DNA Photocleavage Activity Research Articles

Bithiophene‐Functionalized Infrared Two‐Photon Absorption Metal Complexes as Single‐Molecule Platforms for Synergistic Photodynamic, Photothermal, and Chemotherapy

AbstractA planar conjugated ligand functionalized with bithiophene and its Ru(II), Os(II), and Ir(III) complexes have been constructed as single‐molecule platform for synergistic photodynamic, photothermal, and chemotherapy. The complexes have significant two‐photon absorption at 808 nm and remarkable singlet oxygen and superoxide anion production in aqueous solution and cells when exposed to 808 nm infrared irradiation. The most potent Ru(II) complex Ru7 enters tumor cells via the rare macropinocytosis, locates in both nuclei and mitochondria, and regulates DNA‐related chemotherapeutic mechanisms intranuclearly including DNA topoisomerase and RNA polymerase inhibition and their synergistic effects with photoactivated apoptosis, ferroptosis and DNA cleavage. Ru7 exhibits high efficacy in vivo for malignant melanoma and cisplatin‐resistant non‐small cell lung cancer tumors, with a 100 % survival rate of mice, low toxicity to normal cells and low residual rate. Such an infrared two‐photon activatable metal complex may contribute to a new generation of single‐molecule‐based integrated diagnosis and treatment platform to address drug resistance in clinical practice and phototherapy for large, deeply located solid tumors.

Bithiophene-Functionalized Infrared Two-Photon Absorption Metal Complexes as Single-Molecule Platforms for Synergistic Photodynamic, Photothermal, and Chemotherapy.

A planar conjugated ligand functionalized with bithiophene and its Ru(II), Os(II), and Ir(III) complexes have been constructed as single-molecule platform for synergistic photodynamic, photothermal, and chemotherapy. The complexes have significant two-photon absorption at 808 nm and remarkable singlet oxygen and superoxide anion production in aqueous solution and cells when exposed to 808 nm infrared irradiation. The most potent Ru(II) complex Ru7 enters tumor cells via the rare macropinocytosis, locates in both nuclei and mitochondria, and regulates DNA-related chemotherapeutic mechanisms intranuclearly including DNA topoisomerase and RNA polymerase inhibition and their synergistic effects with photoactivated apoptosis, ferroptosis and DNA cleavage. Ru7 exhibits high efficacy in vivo for malignant melanoma and cisplatin-resistant non-small cell lung cancer tumors, with a 100 % survival rate of mice, low toxicity to normal cells and low residual rate. Such an infrared two-photon activatable metal complex may contribute to a new generation of single-molecule-based integrated diagnosis and treatment platform to address drug resistance in clinical practice and phototherapy for large, deeply located solid tumors.

Photodynamic Therapy with Targeted Release of Boron-Dipyrromethene Dye from Cobalt(III) Prodrugs in Red Light.

Boron-dipyrromethene (BODIPY) dyes are promising photosensitizers for cellular imaging and photodynamic therapy (PDT) owing to their excellent photophysical properties and the synthetically tunable core. Metalation provides a convenient way to overcome the drawbacks arising from their low aqueous solubility. New photo-/redox-responsive Co(III) prodrug chaperones are developed as anticancer PDT agents for efficient cellular delivery of red-light-active BODIPY dyes. The photobiological activity of heteroleptic Co(III) complexes derived from tris(2-pyridylmethyl)amine (TPA) and acetylacetone-conjugated PEGylated distyryl BODIPY (HL1) or its dibromo analogue (HL2), [CoIII(TPA)(L1/L2)](ClO4)2 (1 and 2), are investigated. The Co(III)/Co(II) redox potential is tuned using the Co(III)-TPA scaffold. Complex 1 displays the in vitro release of BODIPY on red light irradiation. Complex 2, having good singlet oxygen quantum yield (ΦΔ ∼ 0.28 in DMSO), demonstrates submicromolar photocytotoxicity to HeLa cancer cells (IC50 ≈ 0.23 μM) while being less toxic to HPL1D normal cells in red light. Cellular imaging using the emissive complex 1 shows mitochondrial localization and significant penetration into the HeLa tumor spheroids. Complex 2 shows supercoiled DNA photocleavage activity and apoptotic cell death through phototriggered generation of reactive oxygen species. The Co(III)-BODIPY prodrug conjugates exemplify new type of phototherapeutic agents with better efficacy than the organic dyes alone in the phototherapeutic window.

Structural Characterization of Zinc(II)/Cobalt(II) Complexes of Chiral N-(Anthracen-9-yl)methyl-N,N-bis(2-picolyl)amine and Evaluation of DNA Photocleavage Activity.

We designed and synthesized a chiral ligand N-(anthracen-9-ylmethyl)-1-(pyridin-2-yl)-N-(pyridin-2-ylmethyl)ethanamine (APPE) DNA photocleavage agent to investigate the effects of chirality of bis(2-picolyl)amine on the DNA photocleavage activity of metal complexes. The structures of ZnII and CoII complexes in APPE were analyzed via X-ray crystallography and fluorometric titration. APPE formed metal complexes with a 1 : 1 stoichiometry in both the crystalline and solution states. Fluorometric titration was used to show that the ZnII and CoII association constants of these complexes (log Kas) were 4.95 and 5.39, respectively. The synthesized complexes were found to cleave pUC19 plasmid DNA when irradiated at 370 nm. The DNA photocleavage activity of the ZnII complex was higher than that of the CoII complex. The absolute configuration of the methyl-attached carbon did not affect DNA cleavage activity and, unfortunately, an achiral APPE derivative without the methyl group (ABPM) was found to perform DNA photocleavage more effectively than APPE. One reason for this may be that the methyl group suppressed the structural flexibility of the photosensitizer. These results will be useful for the design of new photoreactive reagents.

Click synthesis, antimicrobial, DNA photocleavage and computational studies of oxindole-tethered 1H-1,2,3-triazoles.

Aim: To obtain new hybrids derived from isatin and triazole. Materials & methods: A series of oxindole-1-H-1,2,3-triazole hybrids (4a-l) were synthesized from 3-sulfenylated N-propargylated oxindoles and organic azides employing Cu(I)-catalyzed azide-alkyne cycloaddition. These compounds were evaluated in vitro for antimicrobial activity by the standard serial dilution method and DNA photocleavage activity. Results: Antimicrobial assay revealed that compounds 4l and 4f exhibited promising efficacy against Candida albicans and Rhizopus oryzae, respectively, with aminimum inhibitory concentrationvalue of 0.0008μmol/mL. Compounds 4h and 4k completely degraded plasmid DNA. Further molecular docking of compounds with 1KZN (4j and 4k) and 5TZ1 (4h and 4l) revealed good binding interactions. Conclusion: Results of the current research can help in the development of new antimicrobial agents with high efficacy.

Exploration of the DNA Photocleavage Activity of O-Halo-phenyl Carbamoyl Amidoximes: Studies of the UVA-Induced Effects on a Major Crop Pest, the Whitefly Bemisia tabaci

The DNA photocleavage effect of halogenated O-carbamoyl derivatives of 4-MeO-benzamidoxime under UVB and UVA irradiation was studied in order to identify the nature, position, and number of halogens on the carbamoyl moiety that ensure photoactivity. F, Cl, and Br-phenyl carbamate esters (PCME) exhibited activity with the p-Cl-phenyl derivative to show excellent photocleavage against pBR322 plasmid DNA. m-Cl-PCME has diminished activity, whereas the presence of two halogen atoms reduced DNA photocleavage. The substitution on the benzamidoxime scaffold was irrelevant to the activity. The mechanism of action indicated function in the absence of oxygen, probably via radicals derived from the N-O bond homolysis of the carbamates and in air via hydroxyl radicals and partially singlet oxygen. The UVA-vis area of absorption of the nitro-benzamidoxime p-Cl-PCMEs allowed for the investigation of their potential efficacy as photopesticides under UVA irradiation against the whitefly Bemisia tabaci, a major pest of numerous crops. The m-nitro derivative exhibited a moderate specificity against the adult population. Nymphs were not affected. The compound was inactive in the dark. This result may allow for the development of lead compounds for the control of agricultural insect pests that can cause significant economic damage in crop production.

Bis-pyrimidine Derivatives: Synthesis and Impact of Olefinic/Aromatic Linkers on Antimicrobial and DNA Photocleavage Activity

Bis-pyrimidine Derivatives: Synthesis and Impact of Olefinic/Aromatic Linkers on Antimicrobial and DNA Photocleavage Activity

Ferrocenyl chalcone armed macrocyclic tet a‐based cobalt(II) and copper(II) complexes: DNA photocleavage activity and photocytotoxicity

Ferrocenyl chalcone armed ‘tet a’ macrocyclic cobalt(II) and copper(II) complexes (1) and (2) were synthesised and characterised by various physico‐chemical methodologies. The complexes exhibit Co(II)/Co(I) and Cu(II)/Cu(I) redox couple (quasi‐reversible) with E1/2 value of −0.82 and −0.82 V, respectively. Complex 1 is oxidised as quasi‐reversible two‐electron transfer processes with oxidation potential of E1pa = 0.64 and E1pc = 0.68 V, and complex 2 with oxidation potential of E1pa = 0.62 and E1pc = 0.66 V over 0.37 V of ferrocene was observed. The above scenario is indicating the positive charge destabilisation of mono‐ and dications originating a challenging condition for ferrocene oxidation. The DNA binding abilities of both the complexes (1 and 2) with calf thymus DNA (CT‐DNA) were investigated by spectroscopic studies (absorption/fluorescence) and electrochemical methods. Absorption spectral studies revealed that complexes 1 and 2 bind with CT‐DNA by partial intercalative mode of binding with Kb values of 1.04 × 106 and 7.29 × 105 M−1, respectively. Chemical nuclease activity is exhibited moderately in these complexes generating singlet oxygen (1O2) species and acting as effective photocleavers of pUC19 DNA in the red light region. As irradiated by red light, their cytotoxicity toward MDA‐MB‐231 displays a typical increase in cytotoxicity values. In comparing the dark and red light irradiated cell, MDA‐MB‐231 cells that were exposed to red light exhibited significant morphological alternations. Cell morphological studies were confirmed the morphological changes with dual staining by using AO/EB, Hoechst 33342 and PI against MDA‐MB‐231 cells. Furthermore, complexes 1 and 2 have less toxicity on Artemia nauplii even at higher concentrations, indicating that the synthesised complexes 1 and 2 are biocompatible.

DNA Interaction, DNA Photocleavage, Photocytotoxicity In Vitro, and Molecular Docking of Naphthyl-Appended Ruthenium Complexes.

With the development of metal-based drugs, Ru(II) compounds present potential applications of PDT (photodynamic therapy) and anticancer reagents. We herein synthesized two naphthyl-appended ruthenium complexes by the combination of the ligand with naphthyl and bipyridyl. The DNA affinities, photocleavage abilities, and photocytotoxicity were studied by various spectral methods, viscosity measurement, theoretical computation method, gel electrophoresis, and MTT method. Two complexes exhibited strong interaction with calf thymus DNA by intercalation. Production of singlet oxygen (1O2) led to obvious DNA photocleavage activities of two complexes under 365 nm light. Furthermore, two complexes displayed obvious photocytotoxicity and low dark cytotoxicity towards Hela, A549, and A375 cells.

Synthesis, Photophysical Properties and DNA-Photocleavage Activity of Silicon Phthalocyanine Derivatives

Synthesis, Photophysical Properties and DNA-Photocleavage Activity of Silicon Phthalocyanine Derivatives

Photoinduced DNA Cleavage and Photocytotoxic of Phenanthroline-Based Ligand Ruthenium Compounds.

The photophysical and biological properties of two new phenanthroline-based ligand ruthenium complexes were investigated in detail. Their DNA interaction modes were determined to be the intercalation mode using spectra titration and viscosity measurements. Under irradiation, obvious photo-reduced DNA cleavages were observed in the two complexes via singlet oxygen generation. Furthermore, complex 2 showed higher DNA affinity, photocleavage activity, and singlet oxygen quantum yields than complex 1. The two complexes showed no toxicity towards tumor cells (HeLa, A549, and A375) in the dark. However, obvious photocytotoxicities were observed in the two complexes. Complex 2 exhibited large PIs (phototherapeutic indices) (ca. 400) towards HeLa cells. The study suggests that these complexes may act as DNA intercalators, DNA photocleavers, and photocytotoxic agents.

Biological evaluation, molecular docking, DNA interaction and thermal studies of new bioactive metal complexes of 2‐hydroxybenzaldehyde and fluorobenzamine Schiff base ligand

Schiff base ligand named 2‐((E)‐(2‐fluorophenylimino)methyl)phenol (HL) was prepared by the condensation of 2‐hydroxybenzaldehyde and 2‐fluorobenzamine in 1:1 molar ratio. The coordination behaviour of a series of transition metal ions with the synthesized HL ligand, [Cr(HL)2] (1), [Fe(HL)2] (2), [Co(HL)2] (3) and [Cu(HL)2] (4) is reported. The structure and bonding of the metal complexes have been deduced by analytical and spectral studies. Based on the above studies, the metal centres were found to be octahedral for all the complexes. The activation thermodynamic properties were calculated using the Coats–Redfern method. Thermal decomposition processes of complexes 1, 2, 3 and 4 are non‐spontaneous; that is, the complexes are thermally stable. The positive value of Gibbs free energy of decomposition (ΔG*) for all the complexes is non‐spontaneous processes. DNA binding properties of these metal complexes, investigated using UV–visible absorption, fluorescence and viscosity measurement studies, imply that the complexes bind to DNA by intercalation. The intrinsic binding constant Kb from the electronic absorption studies are 3.12 × 104 M−1, 1.86 × 104 M−1, 3.96 × 104 M−1 and 5.89 × 104 M−1, and the Stern–Volmer quenching constant Ksv values from fluorescence studies are 2.29 × 104 M−1, 1.92 × 104 M−1, 5.62 × 104 M−1 and 8.91 × 104 M−1, for the complexes 1, 2, 3 and 4, respectively. DNA photo cleavage activities of these complexes were studied with supercoiled pUC19 DNA, in the presence of H2O2. GOLD 3.1 program was used to evaluate binding affinities of complexes with human DNA topoisomerase I protein. in vitro cytotoxic and antimicrobial studies revealed higher activity of metal complexes, compared with the ligand.

Synthesis, structural and pharmacological exploration of 2-(3, 5-dimethyl-1H-pyrazol-1-yl)-acetophenone oximes and their silver complexes

Some new compounds, 2-(3,5-dimethyl-1H-pyrazol-1-yl)-4-substituted acetophenone oximes [4a–4f; here, 4-substituent = H (a), Br (b), Me (c), Cl(d), NO2 (e), F (f)] were synthesized by the reaction of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-arylethanones with hydroxylamine hydrochloride. These compounds were characterized by analyzing their IR, 1H, 13C NMR and mass spectral data. Compounds 4a–4f were further converted into their silver complexes (4g–4l) and chemical structures of which were established on the basis of their X-ray crystallographic data. The antibacterial and DNA photocleavage activity studies were carried out for all the synthesized compounds 4a–4l, and it has been found that compound 4l displayed an excellent level of antibacterial and DNA photocleavage activity. Among the series, Ag-complexes (4g–4l) displayed excellent antibacterial activity against four bacterial strains using Ciprofloxacin as a standard drug. In DNA photocleavage study, it has been observed that compounds 4a, 4e, 4f degraded both forms of DNA, whereas their Ag-complexes degraded DNA completely even at a very low concentration. The intermolecular interactions present in 4g and 4h were described by decomposing Hirshfeld surfaces into 2D fingerprint plots. It was observed that non-polar interactions contribute dominantly in overall intermolecular interactions exit in crystals of both the compounds.

Synthesis, structural investigations, and cytotoxic evaluation of a half‐sandwich Ru(II)‐arene complex

We report the design, synthesis, and cytotoxic evaluation of a new organoruthenium(II) complex (1). Complex 1 was characterized by analytical and spectroscopic methods including single crystal X‐ray diffraction studies. Complex 1 crystallized in an orthorhombic crystal system with Pca21 space group with Ru(II) ion p‐cymene arene unit in a usual “piano‐stool” geometry. The DFT and TDFT studies were carried out to provide better insight about the spectral properties of the complex. The Hirshfeld surface analysis plots revealed significant intermolecular interactions within the crystal structure that essentially involve a network of N–H···H, O–H···O, and C–H···O linkages. DNA photocleavage activity revealed oxidative mechanistic pathway with preferential affinity toward minor groove. Cytotoxic studies of complex 1 via SRB assay revealed moderate but selective activity toward pancreatic and cervical cancer cell lines.

Topoisomerase I Inhibition, DNA Photocleavage Activity, and G-Quadruplex DNA ‘Light Switch’ Based on Nitro-Substituted Ruthenium Complexes

Two ruthenium complexes containing nitro-substituted ligand, [Ru(bpy)2(hnpip)](PF6)2 (1) and [Ru(phen)2(hnpip)](PF6)2 (2) (bpy = 2,2'-bipyridine; phen = 1,10-phenanthroline; hnpip = 2-(3-hydroxyl- 4-nitrophenyl)imidazo[4,5-f][1,10-phenanthroline] were synthesized and characterized. DNA binding behaviors were studied by luminescent titration, UV-vis titration, FRET (FRET = Fluorescence resonance energy transfer) and molecular docking experiments. Complex 2 exhibited “light switch” effect upon addition of G-quadruplex DNA and displayed fluorescent selectivity towards G-quadruplex DNA over other DNAs in the presence of K4[Fe(CN)6]. Fluorescence experiments, FRET experiments and molecular docking results indicated that the selectivity may be attributed to protection of nitro group from water, DNA affinity and the difference in DNA structures. Furthermore, both complexes were found to cleave DNA under irradiation by the formation of singlet oxygen. DNA topoisomerase inhibition experiments indicated that complex 2 exhibited higher topoisomerase I inhibition activity (IC50 = 18 μM) than complex 1 (IC50 = 50 μM). Docking studies revealed that complex 2 stabilized Top1cc complex via π–π interaction and the formation of hydrogen bond.

Bis-dihydroisoxazolines: Synthesis, Structural Elucidation, Antimicrobial Evaluation, and DNA Photocleavage Assay.

Isoxazole is an active core found in many drugs. The aim of this work was to synthesize bis-isoxazoline compounds and to analyze the effect of linker chain length on biological activities. A simple, convenient, and efficient method for the conversion of bischalcones to new bis(4,5-dihydroisoxazole) derivatives was developed by using hydroxylamine hydrochloride under basic medium. Synthesized moieties were also evaluated for their antimicrobial potencies and DNA photocleavage assay. The synthesized compounds were more active than their chalcone precursors and the long-chain linkers (4e&4f) were more potent in antimicrobial, as well as in DNA photocleavage activity. It was found that many of the tested bischalcones and bis-isoxazolines exhibited moderate to significant antimicrobial activity against various strains. Furthermore, the present study also provides significant information and interesting outcomes regarding cyclization, increasing the length of linker chains, and their effects on the DNA photocleavage and antimicrobial activities.

Synthesis, characterization, in vitro DNA photocleavage and cytotoxicity studies of 4-arylazo-1-phenyl-3-(2-thienyl)-5-hydroxy-5-trifluoromethylpyrazolines and regioisomeric 4-arylazo-1-phenyl-5(3)-(2-thienyl)-3(5)-trifluoromethylpyrazoles

1-(2-Thienyl)-2-arylazo-4,4,4-trifluorobutane-1,3-diones (4), generated by the condensation of aryldiazonium salts (2) with 4,4,4-trifluoro-1-(2-thienyl)butane-1,3-dione (3), were used as common intermediates to synthesize regioisomeric 4-arylazo-1-phenyl-5(3)-(2-thienyl)-3(5)-trifluoromethylpyrazoles (5 and 6) and 4-arylazo-1-phenyl-3-(2-thienyl)-5-hydroxy-5-trifluoromethylpyrazolines (7) by reacting with phenylhydrazine in neutral conditions. All the synthesized compounds 4, 5, 6 and 7 were screened for their DNA photocleavage activity on pBR322 supercoiled DNA plasmid under UV radiation at λmax 312 nm without any additive. The results indicated that 3-trifluoromethyl isomers (5) photocleaves plasmid DNA better than the corresponding 5-trifluoromethylpyrazoles (6) and 5-hydroxy5-trifluoromethylpyrazolines (7). 4-(4-nitrophenylazo)-1-phenyl-5-(2-thienyl)-3-trifluoromethylpyrazole 5g, exhibited the best potential as DNA photocleaver, cleaving the supercoiled plasmid (Form-I) into smaller fragments at 20 μM of compound with 60 μM of DNA plasmid in DMSO. Selected seventeen compounds were further screened for their cytotoxicity against four cancer cell lines namely MCF-7, BT-474, SBALL and MOLT-4 and again compound 5g was identified as the most potent compound with an IC50 value of 8.6 ± 3.8 μM against MCF-7 cell line.

Synthesis, characterization, antibacterial and DNA photocleavage study of 1-(2-Arenethyl)-3, 5-dimethyl-1H-pyrazoles

Abstract 1-(2-Arenethyl)-3, 5-dimethyl-1H-pyrazoles (4a-g) were obtained by Wolff-Kishner reduction of 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-1-arylethanones (3a-g). The synthesized compounds were characterized by analyzing their IR, 1H, and 13C-NMR spectral data. Intermediates (3a-g) were synthesized by the solid phase reaction of 3, 5-dimethylpyrazole with different substituted phenacyl bromides under basic condition by adopting reported procedure. All synthesized compounds were screened in vitro for their anti-bacterial potential against four bacterial strains and it was found that the compounds 4c and 4g bearing methoxy and nitro group, respectively, exhibited good level of inhibitory potential which was about 25% of the standard drug, Ciprofloxacin- against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa bacterial strains. Further, DNA photocleavage ability was also explored and it was observed that compounds bearing halogen group (4d, 4e and 4f) displayed good DNA photocleavage activity.

P-Pyridinyl oxime carbamates: synthesis, DNA binding, DNA photocleaving activity and theoretical photodegradation studies.

A number of p-pyridinyl oxime carbamate derivatives were prepared upon the reaction of the corresponding oximes with isocyanates. These novel compounds reacted photochemically in the presence of supercoiled plasmid DNA. Structure–activity relationship (SAR) studies revealed that the substituent on the imine group was not affecting the extend of the DNA damage, whereas the substituent of the carbamate group was critical, with the halogenated derivatives to be able to cause extensive single and double stranded DNA cleavages, acting as “synthetic nucleases”, independently of oxygen and pH. Calf thymus–DNA affinity studies showed a good-to-excellent affinity of selected both active and non-active derivatives. Preliminary theoretical studies were performed, in an effort to explain the reasons why some derivatives cause photocleavage and some others not, which were experimentally verified using triplet state activators and quenchers. These theoretical studies seem to allow the prediction of the activity of derivatives able to pass intersystem crossing to their triplet energy state and thus create radicals able to damage DNA. With this study, it is shown that oxime carbamate derivatives have the potential to act as novel effective photobase generating DNA-photocleavers, and are proposed as new leads for “on demand” biotechnological applications in drug discovery and medicine.

Synthesis and Spectral Studies of 4,4′-(Hydrazine-1,2-diylidenedimethylylidene)-bis-(2- methoxyphenol) and Its Transition Metal Complexes with Promising Biological Activities

The study describes the synthesis, characterization and biological activity of a novel Schiff base ligand and its transition metal complexes. The Schiff base ligand was obtained by a condensation reaction between 4-hydroxy-3-methoxybenzaldehyde (p-vanillin) and hydrazine hydrate using ethanol as solvent. A new series of Ni(II) and Fe(III) complexes were also derived by reaction of prepared Schiff base ligand with NiCl2 and FeCl3. Both the ligand and its metal complexes were characterized by solubility, melting point and elemental analysis. These compounds were further identified by analytical techniques, FTIR, NMR and mass spectrometry. The ligand and its transition metal complexes were also subjected to in vitro biological activities i.e. antimicrobial, antiangiogenic and DNA photo cleavage. For antimicrobial activity compounds were tested against two strains of bacteria and two strains of fungi. Different concentrations of prepared compounds were treated with fertilized chicken eggs and plasmid DNA to find out antiangiogenic and DNA photocleavage activity, respectively.