“…The similar biochemical reactivity of 4 − 6 , with respect to interstrand cross-linking, demonstrates that the aryl O -methyl ether in these structures is sufficiently electron-rich to facilitate the ring opening activation of the aziridine ring to form electrophilic species 11 (illustrated in Scheme for 5 ). This is thought to be the initial point of formation of a covalent bond with the DNA substrate ( , ). 2 Mechanism of Interstrand Cross-Linking by 5 …”
Section: Resultsmentioning
confidence: 99%
“…Initial biological studies have shown highly promising antitumor activity against a variety of cancerous cell lines both in vitro and in vivo ( − ). The clinical candidates FK973 ( 3 ) ( − ) and more recently FK317 ( 4 ) ( − ), both semi-synthetically derived from FR900482, have exhibited highly promising antitumor activity in human clinical trials in Japan and hold significant promise for becoming powerful anticancer drugs alongside the structurally related and widely used antitumor drug mitomycin C (MMC, 7 ) ( , ).…”
FR900482 (1) and FR66979 (2) are structurally novel natural products isolated by Fujisawa in 1987 and have been shown to be highly potent antitumor antibiotics structurally related to the mitomycins. Studies on the mode of action have established that these new agents form covalent DNA interstrand cross-links both in vitro and in vivo as a result of the reactive mitosene intermediate generated upon bioreductive activation. Semisynthetic analogues such as FK973 (3) and FK317 (4) were developed in the search for potentially superior clinical candidates. Although FK317 has been shown to be a potent compound, to date no direct evidence of DNA interstrand cross-link sequence specificity has been reported. In this study, DNA interstrand cross-links were generated by treatment of a synthetic duplex DNA substrate with FK317 (4) and its deacetylated metabolites FR70496 (5) and FR157471 (6). Analysis by gel electrophoresis revealed the formation of orientation isomers displaying electrophoretic mobility vastly greater than the mobilities of those generated from FR900482 (1). Despite these differences, it was established by Fe(II)-EDTA footprinting that FK317 (4) as well as 5 and 6 forms DNA interstrand cross-links within the expected 5'CpG3' step, clearly demonstrating that the phenolic hydrogen in 1 and 2 is not a prerequisite for efficient DNA interstrand cross-linking by the FR class of compounds.
“…The similar biochemical reactivity of 4 − 6 , with respect to interstrand cross-linking, demonstrates that the aryl O -methyl ether in these structures is sufficiently electron-rich to facilitate the ring opening activation of the aziridine ring to form electrophilic species 11 (illustrated in Scheme for 5 ). This is thought to be the initial point of formation of a covalent bond with the DNA substrate ( , ). 2 Mechanism of Interstrand Cross-Linking by 5 …”
Section: Resultsmentioning
confidence: 99%
“…Initial biological studies have shown highly promising antitumor activity against a variety of cancerous cell lines both in vitro and in vivo ( − ). The clinical candidates FK973 ( 3 ) ( − ) and more recently FK317 ( 4 ) ( − ), both semi-synthetically derived from FR900482, have exhibited highly promising antitumor activity in human clinical trials in Japan and hold significant promise for becoming powerful anticancer drugs alongside the structurally related and widely used antitumor drug mitomycin C (MMC, 7 ) ( , ).…”
FR900482 (1) and FR66979 (2) are structurally novel natural products isolated by Fujisawa in 1987 and have been shown to be highly potent antitumor antibiotics structurally related to the mitomycins. Studies on the mode of action have established that these new agents form covalent DNA interstrand cross-links both in vitro and in vivo as a result of the reactive mitosene intermediate generated upon bioreductive activation. Semisynthetic analogues such as FK973 (3) and FK317 (4) were developed in the search for potentially superior clinical candidates. Although FK317 has been shown to be a potent compound, to date no direct evidence of DNA interstrand cross-link sequence specificity has been reported. In this study, DNA interstrand cross-links were generated by treatment of a synthetic duplex DNA substrate with FK317 (4) and its deacetylated metabolites FR70496 (5) and FR157471 (6). Analysis by gel electrophoresis revealed the formation of orientation isomers displaying electrophoretic mobility vastly greater than the mobilities of those generated from FR900482 (1). Despite these differences, it was established by Fe(II)-EDTA footprinting that FK317 (4) as well as 5 and 6 forms DNA interstrand cross-links within the expected 5'CpG3' step, clearly demonstrating that the phenolic hydrogen in 1 and 2 is not a prerequisite for efficient DNA interstrand cross-linking by the FR class of compounds.
In 2008 we published recommendations on chemicals that would be appropriate to evaluate the sensitivity and specificity of new/modified mammalian cell genotoxicity tests, in particular to avoid misleading positive results. In light of new data it is appropriate to update these lists of chemicals. An expert panel was convened and has revised the recommended chemicals to fit the following different sets of characteristics: • Group 1: chemicals that should be detected as positive in in vitro mammalian cell genotoxicity tests. Chemicals in this group are all in vivo genotoxins at one or more endpoints, either due to DNA-reactive or non DNA-reactive mechanisms. Many are known carcinogens with a mutagenic mode of action, but a sub-class of probable aneugens has been introduced. • Group 2: chemicals that should give negative results in in vitro mammalian cell genotoxicity tests. Chemicals in this group are usually negative in vivo and non-DNA-reactive. They are either non-carcinogenic or rodent carcinogens with a non-mutagenic mode of action. • Group 3: chemicals that should give negative results in in vitro mammalian cell genotoxicity tests, but have been reported to induce gene mutations in mouse lymphoma cells, chromosomal aberrations or micronuclei, often at high concentrations or at high levels of cytotoxicity. Chemicals in this group are generally negative in vivo and negative in the Ames test. They are either non-carcinogenic or rodent carcinogens with an accepted non-mutagenic mode of action. This group contains comments as to any conditions that can be identified under which misleading positive results are likely to occur. This paper, therefore, updates these three recommended lists of chemicals and describes how these should be used for any test evaluation program.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
