Crosslinks in DNA

Flamm WG, Bernheim NJ, Fishbein L. On the existence of intrastrand crosslinks in DNA alkylated with sulfur mustard. Biochim Biophys Acta. 1970 224 657-659. 

Kohn KW, Ewig RAG, Erickson LC, Zwelling LA (1981) Measurements of strand breaks and crosslinks in DNA by alkaline elution. In Friedberg E, Hanawalt P (eds) DNA repair a laboratory manual of research procedures. Marcel Dekker, New York, p 379... 

The photochemistry of the phenyl selenide thymidine derivative (203) was examined. It was suggested that the radical (204) and carbocation (205) were produced, while the carbocation was responsible for inter-strand crosslinks in DNA models. Similar results were obtained from an aryl sulfide thymidine-derivative. 

While the critical role of intrastrand 1,2-crosslinks in the mechanism of action of the anti-tumor drug cis- [PtCl2(NH3)2] is well established, much less is known about the few frans-analogs that exhibit similar efficacy. A series of 1,3-adducts has been characterized with 3-mers generally involving purine N7 coordination (32-34), and either monofunctional or interstrand adducts are formed with duplex DNA (35). However, one of the most active compounds, frans-[PtCl2 ( )-HN = C(OMe)Me 2], (2), has been shown to form a 1,2-adduct with 2-mer ribonucleotide sequence r(AG) (36). Though the formation of the... 

Oxygen-free reactions of psoralens, when in close proximity to the target, proceed via the first excited states in which the 3,4-and the 4, 5 7r-bonds of the pyrone and furan moieties, respectively, can undergo C4-cyclization reactions with, e.g., unsaturated bonds of lipids, or the C5=C6 double bonds of thymine in DNA. In reactions with DNA the psoralen is believed to intercalate with DNA in the dark. Subsequent irradiation at 400 nm usually leads to furan-side 4, 5 -monoadduct formation, whereas irradiation at 350 nm increases the formation of crosslinks in which the furan and pyrone rings form C4 cycloadducts to thymines on opposite strands [95], Subsequent irradiation of the 4, 5 -monoadducts at 350 nm leads to formation of crosslinks and conversion into pyrone-side 3,4-monoadducts. Shorter wave-... 

Perez C, Leng M, Malinge JM. Rearrangement of interstrand crosslinks into intrastrand crosslinks in cis-diamminedichloroplatinum(II)-modified DNA. Nucleic Acids Res 1997 25 896-903. 

Since the formation of the ethyleniminium ion is crucial for the cytotoxic activity of the nitrogen mustards, it is not surprising that stable ethylenimine derivatives have antitumor activity. Thiophospho-ramide or thiotepa is the best known compound of this type that has been used clinically. Both thiotepa and its primary metabolite, triethylenephos-phoramide (TEPA), to which it is rapidly converted by hepatic mixed-function oxygenases form crosslinks with DNA. It is mainly used as an intravesicu-lar agent in bladder cancer. Thiotepa produces little toxicity other than myelosuppression. 

Bradley. M.O. Dysart. G. (1985) DNA single-strand breaks, double-strand breaks, and crosslinks in rat testicular germ cells measurements of their fonnation and repair by alkaline and neutral filter elution. Cell Biol. Toxicol.. 1. 181-185... 

Alzheimer s disease (AD) is the most prevalent form of senile dementia. Up to two million people in North America suffer from it, and it is the fourth cause of death in the elderly. The cause and treatment of this disease are therefore extremely important. Although the role of aluminum in AD and its in vivo chemistry is not known in detail, patients with Alzheimer s disease have been shown to have elevated aluminum concentrations in certain parts of the brain. Aluminum appears to concentrate in the nucleus. Crosslinks with DNA strands have been found. Crosslink formation can be reversed by sequestering the aluminum with EDTA. 

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