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Evaluation of the DNA Alkylation Properties of a Chlorambucil‐Conjugated Cyclic Pyrrole‐Imidazole Polyamide
Author(s) -
Hirose Yuki,
Hashiya Kaori,
Bando Toshikazu,
Sugiyama Hiroshi
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.202004421
Subject(s) - conjugate , alkylation , chemistry , chlorambucil , cytotoxicity , capillary electrophoresis , conjugated system , stereochemistry , combinatorial chemistry , biochemistry , chromatography , organic chemistry , biology , in vitro , mathematical analysis , polymer , mathematics , chemotherapy , cyclophosphamide , genetics , catalysis
Hairpin pyrrole‐imidazole polyamides (hPIPs) and their chlorambucil (Chb) conjugates (hPIP‐Chbs) can alkylate DNA in a sequence‐specific manner, and have been studied as anticancer drugs. Here, we conjugated Chb to a cyclic PIP (cPIP), which is known to have a higher binding affinity than the corresponding hPIP, and investigated the DNA alkylation properties of the resulting cPIP‐Chb using the optimized capillary electrophoresis method and conventional HPLC product analysis. cPIP‐Chb conjugate 3 showed higher alkylation activity at its binding sites than did hPIP‐Chb conjugates 1 and 2 . Subsequent HPLC analysis revealed that the alkylation site of conjugate 3 , which was identified by capillary electrophoresis, was reliable and that conjugate 3 alkylates the N3 position of adenine as do hPIP‐Chbs. Moreover, conjugate 3 showed higher cytotoxicity against LNCaP prostate cancer cells than did conjugate 1 and cytotoxicity comparable to that of conjugate 2 . These results suggest that cPIP‐Chbs could be novel DNA alkylating anticancer drugs.