Potent activity against K562 cells by polyamide–seco-CBI conjugates targeting histone H4 genes

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 1; pp. 168 - 174
• Main Authors: Minoshima, Masafumi, Chou, James C., Lefebvre, Sophie, Bando, Toshikazu, Shinohara, Ken-ichi, Gottesfeld, Joel M., Sugiyama, Hiroshi
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 2010; Elsevier
• Subjects: Anticancer agent; Antineoplastic agents; Antineoplastic Agents, Alkylating - chemical synthesis; Antineoplastic Agents, Alkylating - chemistry; Antineoplastic Agents, Alkylating - pharmacology; Apoptosis - drug effects; Biological and medical sciences; DNA - metabolism; DNA alkylating agent; Gene Expression Regulation, Neoplastic - drug effects; Gene Silencing; General aspects; Genes - drug effects; Histone; Histones - genetics; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; K562 Cells; Leukemia, Erythroblastic, Acute - drug therapy; Medical sciences; Nylons - chemical synthesis; Nylons - chemistry; Nylons - pharmacology; Pharmacology. Drug treatments; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Pyrrole–imidazole polyamide; DNA alkylating agent; Anticancer agent; Histone; Pyrrole–imidazole polyamide; Gene Silencing; Antineoplastic agent; Nylon; Pyrrole-imidazole polyamide; Leukemia; Cytotoxicity; Oligomer; Structure activity relation; Inhibition; Mechanism of action; Tumor cell; Human; Pyrrole derivative copolymer; Gene expression; In vitro; Histone H4; Gene silencing; Alkylating agent; Cell line; Nitrogen mustard; Imidazole derivative copolymer; Conjugated compound; Indole derivatives; Nuclear protein
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.11.005

We designed and synthesized conjugates between pyrrole–imidazole polyamides and seco-CBI that alkylate within the coding regions of the histone H4 genes. DNA alkylating activity on the histone H4 fragment and cellular effects against K562 chronic myelogenous leukemia cells were investigated. One of the conjugates, 5-CBI, showed strong DNA alkylation activity and good sequence specificity on a histone H4 gene fragment. K562 cells treated with 5-CBI down-regulated the histone H4 gene and induced apoptosis efficiently. Global gene expression data revealed that a number of histone H4 genes were down-regulated by 5-CBI treatment. These results suggest that sequence-specific DNA alkylating agents may have the potential of targeting specific genes for cancer chemotherapy. We designed and synthesized conjugates between pyrrole–imidazole polyamides and seco-CBI that alkylate within the coding regions of the histone H4 genes. DNA alkylating activity on the histone H4 fragment and cellular effects against K562 chronic myelogenous leukemia cells were investigated. One of the conjugates, 5-CBI, showed strong DNA alkylation activity and good sequence specificity on a histone H4 gene fragment. K562 cells treated with 5-CBI down-regulated the histone H4 gene and induced apoptosis efficiently. Global gene expression data revealed that a number of histone H4 genes were down-regulated by 5-CBI treatment. These results suggest that sequence-specific DNA alkylating agents may have the potential of targeting specific genes for cancer chemotherapy.