@article {5181,
	title = {G(2) DNA damage checkpoint inhibition and antimitotic activity of 13-hydroxy-15-oxozoapatlin},
	journal = {Journal of Biological Chemistry},
	volume = {276},
	number = {51},
	year = {2001},
	note = {ISI Document Delivery No.: 505QLTimes Cited: 24Cited Reference Count: 51},
	month = {Dec},
	pages = {48231-48236},
	type = {Article},
	abstract = {Checkpoints activated in response to DNA damage cause arrest in the G(1) and G(2) phases of the cell cycle. Inhibitors of the G(2) checkpoint may be used as tools to study this response and also to increase the effectiveness of DNA-damaging therapies against cancers lacking p53 function. Using a cell-based assay for G(2) check. point inhibitors, we have screened extracts from the NCI National Institutes of Health Natural Products Repository and have identified 13-hydroxy-15-oxozoapatlin (OZ) from the African tree Parinari curatellifolia. Flow cytometry with a mitosis-specific antibody showed that checkpoint inhibition by OZ was maximal at 10 muM, which released 20\% of irradiated MCF-7 cells expressing defective p53 and 30\% of irradiated HCT116p53(-/-) cells from G(2) arrest. OZ additively increased the response to the checkpoint inhibitors isogranulatimide and debromohymenialdisine, but it did not augment the effects of UCN-01 or caffeine. Unlike other checkpoint inhibitors, OZ did not inhibit ataxia-telangiectasia mutated (ATM), ATM and Rad3-related (ATR), Chk1, Chk2, Plk1, or Ser/Thr protein phosphatases in vitro. Treatment with OZ also caused G(2)-arrested and cycling cells to arrest in mitosis in a state resembling prometaphase. In these cells, the chromosomes were condensed and scattered over disordered mitotic spindles. The results demonstrate that OZ is both a G(2) checkpoint inhibitor and an antimitotic agent.},
	keywords = {ARREST, BHK CELLS, CAFFEINE, CELL-CYCLE CHECKPOINTS, CHROMOSOME ALIGNMENT, G2, P34(CDC2) KINASE, PROTEIN-KINASE, RADIOSENSITIZING AGENT, TYROSINE KINASE, UCN-01},
	isbn = {0021-9258},
	url = {<Go to ISI>://000172927000066},
	author = {Rundle, N. T. and Xu, L. and Andersen, R. J. and Roberge, M.}
}
@article {5042,
	title = {Inhibition of the G(2) DNA damage checkpoint and of protein kinases Chk1 and Chk2 by the marine sponge alkaloid debromohymenialdisine},
	journal = {Journal of Biological Chemistry},
	volume = {276},
	number = {21},
	year = {2001},
	note = {ISI Document Delivery No.: 435FJTimes Cited: 78Cited Reference Count: 61},
	month = {May},
	pages = {17914-17919},
	type = {Article},
	abstract = {Cells can respond to DNA damage by activating checkpoints that delay cell cycle progression and allow time for DNA repair. Chemical inhibitors of the G(2) phase DNA damage checkpoint may be used as tools to understand better how the checkpoint is regulated and may be used to sensitize cancer cells to DNA-damaging therapies. However, few inhibitors are known. We used a cell-based assay to screen natural extracts for G(2) checkpoint inhibitors and identified debromohymenialdisine (DBH) from a marine sponge. DBH is distinct structurally from previously known G(2) checkpoint inhibitors. It inhibited the G(2) checkpoint with an IC50 of 8 muM and showed moderate cytotoxicity (IC50 = 25 muM) toward MCF-7 cells. DBH inhibited the checkpoint kinases Chk1 (IC50 = 3 muM) and Chk2 (IC50 = 3.5 muM) but not ataxia-telangiectasia mutated (ATM), ATM-Rads-related protein, or DNA-dependent protein kinase in vitro, indicating that it blocks two major branches of the checkpoint pathway downstream of ATM. It did not cause the activation or inhibition of different signal transduction proteins, as determined by mobility shift analysis in Western blots, suggesting that it inhibits a narrow range of protein kinases in vivo.},
	keywords = {14-3-3 BINDING, BHK CELLS, CDC25, CELL-CYCLE CHECKPOINTS, CHROMOSOME, CONDENSATION, DEPENDENT KINASES, H3 PHOSPHORYLATION, INDUCED MITOTIC DELAY, MAMMALIAN-CELLS, PHOSPHATASE, RADIOSENSITIZING AGENT},
	isbn = {0021-9258},
	url = {<Go to ISI>://000168866500042},
	author = {Curman, D. and Cinel, B. and Williams, D. E. and Rundle, N. and Block, W. D. and Goodarzi, A. A. and Hutchins, J. R. and Clarke, P. R. and Zhou, B. B. and Lees-Miller, S. P. and Andersen, R. J. and Roberge, M.}
}
@article {4903,
	title = {Improved synthesis of isogranulatimide, a G2 checkpoint inhibitor. Syntheses of didemnimide C, isodidemnimide A, neodidemnimide A, 17-methylgranulatimide, and isogranulatimides A-C},
	journal = {Journal of Organic Chemistry},
	volume = {65},
	number = {2},
	year = {2000},
	note = {ISI Document Delivery No.: 276YFTimes Cited: 44Cited Reference Count: 35},
	month = {Jan},
	pages = {530-535},
	type = {Article},
	abstract = {A concise, improved synthesis of isogranulatimide (6), a naturally occurring substance with G2 checkpoint inhibition activity, is described. Also reported are the syntheses of didemnimide C (18), isodidemnimide A (24), neodidemnimide A (36), 17-methylgranulatimide (9), and isogranulatimides A (10), B (11), and C (12). Compounds 9-12, congeners of isogranulatimide (6), are now available for biological evaluation.},
	keywords = {BHK CELLS, CAFFEINE, CANCER, CELL-CYCLE CHECKPOINTS, CISPLATIN, DERIVATIVES, DNA-REPLICATION, ENHANCEMENT, IMIDAZOLES, RADIOSENSITIZATION},
	isbn = {0022-3263},
	url = {<Go to ISI>://000084905400039},
	author = {Piers, E. and Britton, R. and Andersen, R. J.}
}
@article {4194,
	title = {Granulatimide and isogranulatimide, aromatic alkaloids with G2 checkpoint inhibition activity isolated from the Brazilian ascidian Didemnum granulatum: Structure elucidation and synthesis},
	journal = {Journal of Organic Chemistry},
	volume = {63},
	number = {26},
	year = {1998},
	note = {ISI Document Delivery No.: 153LPTimes Cited: 72Cited Reference Count: 34},
	month = {Dec},
	pages = {9850-9856},
	type = {Article},
	abstract = {Crude methanol ex-tracts of the ascidian Didemum granulatum collected in Brazil showed activity in a new screen for G2 cell cycle checkpoint inhibitors. Bioassay-guided fractionation of the extract yielded the known alkaloids didemnimides A (1) and D (2), the new alkaloid didemnimide E (3), and a new G2 checkpoint inhibitor. Two candidate structures for the inhibitor, named granulatimide (4) and isogranulatimide (5), have been prepared via a short and efficient biomimetic synthesis involving the photolysis of didemnimide A (1). The synthesis revealed that the correct structure for the naturally occurring G2 checkpoint inhibitor is isogranulatimide (5). Granulatimide (4), the other candidate structure, was also found to be a G2 checkpoint inhibitor, and it was subsequently detected in chromatographic fractions associated with purification of D. granulatum alkaloids. Granulatimide (4) and isogranulatimide (5) represent the first examples of a new class of G2 specific cell cycle checkpoint inhibitors and the first ones identified through a rational screening program.},
	keywords = {BHK CELLS, CAFFEINE, CELL-CYCLE CHECKPOINTS, DNA-REPLICATION, HELA-CELLS, INDUCED G(2) DELAY, mitosis, PROTEIN-KINASE, RADIOSENSITIZATION, STAUROSPORINE},
	isbn = {0022-3263},
	url = {<Go to ISI>://000077834800044},
	author = {Berlinck, R. G. S. and Britton, R. and Piers, E. and Lim, L. and Roberge, M. and da Rocha, R. M. and Andersen, R. J.}
}
@article {4389,
	title = {High-throughput assay for G(2) checkpoint inhibitors and identification of the structurally novel compound isogranulatimide},
	journal = {Cancer Research},
	volume = {58},
	number = {24},
	year = {1998},
	note = {ISI Document Delivery No.: 148HTTimes Cited: 83Cited Reference Count: 39},
	month = {Dec},
	pages = {5701-5706},
	type = {Article},
	abstract = {Treatment of cancer cells lacking p53 function with G(2) checkpoint inhibitors sensitizes them to the toxic effects of DNA damage and has been proposed as a strategy for cancer therapy. However, few inhibitors are known, and they have been found serendipitously, We report the development of a G(2) checkpoint inhibition assay that is suitable for high-throughput screening and its application to a screen of 1300 natural extracts. We present the isolation of a new G(2) checkpoint inhibitor, the structurally novel compound isogranulatimide. In combination with gamma-irradiation, isogranulatimide selectively kills MCF-7 cells lacking p53 function.},
	keywords = {ANTITUMOR DRUG, BHK CELLS, CAFFEINE, CELL-CYCLE CHECKPOINTS, DNA-DAMAGE, HELA-CELLS, mitosis, P34(CDC2) KINASE, P53 FUNCTION, PREMATURE, PROTEIN KINASE-C},
	isbn = {0008-5472},
	url = {<Go to ISI>://000077499800017},
	author = {Roberge, M. and Berlinck, R. G. S. and Xu, L. and Anderson, H. J. and Lim, L. Y. and Curman, D. and Stringer, C. M. and Friend, S. H. and Davies, P. and Vincent, I. and Haggarty, S. J. and Kelly, M. T. and Britton, R. and Piers, E. and Andersen, R. J.}
}
