A series of bis(catechol) quaternary ammonium derivatives were designed and synthesized. We investigated their ability to cross-link DNA induced by tyrosinase and found that the o-quinone is key intermediate in the process by using the nucleophile 3-methyl-2-benzothiazolinone hydrazone (MBTH) in the tyrosinase assay. Their cytotoxicities to B16F1, Hela, and CHO cells were tested by MTT assays. The specific and potent abilities to kill the tyrosinase-efficient melanoma cells kindled our interest in exploring the relationship between their abilities of cross-linking DNA and their selective cytotoxicities to cells. Through an integrated approach including intracellular imaging for detection of the dihydroxyphenyl groups, alkaline comet assays, and γ-H2AX immunofluorescence assays, the speculation was confirmed. The bis(catechol) quaternary ammonium derivatives showed notable cell selectivity because they displayed cytotoxicities after being oxidized by tyrosinase, and they were able to target the DNA efficiently in the tyrosinase-efficient melanoma cells, forming both alkylated and cross-linked species.
Many antitumor agents such as cisplatin and nitrogen mustard work through a DNA cross-linking mechanism, in which interstrand cross-linking is especially important. [1] These agents covalently bind to the DNA duplex and inhibit both replication and transcription in tumor cells eventually killing them.[2] However, the application of these drugs has been limited by their toxic side effects in normal cells. The possibility of selectively destroying the DNA of tumor cells by induction has been given much attention in medicinal research. Inducible DNA cross-linking agents have provided a promising method for specifically damaging tumor cells. [3] The inducible formation of o-quinone methide (o-QM) as a precursor of antitumor agents has been reported by many groups because o-QM is highly reactive with DNA.[4] Our group has reported several efficient DNA cross-linking agents derived from an o-QM intermediate induced by a biphenol quaternary ammonium structure [5] and a biphenol selenide structure.[6] Recently, Kodadeks group reported that biotinylated catechol derivatives could cross-link proteins via an o-quinone intermediate induced by NaIO 4 . [7] The quinone intermediate induced by the oxidation of a catechol appears to be a promising agent for studying the properties of complicated biological complexes, [8] and moreover, this oxidative activity can be carried out by a ubiquitous enzyme, that is, tyrosinase.[9] Encouraged by their reports, we designed and synthesized a new family of DNA crosslinking agents: bisA C H T U N G T R E N N U N G (catechol) quaternary ammonium derivatives (Figure 1). We found that they could cross-link DNA potently via an o-quinone intermediate induced by oxidation.Compounds 1-3 are composed of two catechol monomers acting as DNA cross-linking units, and are joined by different linkers that act as DNA binding units. In order to achieve high affinity to DNA, positive charged linkers and quaternary ammonium were considered for use. Furthermore, aliphatic and aromatic chains were investigated to determine which of them resulted in favorable cross-linking reactions, and to determine the relationship between agent flexibility and DNA cross-linking abilities. These compounds were prepared as shown in the supporting information. All new compounds were fully characterized by NMR spectroscopy and HRMS analysis.The DNA-DNA cross-linking abilities of compounds 1-3 were firstly studied using tyrosinase as oxidative agent. Tyrosinase is a binuclear copper enzyme occurs in all organisms, which can catalyze the oxidation of catechols to qui- [a]
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