Photoinduced DNA Interstrand Cross-Linking by Benzene Derivatives: Leaving Groups Determine the Efficiency of the Cross-Linker

Abstract

We have synthesized and characterized two small libraries of 2-OMe or 2-NO2-benzene analogues 2a–i and 3a–i containing a wide variety of leaving groups. Irradiation of these compounds at 350 nm generated benzyl radicals that were spontaneously oxidized to benzyl cations directly producing DNA interstrand cross-links (ICLs). Compounds with a 2-methoxy substituent showed a faster cross-linking reaction rate and higher ICL efficiency than the corresponding 2-nitro analogues. Apart from the aromatic substituent, the benzylic leaving groups greatly affected DNA cross-linking efficiency. Higher ICL yields were observed for compounds with OCH3 (3b), OCH2Ph (3d), or Ph3P+ (3i) as leaving groups than those containing OAc (3a), NMe2 (3e), morpholine (3f), OCH2CHCH2 (3c), SPh (3g), or SePh (3h). The heat stability study of the isolated ICL products indicated that dGs were the preferred alkylation sites in DNA for the benzyl cations produced from 2a–i, 3c, and 3e–i while 3a (L = OAc), 3b (L = OMe), and 3d (L = OCH2Ph) showed a similar photoreactivity toward dGs and dAs. Although the photogenerated benzyl cations alkylated dG, dC, and dA, ICL assay with variation of DNA sequences showed that the ICL reaction occurred with opposing dG/dC but not with staggered dA/dA.

Phenyl Selenide‐Based Precursors as Hydrogen Peroxide Inducible DNA Interstrand Cross‐Linkers

“…The approaches to synthesize phenyl selenide‐based precursors 1 – 3 are derived from previous work [18,32] . Synthesis of precursor 1 is reported by the Zhou group [15] .…”

“…The TBDMS‐protected benzylic alcohols were selectively deprotected upon treatment with p‐toluene sulfonic acid (→ 2c/3 c ) [33] . The following bromination with PBr 3 (→ 2d/3 d ), substitution (→ 2e/3 e ), and deprotection afforded desired products 2 and 3 , respectively (Scheme 2B) [32,33] …”

“…(2‐Hydroxy‐5‐methoxy‐1,3‐phenylene)dimethanol ( 2 a ): [32] To a solution of NaOH (4 g, 100 mmol) in H 2 O (50 mL), 4‐methoxyphenol (6.2 g, 50 mmol) and paraformaldehyde (10.5 g, 116.6 mmol) were added slowly. The resulting reaction mixture was stirred at 35 °C for 24 h. The mixture was acidified with HCl (2.0 M) to pH 5.0, and extracted with ethyl acetate (3×200 mL).…”

“…The approaches to synthesize phenyl selenide-based precursors 1-3 are derived from previous work. [18,32] Synthesis of precursor 1is reported by the Zhou group. [15] It was prepared from commercially available 2,6-dimethylphenol via successive protection (!1 a), followed by bromination with N-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) (!1b), substitution (!1c) and deprotection (!1) (Scheme 2A).…”

“…[33] The following bromination with PBr 3 (!2d/3 d), substitution (!2e/3 e), and deprotection afforded desired products 2 and 3, respectively (Scheme 2B). [32,33]…”