New okadaic acid analogues from the marine sponge Merriamum oxeato and their effect on mitosis

• Published in: Journal of natural products (Washington, D.C.) Vol. 66; no. 6; pp. 838 - 843
• Main Authors: Britton, R, Roberge, M, Brown, C, Soest, R. van, Andersen, R.J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.06.2003; Amer Chemical Soc; American Society of Pharmacognosy
• Subjects: 27-O-acetyldinophysistoxin; 27-O-acetylokadaic acid; animal products; Animals; Biological and medical sciences; Breast Neoplasms; British Columbia; cell lines; cell proliferation; chemical structure; Chemistry, Medicinal; dinophysistoxins; DNA damage; DNA Damage - drug effects; Drug Screening Assays, Antitumor; enzyme inhibition; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - pharmacology; esters; Female; Flow Cytometry; G2 Phase - drug effects; General pharmacology; Humans; Inhibitory Concentration 50; Life Sciences & Biomedicine; Medical sciences; Merriamum oxeato; mitosis; Mitosis - drug effects; Molecular Structure; natural products; okadaic acid; Okadaic Acid - analogs & derivatives; Okadaic Acid - chemistry; Okadaic Acid - isolation & purification; Okadaic Acid - pharmacology; Pharmacognosy. Homeopathy. Health food; Pharmacology & Pharmacy; Pharmacology. Drug treatments; phosphoprotein phosphatase; Phosphoprotein Phosphatases - antagonists & inhibitors; Plant Sciences; Porifera; Porifera - chemistry; Pyrans - chemistry; Pyrans - isolation & purification; Pyrans - pharmacology; Science & Technology; spectral analysis; stereochemistry; Tumor Cells, Cultured - drug effects; Tumor Suppressor Protein p53 - physiology; British Columbia; Pacific Ocean; North Pacific; TRANSFORMATION; ELUCIDATION; DNA-DAMAGE CHECKPOINT; INHIBITION; CELL-CYCLE CHECKPOINTS; ISOGRANULATIMIDE; PROTEIN-KINASES; P53; Antineoplastic agent; Oxygen heterocycle; Marine environment; Acetal; Signal transduction; Cell cycle; Bicyclic compound; G2 Phase; Mammary gland; Human; Enzyme; Pharmacognosy; Transferases; Enzyme inhibitor; Animal origin; Tricyclic compound; In vitro; Biological activity; Spiran; Cell line; Porifera; Protein kinase; Isolation; Invertebrata; Structural analysis
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/np0300129

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 (IC50 = 1 ng/mL) and cellular protein Ser/Thr phosphatases (IC50 = 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 (IC50 = 1 ng/mL), making these compounds poor candidates for therapeutic agents to augment the effectiveness of DNA-damaging therapies.