiophene sulfoximine [5-(phenylimino)-5H-5λ4 -dibenzo[b,d]thiophene S-oxide] was analyzed. The structure resembles a combination of N-phenyl iminodibenzothiophene and dibenzothiophene S-oxide, which generate nitrene and O(3 P) upon UV-A irradiation, respectively. The photochemistry of N-phenyl dibenzothiophene sulfoximine was explored by monitoring the formation of azobenzene, a photoproduct of triplet nitrene, using direct irradiation and sensitized experiments. The reactivity profile was further studied through direct irradiation experiments in the presence of diethylamine (DEA) as a nucleophile. The studies demonstrated that N-phenyl dibenzothiophene sulfoximine underwent S-N photocleavage to release singlet phenyl nitrene which formed a mixture of azepines in the presence of DEA and generated moderate amounts of azobenzene in the absence of DEA to indicate formation of triplet phenyl nitrene.

Synthesis of triphenylphosphonium dibenzothiophene S-oxide derivatives and their effect on cell cycle as photodeoxygenation-based cytotoxic agents

Photodeoxygenation of Dibenzothiophene-S-oxide (DBTO) in UV-A light produces atomic oxygen [O(3P)] and the corresponding sulfide, dibenzothiophene (DBT). Recently, DBTO has been derivatized to study the effect of UV-A light-driven photodeoxygenation in lipids, proteins, and nucleic acids. In this study, two DBTO derivatives with triphenylphosphonium groups were synthesized to promote mitochondrial accumulation. The sulfone analogs of these derivatives were also synthesized and used as fluorescent mitochondrial dyes to assess localization in mitochondria of HeLa cells. These derivatives were then used to study the effect of photodeoxygenation on MDA-MB-231 breast cancer cell line using cell viability assays, cell cycle phase determination tests, and RNA-Seq analysis. The DBTO derivatives were found to significantly decrease cell viability only after UV-A irradiation as a result of generating corresponding sulfides that were found to significantly affect gene expression and cell cycle.

Visible light‐induced photodeoxygenation of polycyclic selenophene Se‐oxides

AbstractPhotodeoxygenation of dibenzothiophene S‐oxide (DBTO) is believed to produce ground‐state atomic oxygen [O(3P)] in solution. Compared with other reactive oxygen species (ROS), O(3P) is a unique oxidant as it is potent and selective. Derivatives of DBTO have been used as O(3P)‐precursors to oxidize variety of molecules, including plasmid DNA, proteins, lipids, thiols, and other small organic molecules. Unfortunately, the photodeoxygenation of DBTO requires ultraviolet irradiation, which is not an ideal wavelength range for biological systems, and has a low quantum yield of approximately 0.003. In this work, benzo[b]naphtho[1,2‐d]selenophene Se‐oxide, benzo[b]naphtho[2,1‐d]selenophene Se‐oxide, dinaphtho[2,3‐b:2’,3’‐d]selenophene Se‐oxide, and perylo[1,12‐b,c,d]selenophene Se‐oxide were synthesized, and their ability to utilize visible light for generating O(3P) was interrogated. Benzo[b]naphtho[1,2‐d]selenophene Se‐oxide produces O(3P) upon irradiation centered at 420 nm. Additionally, benzo[b]naphtho[1,2‐d]selenophene Se‐oxide, benzo[b]naphtho[2,1‐d]selenophene Se‐oxide, and dinaphtho[2,3‐b:2’,3’‐d]selenophene Se‐oxide produce O(3P) when irradiated with UVA light and have quantum yields of photodeoxygenation ranging from 0.009 to 0.33. This work increases the utility of photodeoxygenation by extending the range of wavelengths that can be used to generate O(3P) in solution.

In vitro oxidations of low-density lipoprotein and RAW 264.7 cells with lipophilic O(3P)-precursors.

A beneficial property of photogenerated reactive oxygen species (ROS) is the capability of oxidant generation within a specific location or organelle inside a cell. Dibenzothiophene S-oxide (DBTO), which is known to undergo a photodeoxygenation reaction to generate ground state atomic oxygen [O(3P)] upon irradiation, was functionalized to afford localization within the plasma membrane of cells. The photochemistry, as it relates to oxidant generation, was studied and demonstrated that the functionalized DBTO derivatives generated O(3P). Irradiation of these lipophilic O(3P)-precursors in the presence of LDL and within RAW 264.7 cells afforded several oxidized lipid products (oxLP) in the form of aldehydes. The generation of a 2-hexadecenal (2-HDEA) was markedly increased in irradiations where O(3P) was putatively produced. The substantial generation of 2-HDEA is not known to accompany the production of other ROS. These cellular irradiation experiments demonstrate the potential of inducing oxidation with O(3P) in cells.

Photodeoxygenation of phenanthro[4,5-bcd]thiophene S-oxide, triphenyleno[1,12-bcd]thiophene S-oxide and perylo[1,12-bcd]thiophene S-oxide

ABSTRACTSulfoxides, upon irradiation with ultraviolet (UV) light undergo α-cleavage, hydrogen abstraction, photodeoxygenation, bimolecular photoreduction, and stereo-mutation. The UV irradiation of dibenzothiophene S-oxide (DBTO) yields dibenzothiophene (DBT) as a major product along with ground-state atomic oxygen [O(3P)]. This is a common method for generating O(3P) in solution. The low quantum yield of photodeoxygenation and the requirement of UVA light are drawbacks of using this method. The sulfoxides benzo[b]naphtho-[1,2,d]thiophene S-oxide, benzo[b]naphtho [2,1,d]thiophene S-oxide, benzo[b] phenanthro[9,10-d]thiophene S-oxide, dinaphtho- [2,1-b:1’,2’-d]thiophene S-oxide, and dinaphtho[1,2-b:2’,1’-d]thiophene S-oxide have shown to deoxygenate up to three times faster than DBTO upon UVA irradiation; however, the photodeoxygenation of these sulfoxides does not appear to be limited to the production of O(3P). In this work, phenanthro[4,5-bcd]thiophene S-oxide, triphenyleno[1,12-bcd]thiophene-S-oxide, and perylo[1,12-bcd]thiophene-S-oxide were synthesized and their photodeoxygenation was studied. Phenanthro[4,5-bcd]thiophene-S-oxide, triphenyleno[1,12-bcd]thiophene-S-oxide, and perylo[1,12-bcd]thiophene-S-oxide deoxygenated upon UVA irradiation. However, the common intermediate experiments did not conclusively identify the photodeoxygenation mechanism of these sulfoxides.

Synthesis of Aromatic Disulfonic Acids for Water-Soluble Dibenzo­thiophene Derivatives

There is a need for efficient methods for the synthesis of water-soluble dibenzothiophene (DBT) and dibenzothiophene S-oxide (DBTO) derivatives to allow for the study of atomic oxygen in biological applications. Attaining water-solubility of aromatic compounds is effectively achieved through functionalization with sulfonic acid groups. Three approaches for the synthesis were considered. An indirect approach was unsuccessful. A modular approach was found to be highly effective for one DBTO disulfonic acid derivative (>99% pure). The direct approach was the most straightforward and highest-yielding route. Additionally, a highly effective, scalable, and improved purification method was identified for disulfonic acid DBT and DBTO derivatives, allowing for the isolation of positional isomers and other modifications by using reverse-phase high-performance flash chromatography.

Data for: Wavelength Dependent Photochemistry of Expanded Chromophore and Asymmetric Dibenzothiophene S-Oxides Derivatives

Abstract Irradiation of dibenzothiophene S-oxide (DBTO) is believed to generate ground state atomic oxygen [O(3P)]. The irradiation conditions and the efficiency of the deoxygenation event are not ideal when working with biological systems. Dinaphtho[2,1-b:1′,2′-d]thiophene S-oxide (DNTO) and several other analogs were shown to allow visible light to drive deoxygenation due to red-shifted absorbance of the DBTO derivatives. Additionally, DNTO and its analogs did not substantially improved quantum yield of deoxygenation (Φdeox.). To improve both Φdeox. and absorbance, changes were made to the DBTO scaffold. The first change was an addition of an electron withdrawing group (EWG) to weaken the S O bond strength of the sulfoxide to improve Φdeox.. The second change was the addition of an aromatic substituent to enhance and red-shift the absorbance. Common intermediate experiments were performed in toluene to examine if these new DBTO analogs produced a common oxidant under both UV and visible light irradiation. The separate light sources produced different product ratios suggesting these asymmetric DBTO derivatives have wavelength-dependent mechanisms of oxidation.

Wavelength dependent photochemistry of expanded chromophore and asymmetric dibenzothiophene S-Oxide derivatives

Irradiation of dibenzothiophene S-oxide (DBTO) is believed to generate ground state atomic oxygen [O(3P)]. The irradiation conditions and the efficiency of the deoxygenation event are not ideal when working with biological systems. Dinaphtho[2,1-b:1′,2′-d]thiophene S-oxide (DNTO) and several other analogs were shown to allow visible light to drive deoxygenation due to red-shifted absorbance of the DBTO derivatives. Additionally, DNTO and its analogs did not substantially improved quantum yield of deoxygenation (Φdeox.). To improve both Φdeox. and absorbance, changes were made to the DBTO scaffold. The first change was an addition of an electron withdrawing group (EWG) to weaken the SO bond strength of the sulfoxide to improve Φdeox.. The second change was the addition of an aromatic substituent to enhance and red-shift the absorbance. Common intermediate experiments were performed in toluene to examine if these new DBTO analogs produced a common oxidant under both UV and visible light irradiation. The separate light sources produced different product ratios suggesting these asymmetric DBTO derivatives have wavelength-dependent mechanisms of oxidation.

Thiol Reactivity toward Atomic Oxygen Generated during the Photodeoxygenation of Dibenzothiophene S-Oxide.

Aromatic heterocyclic oxides, such as dibenzothiophene S-oxide (DBTO), have been suggested to release ground state atomic oxygen [O(3P)] upon irradiation, and as such, they have been used to create a condensed phase reactivity profile for O(3P). However, thiols, which are highly reactive with O(3P) in the gas phase, were not previously investigated. An earlier study of O(3P) with proteins in solution indicated a preference for thiols. A further investigation of the apparent thiophilicity provided the subject for this study. DBTO was employed as a putative O(3P)-precursor. However, the effective rate of O(3P) formation was found to be dependent on reactant concentrations in certain cases. All reactants were found to increase the rate of deoxygenation to some extent, but in the presence of reactants containing an alcohol linked to a reactive functional group, deoxygenation occurred substantially more rapidly. The rate enhancement was quantified and attributed to the reaction of activated O atom within the solvent cage prior to escape into the bulk solution. Through competition experiments, the relative rate constants of O(3P) with thiols and other functional groups were found. A small preference for primary thiols was observed over other thiols, sulfides, and alkenes. A much larger preference was observed for thiols, sulfides, and alkenes over aromatic groups. In summary, DBTO was successfully used as an O(3P)-precursor, and the thiophilicity of O(3P) was confirmed and quantified.

Synthesis of asymmetrical dibenzothiophene sulfonate esters

Asymmetrical dibenzothiophene sulfonate esters are key intermediates in the production of site specific dibenzothiophene-S-oxide (DBTO) analogs and are potentially efficacious in the production of organic light-emitting diodes (OLEDs). The synthesis of these asymmetrical DBTs requires a less direct, yet efficient, pathway utilizing Suzuki coupling to add primary alkyl, secondary alkyl, aromatic, and vinylic substituents to the DBT sulfonate ester. The coupling reactions produce a small library of asymmetrical dibenzothiophene sulfonate esters ranging from low to good yield.

Photodeoxygenation of dinaphthothiophene, benzophenanthrothiophene, and benzonaphthothiophene S-oxides.

Photoinduced deoxygenation of dibenzothiophene S-oxide (DBTO) has been suggested to release atomic oxygen [O((3)P)]. To expand the conditions and applications where O((3)P) could be used, generation of O((3)P) at longer wavelengths was desirable. The sulfoxides benzo[b]naphtho-[1,2,d]thiophene S-oxide, benzo[b]naphtho[2,1,d]thiophene S-oxide, benzo[b]phenanthro[9,10-d]thiophene S-oxide, dinaphtho[2,1-b:1',2'-d]thiophene S-oxide, and dinaphtho[1,2-b:2',1'-d]thiophene S-oxide all absorb light at longer wavelengths than DBTO. To determine if these sulfoxides could be used to generate O((3)P), quantum yield studies, product studies, and computational analysis were performed. Quantum yields for the deoxygenation were up to 3 times larger for these sulfoxides compared to DBTO. However, oxidation of the solvent by these sulfoxides resulted in different ratios of oxidized products compared to DBTO, which suggested a change in deoxygenation mechanism. Density functional calculations revealed a much larger singlet-triplet gap for the larger sulfoxides compared to DBTO. This led to the conclusion that the examined sulfoxides could undergo deoxygenation by two different mechanisms.

Determination of sulfoxide bond dissociation enthalpies of dibenzothiophene S‐oxide derivatives with computational methods

Photodeoxygenation of dibenzothiophene S‐oxide (DBTO) has been suggested as a clean way to generate atomic oxygen in solution. Sulfoxide bond dissociation enthalpies (BDEs) are important to the quantum yield and mechanism of this photodeoxygenation. In this study, BDE of substituted DBTO molecules with various functional groups were determined using M062X/aug‐cc‐pV(T + d)Z and MP2/aug‐cc‐pV(T + d)Z levels of theory. The sulfoxide BDE was determined using an isodesmic reaction. The observed effect of substitution was that functional groups with negative σpara values (electron donating) strengthen the sulfoxide bond and that substituents with positive σpara values (electron withdrawing) weaken the sulfoxide bond. The Mulliken charge on sulfur for DBTO and the corresponding dibenzothiophene were identified as a suitable indicator of the predicted S–O BDE. Moreover, steric and hydrogen bonding interactions were found to affect sulfoxide BDE for certain functional groups when located at the 1 or 4 positions of the substituted DBTO. Copyright © 2014 John Wiley & Sons, Ltd.

Photoinduced DNA cleavage by atomic oxygen precursors in aqueous solutions

Reactive oxygen species are known to induce DNA strand cleavage and have been explored as treatments for cancer. The development of aqueous-soluble dibenzothiophene-S-oxide (DBTO) derivatives has made it possible to investigate the mechanism of DNA cleavage by these photoactivatable precursors of atomic oxygen. In addition to the release of atomic oxygen, DBTO can also undergo other processes such as α-cleavage. An objective of this work was to establish whether the extent of strand scission could be attributed to a direct reaction between atomic oxygen and DNA. To accomplish this aim, the extent of strand cleavage upon irradiation of three different DBTO derivatives was measured by the conversion of circular pUC19 plasmid (Form I) to nicked (Form II) as monitored by gel electrophoresis. The interaction of the sulfoxides with DNA was systematically studied by optical melt and fluorescence anisotropy experiments. Thiols are susceptible to rapid oxidation by atomic oxygen, and thus, glutathione was used as a ROS scavenger to determine if DNA cleavage was induced by the release of atomic oxygen. The results from these experiments indicated atomic oxygen was at least partially responsible for the observed strand scission.

Deoxygenation of dibenzothiophene- S-oxide and dibenzoselenophene-Se-oxide: A comparison of direct and sensitized photolysis

Photolysis of dibenzothiophene- S-oxide (DBTO) and dibenzoselenophene-Se-oxide (DBSeO) was examined under direct and sensitized conditions. Quantum yield and solvent oxidation data are used to separate the direct irradiation conditions, plus benzophenone-sensitized and anthraquinone-sensitized irradiation of DBSeO, into one mechanistic class. Acridine-sensitized photolysis of DBSeO and triplet sensizitization of DBTO result in deoxygenation, but go by different mechanisms than the direct irradations. The two sensitized cases that appear mechanistically linked to direct photolysis are ones in which the spectroscopic triplet of DBSeO, which is very likely of comparable energy to the Se O BDE, is populated by triplet energy transfer.

Photocleavage of plasmid DNA by dibenzothiophene S-oxide under anaerobic conditions

The ability of dibenzothiophene S-oxide (1) to photochemically induce strand breaks in plasmid DNA was studied under anaerobic conditions. DNA cleavage is monitored by the conversion of closed circular pUC19 DNA (form I) to the nicked (form II) and linear forms (form III) using densitometer digital imaging of ethidium stained gels. In buffered aqueous–acetonitrile (9:1) solutions the single-strand cleavage is efficient and does not require an alkaline reaction workup. Photodeoxygenation of 1 in buffered aqueous–acetonitrile (9{:}1) solutions containing benzene led to the production of phenol. The effect of solvent deuteration does not support the involvement of 1O2 from a sulfoxide dimerization reaction nor a sensitized photooxygenation reaction. The results are interpreted in terms of a sulfoxide photodeoxygenation via oxygen atoms [O(3P)] where oxidation of DNA can lead to single-strand breaks. Since the reaction of O(3P) atoms with water itself is endoergic, we propose that hydroxyl radicals do not intervene in the DNA cleaving reaction.

Deoxygenation and Other Photochemical Reactions of Aromatic Selenoxides1

Atomic oxygen O(3P) is a potent oxidant that has been well-studied in the gas phase. However, exploration of its reactivity in the condensed organic phase has been hampered by the lack of an appropriate source. Dibenzothiophene-S-oxide (DBTO) and related derivatives have been promoted as photochemical O(3P) sources but suffer from low quantum yields. Photolysis of dibenzoselenophene-Se-oxide (DBSeO) results in the formation of dibenzoselenophene and oxidized solvent in significantly higher quantum yields, ca. 0.1. The oxidation product ratios from toluene obtained from the photolysis of dibenzothiophene-S-oxide and the corresponding selenoxide are the same, strongly suggesting a common oxidizing intermediate, which is taken to be O(3P). An additional product, proposed to be the corresponding selenenic ester, is also observed under deoxygenated conditions. The photochemistry of diphenyl selenoxide includes a minor portion of oxidant-forming deoxygenation, in contrast to previous conclusions (Yamazaki, Y.; Tsuchiya, T.; Hasegawa, T. Bull. Chem. Soc. Jpn. 2003, 201-202).

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