Design of Photoactivated DNA Oxidizing Agents: Synthesis and Study of Photophysical Properties and DNA Interactions of Novel Viologen-Linked Acridines (original) (raw)
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Journal of Physical Chemistry B, 2003
Novel water soluble viologen and pyridinium linked tolylacridines 1a,b and 2a,b were synthesized and their photophysical and DNA binding properties including the photoinduced electron-transfer reactions were investigated. When compared to the cases of the model tolylacridines 3a,b and the pyridinium linked derivatives 2a,b, the singlet excited states of 1a and 1b were efficiently quenched in water and methanol. Intramolecular quenching rate constants (k ET ) calculated in water are found to be 1.2 × 10 10 and 8.8 × 10 10 s -1 for 1a and 1b and 1.4 × 10 8 and 0.9 × 10 8 s -1 for 2a and 2b, respectively, suggesting thereby that the viologen moiety quenches the fluorescence of the acridine chromophore efficiently when compared to the case of the pyridinium moiety. From the intermolecular electron-transfer studies, it was observed that the singlet and triplet excited states of the acridine chromophore are capable of donating an electron to the viologen moiety. DNA binding studies indicated that the p-tolylacridine derivatives 1a and 2a exhibit strong binding to DNA with binding constants of 1.0 × 10 5 and 3.3 × 10 5 M -1 , respectively, whereas the o-tolylacridine derivatives 1b and 2b showed negligible affinity for DNA. The rate constants for the static quenching of 1a and 2a by DNA (k DNA ) are found to be 7 × 10 9 and 3 × 10 9 s -1 , respectively, indicating that 1a is an efficient DNA oxidizing agent. Nanosecond laser flash photolysis studies of these systems in aqueous solutions did not show any transients. However, in the presence of DNA, 1a gave transient absorption due to the reduced methyl viologen radical cation. These results demonstrate that the tolyl spacer group in these systems constitutes an interesting variation which controls both the electron transfer and DNA binding properties, and hence, such molecules and derivatives thereof can have potential application as probes for nucleic acids and as DNA cleaving agents.
Photochemistry and Photobiology, 2001
It was demonstrated that the interaction of the aminoacridizinium salts 2a-2d with DNA depends on the substitution pattern of the chromophore. Spectrophotometric and fluorometric titrations of the acridizinium salts 2a-2d with natural and synthetic polynucleotides reveal that the degree of interaction of the acridizinium salts 2a-2d with the nucleic acid differs significantly. The binding mode of the dyes with DNA was evaluated by circular dichroism and linear dichroism spectroscopy and compared with the parent system 2c. Whereas the 9-aminoacridizinium (2a) mainly intercalates into DNA, the salts 2b-c show a higher degree of association to the DNA backbone. The intercalated aminoacridizinium 2a caused few strand breaks upon UVA exposure, whereas the salts 2b-2d exhibit relatively efficient DNA-damaging properties. All acridizinium salts showed a sequence-selective strand cleavage for guanine-rich DNA regions.
DNA photocleavage by novel intercalating 6-(2-pyridinium)phenanthridinium viologens
FEBS Letters, 1995
A new type of DNA-intercalating viologen dications, derived from the N,N'-dialkyl-6-(2-pyridyl)phenanthridine structure (in which dialkyl is -CH2CH2-, -CH2CH2CH2-, or (-CH3)2, abbreviated dq2pyp, dq3pyp, and Me2pyp, respectively), are able to produce frank strand breaks in supercoiled plasmid DNA upon irradiation with visible light. The amount of photocleavage is similar for the three drugs. The observed DNA photosensitization appears to follow a single-strand cleavage model, as shown by a kinetic analysis of the reaction with dq2pyp. The photodynamic action of the drugs seems to be initiated by a light-induced electron transfer reaction from the nucleobases, given the singlet excited-state redox potentials (ca. + 2.1 V vs. SHE) and the low quantum yields of singlet molecular oxygen production of the drugs (0.1-0.2 in aerated D20).
N, O-Diacyl-4-benzoyl- N-phenylhydroxylamines as photoinduced DNA cleaving agents
Bioorganic & Medicinal Chemistry Letters, 2010
Photoinduced homolytic fission of nitrogen–oxygen bond in N,O-diacyl-4-benzoyl-N-phenylhydroxylamines using ⩾310 nm UV light for 10 min produced acylaminyl and acyloxy radicals, which resulted in single strand cleavage of DNA at pH 7.0. Further the DNA cleaving ability of N,O-diacyl-4-benzoyl-N-phenylhydroxylamines found to depend both on its concentration and acyl substituents.Efficient single strand DNA cleavage by acylaminyl radicals is reported.
Photochemistry and Photobiology, 1997
The acridine and phenanthridine hydroperoxides 3 and 7 were synthesized as photochemical hydroxyl radical sources for oxidative DNA damage studies. The generation of hydroxyl radicals upon UVA irradiation (A = 350 nm) was verified by trapping experiments with 5,5-dimethyl-1-pyrroline N-oxide and benzene. The enzymatic assays of the damage in cell-free DNA from bacteriophage PM2 caused by the acridine and phenanthridine hydroperoxides 3 and 7 under near-UVA irradiation revealed a wide range of DNA modifications. Particularly, extensive single-strand break formation and DNA base modifications sensitive to formamidopyrimidine DNA glycosylase (Fpg protein) were observed. In the photooxidation of calf thymus DNA, up to 0.69 * 0.03% 8-0x0-7,8dihydroguanine was formed by the hydroperoxides 3 and 7 on irradiation, whose yield was reduced up to 40% in the presence of the hydroxyl radical scavengers mannitol and tert-butanol. The acridine and phenanthridine hydroperoxides 3 and 7 also induce DNA damage through the type I photooxidation process, for which photoinduced electron transfer from 2'-deoxyguanosine to the singlet states of 3 and 7 was estimated by the Rehm-Weller equation to possess a negative Gibb's free energy of ca-5 kcaY mol. Control experiments with the sensitizers acridine 1 and the acridine alcohol 4 in calf thymus and PM2 DNA confirmed the photosensitizing propensity of the UVA-absorbing chromophores. The present study emphasizes that for the development of selective and efficient photochemical hydroxyl radical sources, chromophores with low photosensitizing ability must be chosen to avoid type I and type I1 photooxidation processes.
Tunable DNA Photocleavage by an Acridine−Imidazole Conjugate
Inorganic Chemistry, 2005
We report the synthesis and characterization of photonucleases N,N′-bis[2-[bis(1H-imidazol-4-ylmethyl)amino]ethyl]-3,6-acridinediamine (7) and N-[2-[bis(1H-imidazol-4-ylmethyl)amino]ethyl]-3,6-acridinediamine (10), consisting of a central 3,6-acridinediamine chromophore attached to 4 and 2 metal-coordinating imidazole rings, respectively. In DNA reactions employing 16 metal salts, photocleavage of pUC19 plasmid is markedly enhanced when compound 7 is irradiated in the presence of either Hg(II), Fe(III), Cd(II), Zn(II), V(V), or Pb(II) (low-intensity visible light, pH 7.0, 22°C, 8−50 µM 7). We also show that DNA photocleavage by 7 can be modulated by modifying buffer type and pH. Evidence of metal complex formation is provided by EDTA experiments and by NMR and electrospray ionization mass spectral data. Sodium azide, sodium benzoate, superoxide dismutase, and catalase indicate the involvement of type I and II photochemical processes in the metal-assisted DNA photocleavage reactions. Thermal melting studies show that compound 7 increases the T m of calf thymus DNA by 10 ± 1°C at pH 7.0 and that the T m is further increased upon the addition of either Hg(II), Cd(II), Zn(II), or Pb(II). In the case of Fe(III) and V(V), a colorimetric assay demonstrates that compound 7 sensitizes one electron photoreduction of these metals to Fe(II) and V(IV), likely accelerating the production of type I reactive oxygen species. Our data collectively indicate that buffer, pH, Hg(II), Fe(III), Cd(II), Zn(II), V(V), Pb(II), and light can be used to "tune" DNA cleavage by compound 7 under physiologically relevant conditions. The 3,6-acridinediamine acridine orange has demonstrated great promise for use as a photosensitizer in photodynamic therapy. In view of the distribution of iron in living cells, compound 7 and other metal-binding acridine-based photonucleases should be expected to demonstrate excellent photodynamic action in vivo.
Alkyl and aryl sulfonyl p-pyridine ethanone oximes are efficient DNA photo-cleavage agents
Journal of Photochemistry and Photobiology B: Biology, 2016
Sulfonyloxyl radicals, readily generated upon UV irradiation of p-pyridine sulfonyl ethanone oxime derivatives, effectively cleave DNA, in a pH independent manner, and under either aerobic or anaerobic conditions. p-Pyridine sulfonyl ethanone oxime derivatives were synthesized from the reaction of p-pyridine ethanone oxime with the corresponding sulfonyl chlorides in good to excellent yields. All compounds, at a concentration of 100 μM, were irradiated at 312 nm for 15 min, after incubation with supercoiled circular pBluescript KS II DNA and resulted in extended single-and double-strand cleavages. The cleavage ability was found to be concentration dependent, with some derivatives exhibiting activity even at nanomolar levels. Besides that, p-pyridine sulfonyl ethanone oxime derivatives showed good affinity to DNA, as it was observed with UV interaction and viscosity experiments with CT DNA and competitive studies with ethidium bromide. The compounds interact to CT DNA probably by non-classical intercalation (i.e. groove-binding) and at a second step they may intercalate within the DNA base pairs. The fluorescence emission spectra of pre-treated EB-DNA exhibited a significant or moderate quenching. Comparing with the known aryl carbonyloxyl radicals the sulfonyloxyl ones are more powerful, with both aryl and alkyl sulfonyl substituted derivatives to exhibit DNA photo-cleaving ability, in significantly lower concentrations. These properties may serve in the discovery of new leads for "on demand" biotechnological and medical applications.
Photochemical and Photobiological Sciences, 2016
Several stable O-alkyl and aryl sulfonyl conjugated p-nitro-Ph and o-, m-, p-pyridine N'-hydroxy imidamides, were subjected to UV irradiation at 312 nm with supercoiled circular plasmid DNA pBluescript KS II. The generated amidinyl and sulfonyloxyl radicals led to effective DNA photo-cleavage. Both alkyl and aryl sulfonyl derivatives were active and the order p-pyridine > p-nitro-Ph > o-pyridine > m-pyridine was schematized for the N'-hydroxy imidamides moiety. Calf thymus-DNA affinity studies which comprised UV interactions, viscosity experiments and competitive studies with ethidium bromide showed good to excellent affinity of the compounds. These properties revealed sulfonyl amidoximes as novel effective DNA-photo-cleavers and may serve in the discovery of new leads for "on demand" biotechnological and medical applications. † Electronic supplementary information (ESI) available: Photochemical experiments, gel electrophoreses for dose measurements, mechanistic and pH studies, UV DNA affinity calculations and ethidium bromide competitive experiments.
Bioconjugate Chemistry, 1991
A series of reagents containing 3-or 4-nitrobenzamido ligands tethered to 9-aminoacridine via variablelength linkers have been prepared and their properties as photochemical DNA cleavers (photonucleases) examined. When irradiated with-300-nm light, where the nitrobenzamido ligand can absorb, they cleave DNA in an oxygen-independent reaction presumably involving oxygen transfer from the nitro group to the deoxyribose units of the DNA backbone (Nielsen et al., 1988b). This reaction is pH independent and only slightly affected by the linker length, and the DNA fragments are not substrates for DNA polymerase. When-420-nm light is used, were only the 9-aminoacridinyl ligands absorb, the DNA cleavage is also oxygen-independent but pH dependent, requires DNA saturation with the reagent (base paheagent I 2), and is most efficient with the longer linkers. The cleavage is specific for guanine residues and results in 5'-phosphate termini and heterogeneous (more than four products) 3'-termini. One of the products is presumably 3'-hydroxy since DNA photocleaved with nitrobenzamido acridine reagents and 420-nm radiation are substrates for DNA polymerase in a nick translation assay as well as for the Klenow fragment. An electron-transfer mechanism is suggested.