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

Panagiotis S Gritzapis,Zisis V Peitsinis,George Psomas,Konstantina C Fylaktakidou,Nikolaos-Panagiotis Andreou,Katerina R Katsani,Panayiotis C Varras,Alexandros E Koumbis,Konstantinos Dafnopoulos

doi:10.3762/bjoc.16.33

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.

Highlights

Small organic molecules able to bind DNA provide promises for anticancer activity due to alteration of the structure and function of the genetic material
The hydroxylimino structure is verified in 1H NMR spectra from the existence of a broad singlet peak, at 6.2–7.1 ppm integrated for two protons (NH2), whereas NH for the aryl derivatives 9–13 appeared in the area 8.9 to 10.2 ppm
In the IR spectra the NH group appears around 3200–3300 cm−1 and the carbonyl absorption had the characteristics of an ester, rather than an amide, at 1720 and 1750–1786 cm−1 for compounds with the NH adjusted on the aromatic ring

Summary

Introduction

Small organic molecules able to bind DNA provide promises for anticancer activity due to alteration of the structure and function of the genetic material. The interaction of molecules with DNA and their affinity towards this macromolecule plays a key role in photosensitization techniques. Light activated oxidative DNA cleaving agents are called “DNA photocleavers”. These compounds are able to absorb light and to be selectively excited. A requirement for nucleic acid’s and most protein’s “transparency” is irradiating at wavelengths longer than 310 nm [15]. “Transparency” means lack of damage due to irradiation itself and action via its combination with the photosensitizer. It is worth mentioning that, mainly in dermatology, even UVB irradiation is considered of therapeutic use [16,17,18]. Besides the anticancer activities of photosensitizers [19,20,21], “post-antibiotic era” is experimenting with photosensitizers as alternative therapeutics for the fight against multiresistant bacteria both for medicinal [22,23,24,25] and environmental purposes [26,27]

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Results

Conclusion