Synthesis and Oxidation‐Induced DNA Cross‐Linking Capabilities of Bis(catechol) Quaternary Ammonium Derivatives

Abstract

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]

The emerging field of RNA nanotechnology

“…Crosslinking agents, such as psoralen, nitrogen mustard derivatives, and transition metal compounds 112 can promote the formation of stable RNA complexes. Recent advancements include various bifunctional agents separated by linkers and phenolic derivatives 113 to increase the efficiency of crosslinking. Long-range (>9Å) and short range (1.5Å) photoaffinity crosslinking can be achieved using azidophenacyl derivatives and thionucleosides, such as 6-thioguanosine and 4-thiouridine, respectively.…”

1,4-Bis(iodomethyl)benzene

“…For other polymer applications, see: Leir & Stark (1989); Hochberg & Schulz (1993). For additional applications of dihalo-p-xylenes, see: Le Baccon et al (2001); Sobransingh & Kaifer (2006); Song et al (2008); Au et al (2009). For details of halogenÁ Á Áhalogen interactions, see: Pedireddi et al (1994) and for reference structural data, see: Allen et al (1987).…”

Synthesis and incorporation of a furan-modified adenosine building block for DNA interstrand crosslinking

“…1 Examples include the synthesis of a duplex incorporating a preformed crosslinked dinucleotide 2,3 or postsynthetic modification of duplexes by bifunctional crosslinking reagents. 4,5 However, in some cases, the site-specific introduction of a crosslink is problematic due to formation of a mixture of monoadducts, intrastrand and interstrand crosslinks. Introduction of reactive moieties at a specific position within the duplex can circumvent the selectivity issue as is shown for photocrosslinking with 4-thiouridine, 6 5-bromouridine, 7 5-methyleneaminouridine 8 or 8-azidoadenosine.…”