DNA Interstrand Crosslinks by H‐pin Polyamide ( S ) ‐seco ‐CBI Conjugates | Zendy

Guo Chuanxin | Zendy; Asamitsu Sefan | Zendy; Kashiwazaki Gengo | Zendy; Sato Shinsuke | Zendy; Bando Toshikazu | Zendy; Sugiyama Hiroshi | Zendy

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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.

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