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Photoinduced DNA Interstrand Cross‐Linking by 1,1′‐Biphenyl Analogues: Substituents and Leaving Groups Combine to Determine the Efficiency of Cross‐Linker
Author(s) -
Fan Heli,
Sun Huabing,
Zhang Qi,
Peng Xiaohua
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202005064
Subject(s) - chemistry , carbocation , substituent , leaving group , reactivity (psychology) , adduct , radical , biphenyl , medicinal chemistry , dna , ether , alkylation , reaction mechanism , stereochemistry , radical ion , photochemistry , organic chemistry , ion , catalysis , medicine , biochemistry , alternative medicine , pathology
Two series of 1,1′‐biphenyl analogues with various leaving groups (L=OAc, OCH 3 , OCHCH=CH 2 , OCH 2 Ph, SPh, SePh, and Ph 3 P + ) were synthesized. Their reactivity towards DNA and the reaction mechanism were investigated by determining DNA interstrand cross‐link (ICL) efficiency, radical and carbocation formation, and the cross‐linking reaction sites. All compounds induced DNA ICL formation upon 350 nm irradiation via a carbocation that was generated from oxidation of the corresponding free radicals. The ICL efficiency and the reaction rate strongly depended on the combined effect of the leaving group and the substituent. Among all compounds tested, the high ICL efficiency (30–43 %) and fast reaction rate were observed with compounds carrying a nitrophenyl group and acetate ( 2 a ), ether ( 2 b and 2 c) , or triphenylphosphonium salt ( 2 g ) as leaving groups. Most compounds with a 4‐methoxybenzene group showed similar DNA ICL efficiency (≈30 %) with a slow DNA cross‐linking reaction rate. Both cation trapping and free radical trapping adducts were detected in the photo activation process of these compounds, which provided direct evidence for the proposed mechanism. Heat stability study in combination with sequence study suggested that these photo‐generated benzyl cations alkylate DNA at dG, dA, and dC sites.