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Jennie Wang, Mingtao Liu, Chun Yang, Xiaogang Wu, Euphemia Wang, Paul Liu
An HPLC method for the assay of a DNA topoisomerase inhibitor, LMP776 (NSC 725776), has been developed and validated. The stress testing of LMP776 was carried out in accordance with International Conference on Harmonization (ICH) guidelines Q1A (R2) under acidic, alkaline, oxidative, thermolytic, and photolytic conditions. The separation of LMP776 from its impurities and degradation products was achieved within 40 min on a Supelco Discovery HS F5 column (150 mm × 4.6 mm i.d., 5 μm) with a gradient mobile phase comprising 38-80% acetonitrile in water, with 0...
May 30, 2016: Journal of Pharmaceutical and Biomedical Analysis
Daniel E Beck, Keli Agama, Christophe Marchand, Adel Chergui, Yves Pommier, Mark Cushman
Carbohydrate moieties were strategically transported from the indolocarbazole topoisomerase I (Top1) inhibitor class to the indenoisoquinoline system in search of structurally novel and potent Top1 inhibitors. The syntheses and biological evaluation of 20 new indenoisoquinolines glycosylated with linear and cyclic sugar moieties are reported. Aromatic ring substitution with 2,3-dimethoxy-8,9-methylenedioxy or 3-nitro groups exerted strong effects on antiproliferative and Top1 inhibitory activities. While the length of the carbohydrate side chain clearly correlated with antiproliferative activity, the relationship between stereochemistry and biological activity was less clearly defined...
February 27, 2014: Journal of Medicinal Chemistry
Yuko Maede, Hiroyasu Shimizu, Toru Fukushima, Toshiaki Kogame, Terukazu Nakamura, Tsuneharu Miki, Shunichi Takeda, Yves Pommier, Junko Murai
Clinical topoisomerase I (Top1) and II (Top2) inhibitors trap topoisomerases on DNA, thereby inducing protein-linked DNA breaks. Cancer cells resist the drugs by removing topoisomerase-DNA complexes, and repairing the drug-induced DNA double-strand breaks (DSB) by homologous recombination and nonhomologous end joining (NHEJ). Because numerous enzymes and cofactors are involved in the removal of the topoisomerase-DNA complexes and DSB repair, it has been challenging to comprehensively analyze the relative contribution of multiple genetic pathways in vertebrate cells...
January 2014: Molecular Cancer Therapeutics
Maris A Cinelli, P V Narasimha Reddy, Peng-Cheng Lv, Jian-Hua Liang, Lian Chen, Keli Agama, Yves Pommier, Richard B van Breemen, Mark Cushman
Hydroxylated analogues of the anticancer topoisomerase I (Top1) inhibitors indotecan (LMP400) and indimitecan (LMP776) have been prepared because (1) a variety of potent Top1 poisons are known that contain strategically placed hydroxyl groups, which provides a clear rationale for incorporating them in the present case, and (2) the hydroxylated compounds could conceivably serve as synthetic standards for the identification of metabolites. Indeed, incubating LMP400 and LMP776 with human liver microsomes resulted in two major metabolites of each drug, which had HPLC retention times and mass fragmentation patterns identical to those of the synthetic standards...
December 27, 2012: Journal of Medicinal Chemistry
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