Evaluation of alkylating pyrrole-imidazole polyamide conjugates by a novel method for high-throughput sequencer

• Published in: Bioorganic & medicinal chemistry Vol. 26; no. 1; pp. 1 - 7
• Main Authors: Kashiwazaki, Gengo, Maeda, Rina, Kawase, Takashi, Hashiya, Kaori, Bando, Toshikazu, Sugiyama, Hiroshi
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.01.2018; Elsevier
• Subjects: Alkylation; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biochemistry & Molecular Biology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; High-Throughput Screening Assays; Humans; Imidazoles - chemistry; Imidazoles - pharmacology; Life Sciences & Biomedicine; Molecular Structure; Nylons - chemistry; Nylons - pharmacology; Pharmacology & Pharmacy; Physical Sciences; Pyrroles - chemistry; Pyrroles - pharmacology; Science & Technology; Structure-Activity Relationship; DNA ALKYLATION; SMALL MOLECULES; RECOGNITION; HAIRPIN; INDOLE LINKER; CROSS-LINKING; SECO-CBI; CHLORAMBUCIL; BINDING; GENOMIC TARGETS
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.08.057

[Display omitted] N-Methylpyrrole-N-methylimidazole (PI) polyamides are a class of DNA minor groove binders with DNA sequence-specificity. DNA-alkylating PI polyamide conjugates are attractive candidates as anticancer drugs acting through DNA damage and its subsequent inhibition of cell proliferation. One example is a chlorambucil-PI polyamide conjugate targeting the runt-related transcription factor (RUNX) family. RUNX1 has pro-oncogenic properties in acute myeloid leukemia, and recently the chlorambucil-PI polyamide conjugate was demonstrated to have anticancer effects. Herein, we apply another DNA-alkylating agent, seco-CBI, to target the consensus sequence of the RUNX family. Two types of CBI conjugates were prepared and their binding properties were characterized by Bind-n-Seq analysis using a high-throughput sequencer. The sequencing data were analyzed by two methods, MERMADE and our new MR (motif identification with a reference sequence), and the resultant binding motif logos were as predicted from the pairing rules proposed by Dervan et al. This is the first report to employ the MR method on alkylating PI polyamide conjugates. Moreover, cytotoxicity of conjugates 3 and 4 against a human non-small cell lung cancer, A549, were examined to show promising IC50s of 120 nm and 63 nm, respectively. These findings suggest seco-CBI-PI polyamide conjugates are candidates for oncological therapy.