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DNA Interstrand Crosslinks by H‐pin Polyamide ( S ) ‐seco ‐CBI Conjugates
Author(s) -
Guo Chuanxin,
Asamitsu Sefan,
Kashiwazaki Gengo,
Sato Shinsuke,
Bando Toshikazu,
Sugiyama Hiroshi
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201600425
Subject(s) - dna , chemistry , conjugate , stereochemistry , gel electrophoresis , plasmid , combinatorial chemistry , biochemistry , mathematical analysis , mathematics
Although DNA interstrand crosslinking (ICL) agents are widely used as antitumor drugs, DNA sequence‐specific ICL agents are quite rare. In this study, H‐pin imidazole‐pyrrole polyamide 1‐(chloromethyl)‐2,3‐dihydro‐1 H ‐benzo[e]indol‐5‐ol ( seco ‐CBI) conjugates that produce sequence‐specific DNA ICLs were designed and synthesized. Conjugates with H‐pin polyamide and seco ‐CBI moieties were constructed to recognize a 7 bp DNA sequence, and their reactivity and selectivity in DNA alkylation were evaluated by using high‐resolution denaturing gel electrophoresis and sequence‐specific plasmid cleavage. One conjugate ( 6 ), which contained a chiral ( S )‐ seco ‐CBI, exhibited greater sequence‐specific ICL activity toward the target DNA sequence and was cytotoxic to a cancer cell line. Molecular modeling studies indicated that the greater activity of 6 resulted from the relative orientation of the cyclopropane group in the ( S )‐CBI unit.