Bifunctional Phenol Quinone Methide Precursors: Synthesis and Biological Activity

Matija Sambol,Antonija Husak,Đani Škalamera,Nikola Basarić,Ivo Piantanida,Katja Ester

doi:10.5562/cca3455

Abstract

New bifunctional quinone methide (QM) precursors, bisphenols 2a–2e, and monofunctional QM precursor 7 were synthesized. Upon treatment with fluoride, desilylation triggers formation of reactive intermediates, QMs, which was demonstrated by trapping QM with azide or methanol. The ability of QMs to alkylate and cross-link DNA was assayed by investigation of the effects of QMs to DNA denaturing, but without conclusive evidence. Furthermore, treatment of a plasmid DNA with compounds 2a–2e and KF, followed by the analysis by alkaline denaturing gel electrophoresis, did not provide evidence for the DNA cross-linking. MTT test performed on two human cancer cell lines (MCF7 breast adenocarcinoma and SUM159 pleomorphic breast carcinoma), with and without fluoride, indicated that 2a–2e or the corresponding QMs did not exhibit cytotoxic activity, in line with the lack of ability to cross-link DNA. The lack of reactivity with DNA and biological activity were explained by sequential formation of QMs where bifunctional cytotoxic reagent is probably never produced. Instead, the sequential generation of monofunctional QM followed by a faster hydrolysis leads to the destruction of biologically active reagent. The findings described here are particularly important for the rational design of new generation of QM precursor molecules that will attain desirable DNA reactivity and cytotoxicity.

Highlights

Q UINONE methides (QMs) are important intermediates in chemistry and photochemistry of phenols,[1] owing to their applications in organic synthesis,[2] and biological activity.[3]
CH3 13-QMb of QMs to alkylate and cross-link DNA was assayed by investigation of the effects of QMs to DNA denaturing and the treatment of a plasmid DNA with compounds 2a–2e and 7, and KF, followed by the analysis by alkaline denaturing gel electrophoresis
Both methods did not provide evidence for the DNA cross-linking, in agreement with the MTT test performed on two human cancer cell lines (MCF7 breast adenocarcinoma and SUM159 pleomorphic breast carcinoma), which indicated that 2a–2e or the corresponding QMs did not exhibit significant cytotoxic activity

Summary

INTRODUCTION

Q UINONE methides (QMs) are important intermediates in chemistry and photochemistry of phenols,[1] owing to their applications in organic synthesis,[2] and biological activity.[3]. Some thermal reactions to generate QMs include oxidation of phenols,[16] dehydration from hydroxybenzyl alcohols,[17] elimination of nitriles from 1,2-benzoxazines,[18] and the most extensively used, fluoride induced desilylation.[12b,c] On the other hand, photochemical methods offer much milder approach to QMs, for biological systems.[19] The most common reactions to generate QMs in photochemical reactions are photodehydration[20] and photodeamination from the suitably substituted phenols.[4,21] An on-going interest in our group is the photochemical generation of quinone methides (QM) from suitable precursors, and investigation of their biological effects.[22] In particular, we have recently demonstrated that photogenerated QM. Treatment of plasmid DNA in the presence of bisphenols and analysis by alkaline agarose electrophoresis, or measurement of DNA denaturation show that QMs do not cross-link plasmid DNA, and the reasons for the lack of reactivity were disclosed

RESULTS

DISCUSSION

CONCLUSION