4.6 Article

Evaluation of the DNA Alkylation Properties of a Chlorambucil-Conjugated Cyclic Pyrrole-Imidazole Polyamide

期刊

CHEMISTRY-A EUROPEAN JOURNAL
卷 27, 期 8, 页码 2782-2788

出版社

WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202004421

关键词

alkylation; antitumor agents; DNA alkylator; DNA recognition; drug delivery

资金

  1. AMED (Basic Science and Platform Technology Program for Innovative Biological Medicine) [JP18am0301005]
  2. JSPS KAKENHI [JP16H06356]

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The study demonstrated that the conjugation of chlorambucil to cyclic PIPs showed higher DNA alkylation activity and cytotoxicity against prostate cancer cells compared to hairpin PIP-chlorambucil conjugates. The results suggest that the novel cPIP-Chbs could be promising DNA alkylating anticancer drugs.
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.

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