title: Antiproliferative activity of O4-benzo[c]phenanthridine alkaloids against HCT-116 and HL-60 tumor cells.
abstract: The O4-benzo[c]phenanthridine alkaloids exhibit potent antiproliferative activity against cancer cells, which is derived from their ability to inhibit of topoisomerase I and II. It has been reported that in the alkaloids a cationic quaternary ammonium atom, which results in resonance effects between ring A and B, is necessary for increased antiproliferative activity. These findings indicate the role of their substituents at ring A on inhibition of tumor cell proliferation. In the present study, we systematically assessed the cytotoxic activities of naturally occurring alkaloids and their derivatives containing various ring A substituents against two tumor cell lines, HCT-116 colon tumor cells and HL-60 promyelocytic leukemia cells. Among the cationic iminium alkaloids, which displayed more potent activity than the corresponding neutral derivatives, and the 7,8-oxygenated benzo[c]phenanthridine alkaloids, chelerythrine and NK109, exhibited stronger antiproliferative activity than the 8,9- and 9,10-oxygenated alkaloids. The activity of cationic iminium alkaloids could be correlated with the bond lengths of their ring A substituents and the electrostatic potentials of their ammonium molecules by DFT calculation.
authors.affiliation: School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan. Electronic address: nhatae@hoku-iryo-u.ac.jp.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Hatae
authors.affiliation: School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan.
authors.forename: Erina
authors.initials: E
authors.lastname: Fujita
authors.affiliation: School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Shigenobu
authors.affiliation: School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan.
authors.forename: Sayumi
authors.initials: S
authors.lastname: Shimoyama
authors.affiliation: Graduate School of Pharmacy & Pharmaceutical Sciences, and Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan.
authors.forename: Yuhsuke
authors.initials: Y
authors.lastname: Ishihara
authors.affiliation: Graduate School of Pharmacy & Pharmaceutical Sciences, and Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan.
authors.forename: Yuhki
authors.initials: Y
authors.lastname: Kurata
authors.affiliation: Graduate School of Pharmacy & Pharmaceutical Sciences, and Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan.
authors.forename: Tominari
authors.initials: T
authors.lastname: Choshi
authors.affiliation: Graduate School of Pharmacy & Pharmaceutical Sciences, and Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishiyama
authors.affiliation: School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Okada
authors.affiliation: Graduate School of Pharmacy & Pharmaceutical Sciences, and Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hibino
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D053119:Benzophenanthridines / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism; D045325:HCT116 Cells; D018922:HL-60 Cells; D006801:Humans; D010617:Phenanthridines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D053119:Benzophenanthridines; C108284:NK 109; D010617:Phenanthridines; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II
keywords: Antiproliferative activity; Antitumor; Benzo[c]phenanthridine alkaloid; DFT calculation; Iminium ion