DNA cross-linking agent

DNA cross-linking agents (mainly heterocycles) as antitumor drugs 98CRV2723. 

Natural and synthetic heterocycles as DNA cross-linking agents and antitumor drugs 98CRV2723. 

Richter, S. N. Maggi, S. Colloredo-Mels, S. Palumbo, M. Freccero, M. Binol quinone methides as bisalkylating and DNA cross-linking agents. J. Am. Chem. Soc. 2004, 126, 13973-13979. 

Huang X, Okafuji M, Traganos F, Luther E, Holden E, Darzynkiewicz Z. Assessment of histone H2AX phosphorylation induced by DNA topoisomerase I and II inhibitors topotecan and mitoxantrone and by the DNA cross-linking agent cisplatin. Cytometry A. 2004 Apr 58(2) 99-110. 

These compounds exert their biological activity as DNA cross-linking agents. The anticancer activity of this series of compounds is almost identical (albeit more potent and less toxic) to the mitomycins in that the natural product itself must be activated in order to cross-link DNA. A two-electron reduction of FR900482 converts it to a mixture of 307 and 308. Loss of water provides a leucoaziridinomitosene 309. It is this metabolite that undergoes DNA cross-linking to form the DNA adduct 310 (Scheme 59). 

Ando, H. and M. Mishina. Efficient mutagenesis of zebrafish by a DNA cross-linking agent. Neurosci. Lett. 244 81-84, 1998. 

Fanconi s anaemia (FA) is an autosomal disorder with bone marrow failure, variable presence of developmental abnormalities, hypersensitivity to DNA cross-linking agents, and a very high incidence of cancer. Different complementation groups have been cloned, but the exact pathway remains uncertain. However, data suggest that the syndrome is linked to mutations in XRCC9 and XRCCl 1 and therefore to defects in the homologous recombination repair pathway (summarized in [26]). 

Drosophila exhibit hypersensitivity to DNA cross-linking agents and are defective in a deoxyribonuclease. Genetics, 125, 813-819. 

Fanconi anemia Repair of double-strand breaks by homologous recombination DNA cross-linking agents, reactive oxidant chemicals Acute myeloid leukemia, squamous-ceU carcinomas Developmental abnormalities including infertility and deformities of the skeleton anemia... 

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