Bay-Substitution of Perylene Bisimides with Bidentate Nucleophiles: The Case of Aryloxide Anions.

In this study, we delve into the regioselectivity of nucleophilic reactions involving brominated perylene bisimides (PBIs) and various bidentate aryloxide anions, previously associated with an SRN1 mechanism. We present herein a new perspective, suggesting that a single-electron-transfer aromatic nucleophilic substitution (SeT-SNAr) mechanism is a more plausible scenario. Our study reveals the favorable impact of photostimulation on reaction yields, making our method a convenient approach for accessing O-arylated PBIs.

Combining ZnPc-liposomes and chitosan on a hybrid matrix for enhanced photodynamic therapy.

Photodynamic therapy is an alternative treatment for several pathologies, including cancer. This therapy uses a photosensitizer capable of producing reactive oxygen species through irradiation, promoting cellular death. A limitation of photosensitizers is their low solubility in aqueous media. Hence, developing a suitable carrier for photosensitizers for specific applications is a challenge. Cervical cancer is one of the most common cancers in women, and photodynamic therapy could be an attractive alternative therapeutic approach. In this work, we synthesized films composed of chitosan, polyvinylpyrrolidone, and liposomes containing Zn-phthalocyanine. Photophysical characterization of ZnPc incorporated into films was determined by UV-vis and fluorescence. Film properties such as swelling, mechanical properties, and water vapor permeability were performed. Finally, in vitro, photodynamic evaluation of these films was performed on HeLa cells. The results indicate that incorporating Zn-Pc-liposomes into films decreases cell viability by >95 %.

Photoinactivation of non-tuberculous mycobacteria using Zn-phthalocyanine loaded into liposomes.

Non-tuberculous mycobacteria are a heterogeneous group of environmental bacteria and other than the well-known Mycobacterium tuberculosis complex and Mycobacterium leprae. They could cause localized or disseminated infections. Mycobacterium chelonae and Mycobacterium fortuitum are among the most clinically relevant non-tuberculous mycobacteria species. The infections treatment is complex since they are resistant to antituberculosis drugs and the biofilm formation makes them impermeable to several antibiotics. Antimicrobial photodynamic therapy (aPDT) constitutes an alternative to eliminate pathogens, principally those antimicrobials resistant. Among explored photosensitizers, phthalocyanines are considered excellent, but with a disadvantage: a lack solubility in aqueous media. Consequently, several nanocarriers have been studied in the last years. In this work, a Zn-phthalocyanine into liposomes was evaluated to photoinactivate M. fortuitum and M. chelonae. The results show a higher photodynamic activity of ZnPc into liposomes respect to solution. Furthermore, M. fortuitum was more sensible to aPDT than M. chelonae.

Chalcogen Atoms as Electron Donors in Proton-Coupled Electron Transfer Reactions.

Proton-coupled electron transfer (PCET) reactions are crucial for the optimal functioning of a broad scope of chemical and biological processes. In this report, we present an unprecedented type of concerted PCET (cPCET), in which a chalcogen atom acts as the electron donor. The nature of this mechanism is key for understanding the reactivity of different radical-trapping antioxidants having heavy chalcogens (S, Se, or Te) in their structures. Moreover, this chalcogen-assisted cPCET is likely to be occurring in multiple systems of biological interest.

1-Substituted Perylene Derivatives by Anionic Cyclodehydrogenation: Analysis of the Reaction Mechanism.

Perylene derivatives constitute a promising class of compounds with technological applications mainly due to their optoelectronic properties. One mechanism proposed to synthesize them, starting from binaphthyl derivatives, is anionic cyclodehydrogenation (under reductive conditions). However, the scope of this reaction is limited. In the present study, we report a theoretical and experimental analysis of this particular reaction mechanism for its use in the synthesis of 1-substituted perylenes. Different substituents at position 2 of 1,1'-binaphthalene were evaluated: -OCH3, -OSi(CH3)2C(CH3)3, and -N(CH3)2. Based on density functional theory (DFT) calculations on the proposed mechanism, we suggest that the cyclization takes place from binaphthyl dianion instead of its radical anion. This dianion has an open-shell diradical nature, and this could be the species that was detected by EPR in previous studies. The O-substituted derivatives could not afford the perylene derivatives since their radical anions fragment and the necessary binaphthyl dianion could not be formed. On the other hand, 49% of N,N-dimethylperylen-1-amine was obtained starting from the N-substituted 2-binapthyl derivative as a substrate, employing a simpler experimental methodology.

Betanidin pK a Prediction Using DFT Methods.

Betalains can be used in food, drugs, and cosmetic industries and have shown their bioactive potential. These properties are strongly influenced by pH and other physicochemical conditions. The pK a values for the polyprotic Betanidin (Bd) molecule are unknown, and they are crucial to elucidate the oxidation mechanism in which its pigment is involved. In the present study, the values of pK a for all protic groups of Bd were analyzed using five hybrid density functionals (B3LYP, B3PW91, ωB97XD, PBE0, and M06-2X), five basis sets (6-31+G(d), 6-31+G(d,p), 6-31++G(d,p), 6-311+G(d,p), and 6-311++G(d,p)) and the solvation model based on density (SMD) implicit solvation model. Moreover, one and three explicit water molecules were added to improve the solvation free energy values. Furthermore, the values of pK a of betanin, betalamic acid, and cyclo-dihydroxyphenylalanine (DOPA) were studied. Based on these analyses, we propose the acid-base behavior of Bd in water and develop new tools to understand their chemical reactivity.

Zn phthalocyanines loaded into liposomes: Characterization and enhanced performance of photodynamic activity on glioblastoma cells.

Photodynamic therapy (PDT) is considered a promising strategy for cancer treatment. PDT utilizes light in combination with a photosensitizer (PS) to induce several phototoxic reactions. Phthalocyanines (Pcs), a second generation of photosensitizers, have been studied in several cancer models. Among these, Pcs, have become of interest for the treatment of glioblastomas which are one of the most common and aggressive forms of tumors of the central nervous system. Due to the lipophilic nature of Pcs and their limited solubility in water, Pcs can be loaded in liposomes. In this work, we characterized liposomes of ZnPc and TAZnPc and their effectiveness to photoinactivate glioblastoma cells, was evaluated. Both Pcs show an increase in their photosensitizing activity when they were administrated in Dipalmitoylphosphatidylcholine-cholesterol liposomes compared to Pcs administrated in dimethylformamide.

Arenium cation or radical cation? An insight into the cyclodehydrogenation reaction of 2-substituted binaphthyls mediated by Lewis acids.

Perylene and its derivatives are some of the most interesting chromophores in the field of molecular design. One of the most employed methodologies for their synthesis is the cyclodehydrogenation of binaphthyls mediated by Lewis acids. In this article, we investigated the cyclodehydrogenation reaction of 2-substituted binaphthyls to afford the bay-substituted perylene. By using AlCl3 as a Lewis acid and high temperatures (the Scholl reaction), two new products bearing NH2 and N(CH3)2 groups at position 2 of the perylene ring were synthesized. Under these conditions, we were also able to obtain terrylene from ternaphthalene in 38% yield after two cyclodehydrogenation reactions in a single step. The attempts to promote the formation of a radical cation (necessary intermediary for the oxidative aromatic coupling mechanism) by using FeCl3 or a strong oxidant like 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) did not yield the expected products. DFT calculations suggested that the lack of reaction for oxidative aromatic coupling is caused by the difference between the oxidation potentials of the donor/acceptor couple. In the case of the Scholl reaction, the regiochemistry involved in the formation of the σ-complex together with the activation energy of the C-C coupling reaction helped to explain the differences in the reactivity of the different substrates studied.

Impact of benzannulation on ESIPT in 2-(2'-hydroxyphenyl)-oxazoles: a unified perspective in terms of excited-state aromaticity and intramolecular charge transfer.

Hydroxyphenyl-azoles are among the most popular ESIPT (Excited State Intramolecular Proton Transfer) scaffolds and as such, they have been thoroughly studied. Nevertheless, some aspects regarding the interplay between the emissive properties of these fluorophores and the size of their π-conjugated framework remain controversial. Previous studies have demonstrated that benzannulation of 2'-hydroxyphenyl-oxazole at the phenol group of the molecule can lead to either red- or blue-shifted fluorescence emission, depending on the site where it occurs. In this report, benzannulation at the heterocyclic unit (the oxazole site) is analysed in order to get the whole picture. The extension of π-conjugation does not significantly affect the ESIPT emission wavelength, but it leads instead to higher energy barriers for proton transfer in the first excited singlet state, as a consequence of dramatic changes in the charge transfer character of excitation caused by successive benzannulation. Theoretical calculations revealed an interesting connection between intramolecular charge transfer and excited-state aromaticity in the S1 state. The theoretical approach presented herein allows the behaviour of hydroxyphenyl-oxazoles in the excited state to be rationalized and, more generally, a deeper understanding of the factors governing the ESIPT process to be obtained, a crucial point in the design of new and efficient fluorophores.

Adiabatic deprotonation as an important competing pathway to ESIPT in photoacidic 2-phenylphenols.

ESIPT (Excited State Intramolecular Proton Transfer) to C atom in 2-phenylphenol is known to be an intrinsically inefficient process. However, to the best of our knowledge, a structure-ESIPT efficiency relationship has not been elucidated yet. Here, we show that there exists a competitive interplay between photoacidity and ESIPT efficiency for the 2-phenylphenol system. The attachment of electron withdrawing groups to the phenol moiety promotes adiabatic deprotonation in the excited state and diminishes the charge transfer character of the excitations, and both these factors contribute in decreasing the ESIPT reaction yield. On the other hand, unfavorable conformational distribution in the ground state also appears as another important aspect responsible for the low ESIPT extent of 2-phenylphenol. A new derivative bearing electron donating, bulky substituents at ortho and para positions of the phenol ring shows an outstanding ESIPT performance, which demonstrates that the efficiency of the process can be significantly enhanced by modifying the substitution pattern. We anticipate that our results will help to guide the molecular designing of new compounds with high ESIPT efficiency.

Effectiveness of ZnPc and of an amine derivative to inactivate Glioblastoma cells by Photodynamic Therapy: an in vitro comparative study.

Glioblastoma multiforme is considered to be one of the most aggressive types of tumors of the central nervous system, with a poor prognosis and short survival periods of ~ one year. The current protocol for glioblastoma treatment includes the surgical excision of the primary tumor followed by radio and chemotherapy. Photodynamic therapy (PDT) is considered a promising strategy for the treatment of several types of tumors. Phthalocyanines (Pcs) are good photosensitizers (PSs) for PDT because they induce cell death in several cellular models. ZnPc (Zn(II)phthalocyanine) is a well-known Pc, extensively tested in different cells and tumor models, but its evaluation on a glioblastoma model has been poorly studied. Herein, we compare the capacity of ZnPc and one of its derivatives, Zn(II)tetraminephthalocyanine (TAZnPc), to photoinactivate glioblastoma cells (T98G, MO59, LN229 and U87-MG) in culture. We measured the cellular uptake, the toxicity in the dark and the subcellular localization of the different Pcs, as well as the clonogenic capacity of surviving cells after PDT. The mechanism of cell death induced after PDT was determined by measuring caspase 3 activation, DNA fragmentation, phosphatidylserine externalization, mitochondrial morphological changes and loss of mitochondrial membrane potential as well as lysosomal membrane integrity. Overall, ZnPc and TAZnPc present good properties to be used as PSs with photoinactivation capacity on glioblastoma cells.

Contribution of organic acids to α-terpinene antioxidant activity.

DPPH scavenging activity and antioxidant activity in canola oil of α-terpinene, BHT (butylated hydroxytoluene) and acetic, malic and citric acids and their mixtures were determined to examine the synergistic effect on the antioxidant activity. The results demonstrated that α-terpinene and organic acids had low or any activity against DPPH and BHT showed an IC50 of 0.035 mM. When mixed with organic acids, α-terpinene increased its activity showing a synergistic effect. The mix of α-terpinene (1.58 mM) and citric acid (2.91 mM) showed the higher synergistic effect in DPPH (121.82). BHT scavenging activity was inhibited by organic acids. Although the DPPH scavenging activity was enhanced for α-terpinene and inhibited for BHT by organic acids, the antioxidant activity in canola oil was not. It indicated that the scavenging DPPH activity and antioxidant activity in canola oil of a compound or a mixture of compounds are not always positively correlated with each other.

Photodynamic inactivation of multiresistant bacteria (KPC) using zinc(II)phthalocyanines.

The worldwide increase in antibiotic resistance has led to search of alternatives anti-microbial therapies such as photodynamic inactivation. The aim of this paper was to evaluate the photodynamic activity in vitro of a neutral and two cationic Zn phthalocyanines. Their photokilling activity was tested on Escherichia coli ATCC 25922 and Klebsiella pneumoniae Carbapenemase (KPC)-producing. After treating bacteria with phthalocyanines, the cultures were irradiated with white light. As a result, the bacteria were inactivated in presence of cationic phthalocyanines. The photoinactivation was dependent of the irradiation time and phthalocyanine concentration. The most effective photosensitizer on KPC-producing was Zinc(II)tetramethyltetrapyridino[2,3-b:2',3'-g:2″,3″-l:2‴,3‴-q]porphyrazinium methylsulfate (ZnTM2,3PyPz). After irradiation using the water soluble ZnTM2,3PyPz (3µM) the viability of KPC (30min of irradiation) and E. coli (10min of irradiation) decreased ≈99.995%.

Effect of different C3-aryl substituents on the antioxidant activity of 4-hydroxycoumarin derivatives.

The antioxidant activity of 4-hydroxycoumarin synthetic derivatives and 4-methylumbelliferone were determined taking 4-hydroxycoumarin as the reference compound. Six 3-aryl-4-hydroxycoumarin derivatives were synthesized from 4-hydroxycoumarin as precursor in order to evaluate changes in their antioxidant properties due to C3-aryl substituent nature. Free radical scavenging capacities of these compounds against two different species DPPH(·) and ABTS(·+) and the protecting ability towards the ß-carotene-linoleic acid co-oxidation enzymatically induced by lipoxygenase were measured. In addition, the relationship between the activities of these molecules against DPPH radical and the bond dissociation energy of O-H (BDE) calculated using methods of computational chemistry was evaluated.

A different route to the synthesis of 9,10-disubstituted phenanthrenes.

We here report the synthesis of 10-aryl-9-hydroxy- and 10-aryl-9-aminophenanthrenes by reaction of the anions of 9-phenanthrol and 9-aminophenanthrene, respectively, with aryl halides (iodobenzene, 4-iodoanisole, 9-bromophenantrene). Good yields of 9,10-disubstituted phenanthrenes were obtained in these reactions (>75% and approximately 50% for the 9-amino and 9-hydroxyphenanthrene rings, respectively). Extension of the procedure to the reaction of both anions with o-dihalobenzenes leads to the synthesis of the ring closure products (aza- or oxa-indeno[1,2-l]phenanthrene), which bear a pentacyclic aromatic condensed ring system, although in lower overall yields (approximately 35%).

Diastereoselective C-arylation of prochiral enolates by the SRN1 reaction.

Chiral phenyl acetamide enolate ions were diastereoselectively arylated using aromatic substrates by means of the S(RN)1 reaction. The substitution took place with a diastereomeric excess that varied from 31-98%, depending on the enolate counterion, the reaction temperature, the solvent, and the aromatic substrate. The absolute configuration of the new stereogenic center of the products (4R,5S)-1,5-dimethyl-4-phenyl-3-[2'-phenyl-2'-arylacetyl]-imidazolidin-2-one (Aryl = 3-quinolyl, 1-naphthyl, 4-anisyl, 4-benzonitryl, 4-tolyl, 9-phenanthryl) was determined by (1)H NMR spectroscopy and theoretical calculations.

Conformational studies of novel antiretroviral analogs of zidovudine.

Conformational properties of three novel zidovudine analogs, namely 3'-azido-3'-deoxy-5'-O-isonicotinoylthymidine (AZT-Iso, 2), (-)-trans-(5S,6S)-5-bromo-6, 5'-epoxy-5,6-dihydro-3'-azido-3'-deoxythymidine (3) and (+)-trans-(5R,6R)-5-bromo-6,5'-epoxy-5,6-dihydro-3'-azido-3'-deoxythymidine (4), have been investigated by AM1 calculations and NMR studies, and compared with those of the parent nucleoside (AZT, 1). Based on the results obtained the following correlation may be established, a) AZT and AZT-Iso exhibit a conformational behavior analog to other pyrimidinic nucleosides, displaying a dynamic equilibrium in solution where the two conformers (North and South) undergo a constant transformation. b) Compounds 3 and 4 show a different conformational profile. The estimate of the pseudorotation phase angle reveals the rigid structures of the latter compounds, which do not evidence conformational equilibrium in solution; the azide group being the only group free to rotate. c) Diastereoisomers 3 and 4 exhibit an extra conformational parameter compared with other pyrimidinic nucleosides: the chair or boat conformation in the third ring formed between the sugar and the base. In all cases, a reasonable correlation was obtained between theoretical and NMR spectroscopic data.