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

ABSTRACT: 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.

SUBMITTER: Gritzapis PS

PROVIDER: S-EPMC7082612 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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<i>p</i>-Pyridinyl oxime carbamates: synthesis, DNA binding, DNA photocleaving activity and theoretical photodegradation studies.

Gritzapis Panagiotis S PS Varras Panayiotis C PC Andreou Nikolaos-Panagiotis NP Katsani Katerina R KR Dafnopoulos Konstantinos K Psomas George G Peitsinis Zisis V ZV Koumbis Alexandros E AE Fylaktakidou Konstantina C KC

Beilstein journal of organic chemistry 20200309

A number of <i>p</i>-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 ...[more]

PMID: 32256851

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Project description:Two Zinc(ii) complexes [Zn4(L1)4]·2H2O (1) and [Zn2(L2)2]·2H2O (2) of pyruvaldehydethiosemicarbazone ligands are reported. The complexes were characterized by elemental analysis, IR, NMR, UV-vis spectroscopy and by single-crystal X-ray crystallography. X-ray crystal structure determinations of the complexes show that though Zn : ligand stoichiometry is 1 : 1 in both the complexes, the molecular unit is tetranuclear for 1 and binuclear for 2. Both the complexes show selective sensing of ATP at pH 7.4 (0.01 M HEPES) in CH3CN-H2O (9 : 1) medium in the presence of other anions like AcO-, NO3 -, F-, Cl-, H2PO4 -, HPO4 2- and P2O7 2-. The UV-titration experiments of complexes 1 and 2 with ATP results in binding constants of 2.0(±0.07) × 104 M-1 and 7.1(±0.05) × 103 M-1 respectively. The calculated detection limits of 6.7 μM and 1.7 μM for 1 and 2 respectively suggest that the complexes are sensitive detectors of ATP. High selectivity of the complexes is confirmed by the addition of ATP in presence of an excess of other anions. DFT studies confirm that the ATP complexes are more favorable than those with the other inorganic phosphate anions, in agreement with the experimental results. Phosphatase like activity of both complexes is investigated spectrophotometrically using 4-nitrophenylphosphate (NPP) as a substrate, indicating the complexes possess significant phosphate ester hydrolytic efficiency. The kinetics for the hydrolysis of the substrate NPP was studied by the initial rate method at 25 °C. Michaelis-Menten derived kinetic parameters indicate that rate of hydrolysis of the P-O bond by complex 1 is much greater than that of complex 2, the k cat values being 212(±5) and 38(±2) h-1 respectively. The DNA binding studies of the complexes were investigated using electronic absorption spectroscopy and fluorescence quenching. The absorption spectral titrations of the complexes with DNA indicate that the CT-DNA binding affinity (K b) of complex 1 (2.10(±0.07) × 106 M-1) is slightly greater than that of 2 (1.11(±0.04) × 106 M-1). From fluorescence spectra the apparent binding constant (K app) values were calculated and they are found to be 5.41(±0.01) × 105 M-1 for 1 and 3.93(±0.02) × 105 M-1 for 2. The molecular dynamics simulation demonstrates that the Zn(ii) complex 1 is a good intercalator of DNA.

Dataset Information

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

Publications

<i>p</i>-Pyridinyl oxime carbamates: synthesis, DNA binding, DNA photocleaving activity and theoretical photodegradation studies.

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