Riboflavin-Induced DNA Damage and Anticancer Activity in Breast Cancer Cells under Visible Light: A TD-DFT and In Vitro Study.

Targeted treatments for breast cancer that minimize harm to healthy cells are highly sought after. Our study explores the potentiality of riboflavin as a targeted anticancer compound that can be activated by light irradiation. Here, we integrated time-dependent density functional theory (TD-DFT) calculations and an in vitro study under visible light. The TD-DFT calculations revealed that the electronic charge transferred from the DNA base to riboflavin, with the most significant excitation peak occurring within the visible light range. Guided by these insights, an in vitro study was conducted on the breast cancer cell lines MCF-7 and MDA-MB-231. The results revealed substantial growth inhibition in these cell lines when exposed to riboflavin under visible light, with no such impact observed in the absence of light exposure. Interestingly, riboflavin exhibited no/minimal growth-inhibitory effects on the normal cell line L929, irrespective of light conditions. Moreover, through EtBr displacement (DNA-EtBr) and the TUNEL assay, it has been illustrated that, upon exposure to visible light, riboflavin can intercalate within DNA and induce DNA damage. In conclusion, under visible light conditions, riboflavin emerges as a promising candidate with a selective and effective potent anticancer agent against breast cancer while exerting a minimal influence on regular cellular activity.

Chemical versatility of azide radical: journey from a transient species to synthetic accessibility in organic transformations.

The generation of azide radical (N3˙) occurs from its precursors primarily via a single electron transfer (SET) process or homolytic cleavage by chemical methods or advanced photoredox/electrochemical methods. This in situ generated transient open-shell species has unique characteristic features that set its reactivity. In the past, the azide radical was widely used for various studies in radiation chemistry as a 1e- oxidant of biologically important molecules, but now it is being exploited for synthetic applications based on its addition and intermolecular hydrogen atom transfer (HAT) abilities. Due to the significant role of nitrogen-containing molecules in synthesis, drug discovery, biological, and material sciences, the direct addition onto unsaturated bonds for the simultaneous construction of C-N bond with other (C-X) bonds are indeed worth highlighting. Moreover, the ability to generate O- or C-centered radicals by N3˙ via electron transfer (ET) and intermolecular HAT processes is also well documented. The purpose of controlling the reactivity of this short-lived intermediate in organic transformations drives us to survey: (i) the history of azide radical and its structural properties (thermodynamic, spectroscopic, etc.), (ii) chemical reactivities and kinetics, (iii) methods to produce N3˙ from various precursors, (iv) several significant azide radical-mediated transformations in the field of functionalization with unsaturated bonds, C-H functionalization via HAT, tandem, and multicomponent reaction with a critical analysis of underlying mechanistic approaches and outcomes, (v) concept of taming the reactivity of azide radicals for potential opportunities, in this review.

Photocatalytic Conversion of Benzyl Alcohols/Methyl Arenes to Aryl Nitriles via H-Abstraction by Azide Radical.

This report presents the visible-light-assisted synthesis of aryl nitriles from easily accessible alcohols or methyl arenes in the presence of O2 . Organic photoredox catalyst, 4CzIPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene), induces single electron transfer (SET) from azide N3 - and generates azide radical N3 ⋅.The photogenerated N3 ⋅ abstracts H atom from α-C-H bond of benzylic system, which provides aldehyde and hydrazoic acid (HN3 ) in situ. This reaction subsequently forms azido alcohol intermediate that transforms into nitrile with the assistance of triflic acid (Brønsted acid). A range of alcohols and methyl arenes successfully underwent cyanation at room temperature with good to excellent yields and showed good functional group tolerance.

Organophotoredox-Mediated Amide Synthesis by Coupling Alcohol and Amine through Aerobic Oxidation of Alcohol.

The combination of an organic photocatalyst [4CzIPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6 dicyanobenzene) or 5MeOCzBN (2,3,4,5,6-pentakis(3,6-dimethoxy-9 H-carbazol-9-yl)benzonitrile)], quinuclidine, and tetra-n-butylammonium phosphate (hydrogen-bonding catalyst) was employed for amide bond formations. The hydrogen-bonded OH group activated the adjacent C-H bond of alcohols towards hydrogen atom transfer (HAT) by a radical species. The quinuclidinium radical cation, generated through single-electron oxidation of quinuclidine by the photocatalyst, employed to abstract a hydrogen atom from the α-C-H bond of alcohols selectively due to a polarity effect-produced α-hydroxyalkyl radical, which subsequently converted to the corresponding aldehyde under aerobic conditions. Then the coupling of the aldehyde and an amine formed a hemiaminal intermediate that upon photocatalytic oxidation produced the amide.

Direct Oxygenation of C-H Bonds through Photoredox and Palladium Catalysis.

This report presents the oxygenation of C-H bonds via the merger of photocatalysis and Pd catalysis. Herein, we describe the utilization of a photocatalyst to oxidize an organopalladium(II) intermediate to high-valent PdIII or PdIV intermediates, which promotes the formation of C-O bonds. The demonstrated method works efficiently with various directing groups, such as oxime ether and benzothiazole. The applicability of this direct C-O bond formation method is shown by synthesizing several metal complexes of 2-(benzo[d]thiazol-2-yl)phenol that can be used in organic light-emitting diodes and pharmaceuticals.

One- and Two-Photon-Activated Cysteine Persulfide Donors for Biological Targeting.

Persulfides have been considered as potential signaling compounds similar to the H2S in "S-persulfidation", a sulfur-mediated redox cycle. The research of this sulfur-mediated species is hindered because of the lack of efficient persulfide donors. In this current study, we have developed one- and two-photon-activated persulfide donors based on an o-nitrobenzyl (ONB) phototrigger, which releases the biologically active persulfide (N-acetyl l-cysteine persulfide, NAC-SSH) in a spatiotemporal manner. Next, we have demonstrated the detection of persulfide release both qualitatively and quantitatively using the well-known "turn on" fluorescence probe, that is, monobromobimane, and the trapping agent, that is, 2,4-dinitrofluorobenzene, respectively. Furthermore, we examined the cytotoxicity of synthesized persulfide donors on HeLa cells and the cytoprotective ability in the highly oxidizing cellular environment.

o-Hydroxycinnamate for sequential photouncaging of two different functional groups and its application in releasing cosmeceuticals.

We demonstrated a new approach for the sequential photouncaging of two different functional groups from o-hydroxycinnamate. The second caged molecule initially remains in the locked state and is released only after attaining its unlocked state upon in situ generation of the second phototrigger, i.e., coumarin, thereby leading to the sequential release of alcohol and carboxylic acid. We have utilised the above strategy for the controlled release of cosmeceutical agents.

A water soluble light activated hydrogen sulfide donor induced by an excited state meta effect.

We have utilized an m-amino benzyl based photoremovable protecting group (PRPG) to develop a new water soluble H2S donor. It efficiently releases H2S on demand in a spatio-temporally controlled fashion by an excited state "meta effect" with good chemical and photochemical quantum yield in an aqueous environment. The efficient photorelease of H2S under physiological conditions was also demonstrated by in vitro studies.

Real-time monitoring of a photoactivated hydrogen persulfide donor for biological entities.

Hydrogen persulfide (H2S2) plays an important role in sulfur-based redox signaling mechanisms. Herein, we developed a visible light activated ESIPT based H2S2 donor using a p-hydroxyphenacyl phototrigger. The unique feature of the designed H2S2 donor system is the ability to monitor the H2S2 release in real time through a non-invasive fluorescence color change approach, with the color changing from green to blue. Next, we demonstrated the detection and quantification of H2S2 using a fluorescein based "turn-on" fluorescent probe. Furthermore, in vitro studies of the designed H2S2 donor demonstrated the real-time monitored H2S2 release and cytoprotective ability in the highly oxidizing cellular environment of MDA-MB-468 cells.

One- and two-photon responsive sulfur dioxide (SO2) donors: a combinatorial drug delivery for improved antibiotic therapy.

One- and two-photon activated sulfur dioxide donors based on a 4,5-dimethoxy-2-nitrobenzyl phototrigger have been developed. The designed donors have the ability to release not only SO2 but also a hydroxy-compound in a simultaneous manner. Furthermore, we demonstrated their application in combinatorial therapy by the dual release of SO2 and an active drug, i.e. ferulic acid ethyl ester (FAEE) with self-monitoring ability. Next, we investigated the in vitro cellular uptake and the capability of SO2 generation from the donors using a well-known coumarin-hemicyanine fluorescent probe. Finally, we evaluated the antibacterial activity of the designed donors (5a, 5b and 6) by broth dilution and agar well diffusion methods on E. cloacae cells (MTCC 509). The results show that the donor 5a exhibits enhanced antibacterial efficacy compared to 5b and 6, due to the synergetic effect of dually released SO2 and FAEE.

Tetraphenylethylene conjugated p-hydroxyphenacyl: fluorescent organic nanoparticles for the release of hydrogen sulfide under visible light with real-time cellular imaging.

Hydrogen sulfide (H2S) behaves like a two-edged sword, at low concentrations it has beneficial and cytoprotective effects, while at higher concentrations it exhibits toxicity. Hence there is a keen interest in developing light responsive H2S donors with a spatio-temporal controlled release. Herein, we report visible light activatable tetraphenylethylene conjugated p-hydroxyphenacyl (TPE-pHP-H2S) nanoparticles for the release of hydrogen sulfide (H2S) with a real time monitoring ability. Our newly designed photoresponsive single component organic nanoparticle based H2S donor is built by integrating the tetraphenylethylene (TPE) moiety and p-hydroxyphenacyl (pHP) group so that it can display both aggregation-induced emission (AIE) and excited state intramolecular proton transfer (ESIPT) properties. Aggregation-induced emission enhancement was exhibited by our TPE-pHP-H2S NP donor, which was then explored for the cellular imaging application. The ESIPT by the pHP moiety provided unique advantages to our TPE-pHP-H2S NP donor which include (i) the excitation wavelength extended to >410 nm (ii) a large Stokes shift (iii) a low inner filter effect and (iv) real-time monitoring of H2S release by a simple fluorescent colour change. In vitro studies showed that the TPE-pHP-H2S NP donor presents excellent properties like real-time monitoring, photoregulated H2S release and biocompatibility.

ESIPT-induced fluorescent o-hydroxycinnamate: a self-monitoring phototrigger for prompt image-guided uncaging of alcohols.

o-Hydroxycinnamate derivatives are well-known phototriggers for fast and direct release of alcohols and amines without proceeding through the cleavage of carbonate or carbamate linkages. Despite these unique features, o-hydroxycinnamates lack extensive applications in biological systems mainly because of their non-fluorescent nature. To overcome this limitation, we have attached a 2-(2'-hydroxyphenyl) benzothiazole (HBT) moiety, capable of rapid excited-state intramolecular proton transfer (ESIPT) to the o-hydroxycinnamate group. The ESIPT effect induced two major advantages to the o-hydroxycinnamate group: (i) large Stokes' shifted fluorescence (orange colour) properties and (ii) distinct fluorescence colour change upon photorelease. In vitro studies exhibited an image guided, photoregulated release of bioactive molecules by the o-hydroxycinnamate-benzothiazole-methyl salicylate conjugate and real-time monitoring of the release action.

Photocaging of Single and Dual (Similar or Different) Carboxylic and Amino Acids by Acetyl Carbazole and its Application as Dual Drug Delivery in Cancer Therapy.

A new fluorescent photoremovable protecting group (FPRPG) based on acetylcarbazole framework has been explored for the first time release of single and dual (similar or different) substrates from single chromophore. Mechanistic studies of the photorelease process revealed that photorelease of two (similar or different) substrates from acetyl carbazole proceeds via a stepwise pathway. Further, we constructed photoresponsive dual drug delivery system (DDS) to release two different anticancer drugs (caffeic acid and chlorambucil, 1 equiv each). In vitro study reveals that our DDS exhibit excellent properties like biocompatibility, cellular uptake, and photoregulated dual drug release.

A p-Hydroxyphenacyl-Benzothiazole-Chlorambucil Conjugate as a Real-Time-Monitoring Drug-Delivery System Assisted by Excited-State Intramolecular Proton Transfer.

Among the well-known phototriggers, the p-hydroxyphenacyl (pHP) group has consistently enabled the very fast, efficient, and high-conversion release of active molecules. Despite this unique behavior, the pHP group has been ignored as a delivery agent, particularly in the area of theranostics, because of two major limitations: Its excitation wavelength is below 400 nm, and it is nonfluorescent. We have overcome these limitations by incorporating a 2-(2'-hydroxyphenyl)benzothiazole (HBT) appendage capable of rapid excited-state intramolecular proton transfer (ESIPT). The ESIPT effect also provided two unique advantages: It assisted the deprotonation of the pHP group for faster release, and it was accompanied by a distinct fluorescence color change upon photorelease. In vitro studies showed that the p-hydroxyphenacyl-benzothiazole-chlorambucil conjugate presents excellent properties, such as real-time monitoring, photoregulated drug delivery, and biocompatibility.

Coumarin-containing-star-shaped 4-arm-polyethylene glycol: targeted fluorescent organic nanoparticles for dual treatment of photodynamic therapy and chemotherapy.

Single component fluorescent organic polymeric nanoparticles (NPs) have been synthesized based on a star shaped 4-arm PEG containing coumarin chromophore for the concomitant employment of photodynamic therapy (PDT) and chemotherapy synergistically to wipe out tumour cells with a high efficiency. Polymeric NPs are emerging as the most promising nanoparticulates in the area of drug delivery systems due to their ability to overcome the disadvantages like premature and imprecise control over the drug release, lack of loading capacity etc. Among polymeric NPs, star shaped branched polymers have attracted great attention mainly due to their multiple functionalization properties. Hence, herein we have made use of a multi-arm PEG, functionalized with a targeting unit biotin and a coumarin fluorophore for site-specific and image guided synergic treatment of cancer cells. The anticancer drug chlorambucil is released by the coumarin chromophore in a photocontrolled manner. In addition to that, coumarin also generated singlet oxygen upon irradiation with UV/vis light (≥365 nm) with a moderate quantum yield of ∼0.37. In vitro application of thus prepared organic polymeric nanoparticles (PEG-Bio-Cou-Cbl) in the HeLa cell line shows a reduction of cell viability by up to ∼5% in the case of a combined treatment of PDT and chemotherapy whereas analogous organic polymeric NPs without the chemotherapeutic drug (PEG-Bio-Cou) result in ∼49% cell viability by means of PDT process only.

Benzo[a]acridinylmethyl esters as pH sensitive fluorescent photoactive precursors: synthesis, photophysical, photochemical and biological applications.

A newsworthy class of carboxylate esters based on the (benzo[a]acridin-12-yl)methyl (BAM) chromophore has been shown to perform dual functions as a "pH sensitive fluorescent probe" and a "phototrigger" for acids. The photophysical properties of all the BAM ester conjugates were investigated and found to be highly sensitive to solvent polarity, H-bonding capability and pH of the environment. On irradiation using UV light (≥410 nm), BAM ester conjugates underwent heterolytic cleavage of C-O bonds resulting in efficient release of carboxylic and amino acids. Interestingly, the newly synthesized BAM chromophore was also explored for the construction of a drug delivery system (DDS). In the current DDS, the BAM chromophore plays two important roles: (i) a "fluorophore" for cell imaging and (ii) a "phototrigger" for the drug release. In vitro biological studies revealed that the newly developed BAM based DDS has a good biocompatibility, cellular uptake properties and efficient photoregulated anticancer drug release ability.

Effect of feeding graded doses of Citrinin on clinical and teratology in female Wistar rats.

Citrinin is the one of the well-known mycotoxins, which is possibly spread all over the world. The graded doses of citrinin (1, 3 and 5 ppm CIT in feed) in female Wistar rats 10 weeks prior to mating, during mating and during organogenesis resulted in resorptions and post implantation losses, decreased fetal body weights and crown-rump lengths in fetuses of all groups. Various developmental anomalies recorded in fetuses of treated rats included gross (wrist drop, curled tail, stretched forelimb, subcutaneous haematoma), skeletal (incomplete ossification of skull bones, incomplete fusion of vertebral bodies, complete and partial agenesis of sternaebrae, metacarpals, metatarsals and phalanges, fused ribs and swing out ribs) and visceral (internal and external hydrocephalus, cerebellar hypoplasia, microphthalmia, roundening of heart, contracted kidneys, dilated renal pelvis and cryptorchid testes). The results suggest that CIT has adverse effects on fetal development which may be due to the longer bioavailability of citrinin in the animals.

A Molecular Engineering Approach to Achieve Wavelength-Selective Photorelease Using a Dynamic Photocage.

We introduce a molecular engineering strategy for wavelength-selective photorelease of alcohols and carboxylic acids, employing a dynamic photocage featuring an (E)-3-(6-acetyl-2-hydroxynaphthalen-1-yl)acrylate moiety. Initially activated by visible light (λ ≥ 410 nm), it releases alcohol, generating a second photocage. Subsequent exposure to shorter wavelengths (λ ≤ 365 nm) selectively releases carboxylic acid, albeit at a reduced rate.

Two-Photon-Responsive "TICT + AIE" Active Naphthyridine-BF2 Photoremovable Protecting Group: Application for Specific Staining and Killing of Cancer Cells.

The combined effects of twisted intramolecular charge transfer (TICT) and aggregation-induced emission (AIE) phenomena have demonstrated a significant influence on excited-state chemistry. These combined TICT and AIE features have been extensively utilized to enhance photodynamic and photothermal therapy. Herein, we demonstrated the synergistic capabilities of TICT and AIE phenomena in the design of the photoremovable protecting group (PRPG), namely, NMe2-Napy-BF2. This innovative PRPG incorporates TICT and AIE characteristics, resulting in four remarkable properties: (i) red-shifted absorption wavelength, (ii) strong near-infrared (NIR) emission, (iii) viscosity-sensitive emission property, and (iv) accelerated photorelease rate. Inspired by these intriguing attributes, we developed a nanodrug delivery system (nano-DDS) using our PRPG for cancer treatment. In vitro studies showed that our nano-DDS manifested effective cellular internalization, specific staining of cancer cells, high-resolution confocal imaging of cancerous cells in the NIR region, and controlled release of the anticancer drug chlorambucil upon exposure to light, leading to cancer cell eradication. Most notably, our nano-DDS exhibited a substantially increased two-photon (TP) absorption cross section (435 GM), exhibiting its potential for in vivo applications. This development holds promise for significant advancements in cancer treatment strategies.