Pyridine and p-Nitrophenyl Oxime Esters with Possible Photochemotherapeutic Activity: Synthesis, DNA Photocleavage and DNA Binding Studies

Abstract

Compared to standard treatments for various diseases, photochemotherapy and photo-dynamic therapy are less invasive approaches, in which DNA photocleavers represent promising tools for novel "on demand" chemotherapeutics. A series of p-nitrobenzoyl and p-pyridoyl ester conjugated aldoximes, amidoximes and ethanone oximes were subjected to UV irradiation at 312 nm with supercoiled circular plasmid DNA. The compounds which possessed appropriate properties were additionally subjected to UVA irradiation at 365 nm. The ability of most of the compounds to photocleave DNA was high at 312 nm, whereas higher concentrations were required at 365 nm as a result of their lower UV absorption. The affinity of selected compounds to calf-thymus (CT) DNA was studied by UV spectroscopy, viscosity experiments and competitive studies with ethidium bromide (EB) revealing that all compounds interacted with CT DNA. The fluorescence emission spectra of the pre-treated EB-DNA exhibited a moderate to significant quenching in the presence of the compounds indicating the binding of the compounds to CT DNA via intercalation as concluded also by DNA-viscosity experiments. For the oxime esters the DNA photocleavage and affinity studies aimed to clarify the role of the oxime nature (aldoxime, ketoxime, amidoxime) and the role of the pyridine and p-nitrophenyl moieties both as oxime substituents and ester conjugates.

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

“…Small organic molecules able to bind DNA provide promises for anticancer activity due to alteration of the structure and function of the genetic material. Amongst a plethora of such binders [1][2][3][4][5][6][7][8], various oxime derivatives were found to show affinity towards DNA [9][10][11][12], whereas others were found to cleave DNA as metal-free artificial nucleases [13,14].…”

“…O-Acyl amidoximes, ketoximes and aldoximes (I, II and III, respectively, Figure 1) are also recognized as DNA "photocleavage" agents owing their action to the homolysis of their vulnerable N-O bond, at 312 nm [9,[39][40][41][42][43] or 365 nm [44,45] yielding photogenerated carbonyloxyl radicals (CRs), which are able to cause oxidative DNA damage. We have recently reported the DNA photocleavage from sulfonylamidoximes and ethanone oximes (IV and V, Figure 1), which were found to attack DNA via sulfonyloxyl radicals (SRs) [10,11].…”

“…Based on our interest in the chemistry and biology of the oxime functionality [54][55][56][57], as well as in their DNA photolytic interaction upon UV irradiation [9][10][11]43] we have decided to investigate the behaviour of carefully designed O-carbamoyl derivatives of p-pyridine amidoxime, ethanone oxime and aldoxime (VI, VII, VIII, R 1 = p-pyridyl, Figure 1) as DNA photosensitizers. Based on our previous ex-Scheme 1: Synthesis of O-carbamoyl amidoximes (8)(9)(10)(11)(12)(13), ethanone oximes (15)(16)(17)(18)(19)(20) and aldoximes (22)(23)(24)(25)(26)(27). Oxime 1 or 14 or 21, Et 3 N (1.1 equiv), R-NCO (1.1-1.8 equiv), dry chloroform or tetrahydrofuran, Ar, 0 °C → rt or reflux, 19-97%.…”

Photocytotoxic Copper(II) Complexes with Schiff‐Base Scaffolds for Photodynamic Therapy

“…[11][12][13][14] Furthermore, comparedt op latinum and ruthenium complexes,copper complexes have demonstratedgood antitumor activity with fewer side effects. [20][21][22][23][24] In as imilar fashion, metal complexes with Schiff-base scaffolds have been effectively applied as antibacterial chemotherapeutic moieties in medicine. [20][21][22][23][24] In as imilar fashion, metal complexes with Schiff-base scaffolds have been effectively applied as antibacterial chemotherapeutic moieties in medicine.…”

“…[15][16][17][18][19] Moreover,av ariety of pyridine-ligand-based complexes have exhibited high reactivity toward DNA cleavage and cell apoptosis. [20][21][22][23][24] In as imilar fashion, metal complexes with Schiff-base scaffolds have been effectively applied as antibacterial chemotherapeutic moieties in medicine. [25,26] The chemotherapeutic effect of Cu II -containing Schiff-base complexes may be enhanced by tuningt he electronic properties of the metal centero rt he ligandst hrough coordination.…”