Synthesis, cytotoxicity, DNA binding and topoisomerase II inhibition of cassiarin A derivatives.
Four series of cassiarin A derivatives with alkanoyl (3a-3d), aroyl (4a-4d), hydroxy/amino-substituted ethylene glycol (5a-5c) and selenium-containing (6a) side chains were synthesized. Their antitumor activities were evaluated against BT474, CHAGO, HepG2, KATO-III, SW620 and CaSki cancer cell lines. Preliminary results demonstrated that 5b had moderate activities against HepG2 and KATO-III cell lines, while 5c showed moderate to high cytotoxicity against most tested cell lines. In addition, 6a exhibited moderate cytotoxicity against cervical cells, CaSki. DNA-binding and ethidium bromide displacement experiments suggested that 5c and 5b binds to DNA via an intercalative mode, whereas 6a did not. However, the selenium-containing cassiarin A derivative 6a inhibited topoisomerase II with more than 95% inhibition at the concentration of 50 μM. These cassiarin A derivatives showed lower toxicity to normal cells, WI-38 than amonafide therefore they are potential lead compounds to be further developed as new anticancer agents.
Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
Urarika
U
Luesakul
Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
Tanapat
T
Palaga
Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
Kuakarun
K
Krusong
Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
Nattaya
N
Ngamrojanavanich
Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
Tirayut
T
Vilaivan
Antibody Production Research Unit, Institute of Biotechnology and Genetic Engineering, Chulalongkorn University, Bangkok 10330, Thailand.
Songchan
S
Puthong
Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand. Electronic address: nongnuj.j@chula.ac.th.
Nongnuj
N
Muangsin
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D056945:Hep G2 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; D059005:Topoisomerase II Inhibitors; C524027:cassiarin A; D004247:DNA; C427203:calf thymus DNA; D004250:DNA Topoisomerases, Type II
Amonafide; Cassiaria A; DNA-binding; Selenium compound; Topoisomerase II