Competing Photocleavage on Boron and at the -Position in BODIPY Photocages.

BODIPY photocages (photocleavable protective groups) have stirred interest because they can release biologically active cargo upon visible light excitation. We conducted combined theoretical and experimental investigations on selected BODIPY photocages to elucidate the mechanism of the competing photocleavage at the boron and -position. Based on the computations, the former reaction involves elongation of the B-C bond, yielding a tight borenium cation and methyl anion.

Excited-state antiaromaticity relief drives facile photoprotonation of carbons in aminobiphenyls.

A combined computational and experimental study reveals that -, - and -aminobiphenyl isomers undergo distinctly different photochemical reactions involving proton transfer. Deuterium exchange experiments show that the -isomer undergoes a facile photoprotonation at a carbon atom excited-state intramolecular proton transfer (ESIPT). The -isomer undergoes water-assisted excited-state proton transfer (ESPT) and a photoredox reaction proton-coupled electron transfer (PCET).

Dipeptides Containing Pyrene and Modified Photochemically Reactive Tyrosine: Noncovalent and Covalent Binding to Polynucleotides.

Dipeptides and were synthesized from unnatural amino acids containing pyrene as a fluorescent label and polynucleotide binding unit, and modified tyrosine as a photochemically reactive unit. Photophysical properties of the peptides were investigated by steady-state and time-resolved fluorescence. Both peptides are fluorescent ( = 0.

3-Substituted 2-Aminonaphthalene Photocages for Carboxylic Acids and Alcohols; Decaging Mechanism and Potential Applications in Synthesis.

3-Hydroxymethyl-2-aminonaphthalene photocage (photoremovable protecting group) was synthesized and transformed to different ethers and esters to investigate the applicability to decage alcohols and carboxylic acids, respectively. The photoelimination of carboxylic acids takes place relatively efficiently (Φ = 0.11) upon excitation with near-visible light, contrary to the elimination of alcohols.

Antiproliferative activity of meso-substituted BODIPY photocages: Effect of electrophiles vs singlet oxygen.

A series of BODIPY compounds with a methylphenol substituent at the meso-position and halogen atoms on the BODIPY core, or OCH or OAc substituents at the phenolic moiety was synthesized. Their spectral and photophysical properties and the photochemical reactivity upon irradiation in CHOH were investigated. The molecules with the phenolic substituent at the meso-position undergo more efficient photo-methanolysis at the boron atom, while the introduction of the OCH group at the phenolic moiety changes the reaction selectivity towards the cleavage at the meso-position.

Excited State Intramolecular Proton Transfer (ESIPT) from -NH to the Carbon Atom of a Naphthyl Ring.

Excited state intramolecular proton transfer (ESIPT) has been documented from an amino NH group to a carbon atom of an adjacent aromatic ring. This finding changes the paradigm, as hitherto such processes have not been considered as plausible due to slow protonation of carbon and low (photo)acidity of the NH group. The ESIPT was studied by irradiation of 2-(2-aminophenyl)naphthalene in CHCN-DO, whereupon regiospecific incorporation of deuterium takes place at the naphthalene position 1, with a quantum yield of Φ = 0.

Photogeneration of quinone methide from adamantylphenol in an ultrafast non-adiabatic dehydration reaction.

The ultrafast photochemical reaction of quinone methide (QM) formation from adamantylphenol was monitored in real time using femtosecond transient absorption spectroscopy and fluorescence upconversion in solution at room temperature. Experiments were complemented by theoretical studies simulating the reaction pathway and elucidating its mechanism. Excitation with sub-20 fs UV pulses and broadband probing revealed ultrafast formation of the long-lived QM intermediate directly in the ground state, occurring with a time constant of around 100 fs.

Chromo-Orthogonal Deprotection of Carboxylic Acids by Aminonaphthalene and Aminoaniline Photocages.

Photoremovable protecting groups (photocages) based on 1-amino-2-hydroxymethylnaphthalene were developed, and their applicability to release alcohols and carboxylic acids in photohydrolysis was investigated. Compound cannot release alcohol since -demethylation takes place instead. However, the photorelease of carboxylic acids from - was demonstrated on caged substrates, including some nonsteroidal drugs and a neurotransmitter.

Non-Covalent Binding of Tripeptides-Containing Tryptophan to Polynucleotides and Photochemical Deamination of Modified Tyrosine to Quinone Methide Leading to Covalent Attachment.

A series of tripeptides TrpTrpPhe (), TrpTrpTyr (), and TrpTrpTyr[CHN(CH)] () were synthesized, and their photophysical properties and non-covalent binding to polynucleotides were investigated. Fluorescent Trp residues (quantum yield in aqueous solvent Φ = 0.03-0.

Photochemical Reactivity of Naphthol-Naphthalimide Conjugates and Their Biological Activity.

Quinone methide precursors -, with different alkyl linkers between the naphthol and the naphthalimide chromophore, were synthesized. Their photophysical properties and photochemical reactivity were investigated and connected with biological activity. Upon excitation of the naphthol, Förster resonance energy transfer (FRET) to the naphthalimide takes place and the quantum yields of fluorescence are low (Φ ≈ 10).

Wavelength dependent photochemistry of BODIPY-phenols and their applications in the fluorescent labeling of proteins.

A series of BODIPY dyes were synthesized, that were at the 3, or 3 and 5 positions, substituted by photochemically reactive quinone methide (QM) precursor moieties. Fluorescence properties of the molecules were investigated and we demonstrated that the molecules undergo wavelength dependent photochemistry. Photodeamination to deliver QMs takes place only upon excitation to higher excited singlet states, showing unusual anti-Kasha photochemical reactivity.

[3 + 2] Cycloaddition with photogenerated azomethine ylides in β-cyclodextrin.

Stability constants for the inclusion complexes of cyclohexylphthalimide and adamantylphthalimide with β-cyclodextrin (β-CD) were determined by H NMR titration, = 190 ± 50 M, and = 2600 ± 600 M, respectively. Photochemical reactivity of the inclusion complexes and was investigated, and we found out that β-CD does not affect the decarboxylation efficiency, while it affects the subsequent photochemical H-abstraction, resulting in different product distribution upon irradiation in the presence of β-CD. The formation of ternary complexes with acrylonitrile (AN) and or was also essayed by H NMR.

Photoelimination of Nitrogen from Diazoalkanes: Involvement of Higher Excited Singlet States in the Carbene Formation.

Although diazoalkanes are important carbene precursors in organic synthesis, a comprehensive mechanism of photochemical formation of carbenes from diazoalkanes has not been proposed. Synergies of experiments and computations demonstrate the involvement of higher excited singlet states in the photochemistry of diazoalkanes. In all investigated diazoalkanes, excitation to S results in nonreactive internal conversion to S.

Substituted adamantylphthalimides: Synthesis, antiviral and antiproliferative activity.

In this study, three groups of adamantylphthalimides, bearing different substituents at the phthalimide moiety, N-(4'-R )phthalimidoadamantanes (1-7), 3-[N-(4'-R )phthalimido]-1-adamantanols (8-10), and 3-[N-(4'-R )phthalimido]adamantane-1-carboxylic acids (11-15), were synthesized and screened against tumor cells and viruses. The most potent compounds are not substituted at the adamantane and bear an OH or NH substituent at the phthalimide (compounds 3 and 5). The antiproliferative activities of compounds 3 and 5 are in the micromolar range, much higher than the one of thalidomide.

Labeling of Proteins by BODIPY-Quinone Methides Utilizing Anti-Kasha Photochemistry.

A novel approach for the photolabeling of proteins by a BODIPY fluorophore is reported that is based on an anti-Kasha photochemical reaction from an upper singlet excited state () leading to the deamination of the BODIPY quinone methide precursor. On the other hand, the high photochemical stability of the dye upon excitation by visible light to allows for the selective fluorescence detection from the dye or dye-protein adduct, without concomitant bleaching or hydrolysis of the protein-dye adduct. Therefore, photolabeling and fluorescence monitoring can be uncoupled by using different excitation wavelengths.

Formation of Quinone Methides by Ultrafast Photodeamination: A Spectroscopic and Computational Study.

Formation of quinone methides (QMs) by photoelimination of an ammonium salt from cresol derivatives was investigated by femtosecond transient absorption spectroscopy (fs-TA) and computationally by time-dependent density functional theory using the PCM(water)/(TD-)B3LYP/6-311++G(d,p) level of theory. The photoelimination takes place in an adiabatic ultrafast reaction on the S potential energy surface delivering the corresponding QMs(S), which were detected by fs-TA. Computations predicted a high-energy cation intermediate in the pathway between the Franck-Condon state of a monoammonium salt and the corresponding QM(S) that was not detected by fs-TA.

Photoelimination of nitrogen from adamantane and pentacycloundecane (PCU) diazirines: a spectroscopic study and supramolecular control.

Photochemical reactivity of pentacycloundecane (PCU) and adamantane diazirines was investigated by preparative irradiation in different solvents, laser flash photolysis (LFP) and quantum chemical computations. In addition, formation of inclusion complexes for diazirines with cucurbit[7]uril, β- and γ-cyclodextrin (β- and γ-CD) was investigated by 1H NMR spectroscopy, isothermal microcalorimetry and circular dichroism spectroscopy, followed by the investigation of photochemical reactivity of the formed complexes. Diazirines undergo efficient photochemical elimination of nitrogen (ΦR > 0.

Competing photochemical reactions of bis-naphthols and their photoinduced antiproliferative activity.

The photophysical properties and photochemical reactivities of a series of bis-naphthols 4a-4e and bis-anthrols 5a and 5e were investigated by preparative irradiation in CH3OH, fluorescence spectroscopy and laser flash photolysis (LFP). Methanolysis taking place via photodehydration (bis-naphthols: ΦR = 0.04-0.

Photocyclization of Tetra- and Pentapeptides Containing Adamantylphthalimide and Phenylalanines: Reaction Efficiency and Diastereoselectivity.

A series of tetrapeptides and pentapeptides was synthesized bearing a phthalimide chromophore at the N-terminus. The C-terminus of the peptides was strategically substituted with an amino acid, Phe, Phe(OMe), or Phe(OMe) characterized by different oxidation potentials. The photochemical reactivity of the peptides was investigated by preparative irradiation and isolation of photoproducts, as well as with laser flash photolysis.

Photodeamination to quinone methides in cucurbit[n]urils: potential application in drug delivery.

We demonstrate a proof of principle for a new approach in the development of a drug delivery system. A positively charged prodrug (phenol) can form a stable inclusion complex with CB[7], which enables more efficient delivery of the prodrug. After photochemical transformation (photoactivation) inside the complex, an active drug quinone methide (QM) is formed and released from the complex, since it is a neutral molecule and forms a less stable complex with CB[7].

Ultrafast Adiabatic Photodehydration of 2-Hydroxymethylphenol and the Formation of Quinone Methide.

The photochemical reactivity of 2-hydroxymethylphenol (1) was investigated experimentally by photochemistry under cryogenic conditions, by detecting reactive intermediates by IR spectroscopy, and by using nanosecond and femtosecond transient absorption spectroscopic methods in solution at room temperature. In addition, theoretical studies were performed to facilitate the interpretation of the experimental results and also to simulate the reaction pathway to obtain a better understanding of the reaction mechanism. The main finding of this work is that photodehydration of 1 takes place in an ultrafast adiabatic photochemical reaction without any clear intermediate, delivering quinone methide (QM) in the excited state.

Direct Observation of Photoinduced Ultrafast Generation of Singlet and Triplet Quinone Methides in Aqueous Solutions and Insight into the Roles of Acidic and Basic Sites in Quinone Methide Formation.

Femtosecond time-resolved transient absorption spectroscopy experiments and density functional theory computations were done for a mechanistic investigation of 3-(1-phenylvinyl)phenol (1) and 3-hydroxybenzophenone (2) in selected solvents. Both compounds went through an intersystem crossing (ISC) to form the triplet excited states Tππ* and Tnπ* in acetonitrile but behave differently in neutral aqueous solutions, in which a triplet excited state proton transfer (ESPT) induced by the ISC process is also proposed for 2 but a singlet ESPT without ISC is proposed for 1, leading to the production of the triplet quinone methide (QM) and the singlet excited QM species respectively in these two systems. The triplet QM then underwent an ISC process to form an unstable ground state intermediate which soon returned to its starting material 2.

Hydroxymethylaniline Photocages for Carboxylic Acids and Alcohols.

ortho-, meta- and para-Hydroxymethylaniline methyl ethers 3-5-OMe and acetyl derivatives 3-5-OAc were investigated as potential photocages for alcohols and carboxylic acids, respectively. The measurements of photohydrolysis efficiency showed that the decaging from ortho- and meta-derivatives takes place efficiently in aqueous solution, but not for the para-derivatives. Contrary to previous reports, we show that the meta-derivatives are better photocages for alcohols, whereas ortho-derivatives are better protective groups for carboxylic acids.

Selective photocytotoxicity of anthrols on cancer stem-like cells: The effect of quinone methides or reactive oxygen species.

Cancer stem cells (CSCs) are a subpopulation of cancer cells that share properties of embryonic stem cells like pluripotency and self-renewal and show increased resistance to chemo- and radiotherapy. Targeting CSC, rather than cancer cells in general, is a novel and promising strategy for cancer treatment. Novel therapeutic approaches, such as photodynamic therapy (PDT) have been investigated.

Photochemical Formation of Anthracene Quinone Methide Derivatives.

Anthrols 2-7 were synthesized and their photochemical reactivity investigated by irradiations in aq CHOH. Upon excitation with visible light (λ > 400 nm) in methanolic solutions, they undergo photodehydration or photodeamination and deliver methyl ethers, most probably via quinone methides (QMs), with methanolysis quantum efficiencies Φ = 0.02-0.