Alkyl and aryl sulfonyl p-pyridine ethanone oximes are efficient DNA photo-cleavage agents

Abstract

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. pPyridine 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.

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

“…The results regarding the carbamoyl amidoxime 8-13 are depicted in Figure 5A. Interestingly, we note that in the series of carbonyl aldoximes, ketoximes and amidoximes [9,43], as well as sulfonyl amidoximes and ethanone oximes [10,11], the PNP derivatives were by far the most active derivatives. Additionally, halogenated sulfonylethanone oxime derivatives were less reactive than the PNP one [10].…”

“…Our previous DNA-binding studies with a series of amidoxime, ethanone oxime and aldoxime carboxylates as well as sulfonates of high, moderate or poor DNA photocleaving ability showed no substantial differences on the DNA affinities among the three kinds of oxime functionalities [9][10][11]. Thus, in the present study, due to the fact that all three series of oxime derivatives exhibited the same photocleaving activity we have chosen to investigate the DNA affinity of an active and a nonactive DNA photocleaver in order to, hopefully, explain the cause of the activity.…”

“…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]. All the above radical species exhibit photoreactivity towards DNA.…”

“…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].…”

“…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%.…”