title: New okadaic acid analogues from the marine sponge Merriamum oxeato and their effect on mitosis.
abstract: Inhibitors of the G2 DNA damage checkpoint can selectively sensitize cancer cells with impaired p53 tumor suppressor activity to killing by DNA-damaging drugs or ionizing radiation and have been proposed as a promising therapeutic strategy. An extract from the Northeastern Pacific marine sponge Merriamum oxeato showed G2 checkpoint inhibitory activity, and fractionation identified the known dinoflagellate toxin dinophysistoxin 1 (1) and the two novel analogues 27-O-acetylokadaic acid (2) and 27-O-acetyldinophysistoxin 1 (3) as the active compounds. The mixture of 1, 2, and 3 was extremely potent at inhibiting the G2 checkpoint (IC(50) = 1 ng/mL) and cellular protein Ser/Thr phosphatases (IC(50) = 1 ng/mL), and it radiosensitized MCF-7 breast cancer cells expressing mutated p53 at all concentrations tested. However, the mixture of 1, 2, and 3 was also very toxic to cells not exposed to DNA damage (IC(50) = 1 ng/mL), making these compounds poor candidates for therapeutic agents to augment the effectiveness of DNA-damaging therapies.
authors.affiliation: Department of Chemistry, University of British Columbia, Vancouver, British Columbia, V6T 1Z1, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Britton
authors.forename: Michel
authors.initials: M
authors.lastname: Roberge
authors.forename: Colleen
authors.initials: C
authors.lastname: Brown
authors.forename: Rob
authors.initials: R
authors.lastname: van Soest
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Andersen
mesh_terms: D000818:Animals; D001943:Breast Neoplasms; D001955:British Columbia; D004249:DNA Damage / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008938:Mitosis / Q000187:drug effects*; D015394:Molecular Structure; D019319:Okadaic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D011161:Porifera / Q000737:chemistry*; D011714:Pyrans / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: C478724:27-O-acetyldinophysistoxin 1; C478723:27-O-acetylokadaic acid; D004791:Enzyme Inhibitors; D011714:Pyrans; D016159:Tumor Suppressor Protein p53; D019319:Okadaic Acid; C051904:dinophysistoxin 1; D010749:Phosphoprotein Phosphatases