DNA cisplatin

What kind of processes are involved in deplatination and what are the mechanisms leading to repair of the DNA-cisplatin binding ... 

Cisplatin, a bright yellow compound, is odministered intravenously to cancer patients. It destroys the cancer cells ability to reproduce by changing the configuration of their DNA. Cisplatin binds to two sites on a strand of DNA, causing it to bend about 33° away from the rest of the strand. 

X-ray diffraction studies pravided this model of DNA-cisplatin binding in which the two chloride ligands in cisplatin are replaced by the N atoms in adjacent guanine bases on one strand of DNA. The structure of the cisplatin-DNA adduct is partially stabilized by hydrogen bonds (red dotted lines). For simplicity, all H atoms in the DNA molecule are omitted. 

Since free platinum intercalates or intracalates in DNA, cisplatin can be cytotoxic towards lung cancer cells, but it can also enhance carcinogenicity in experimental animals (Leopold et al. 1981). (-)-Epigallocatechin gallate can prevent cisplatin-induced lung tumorigenesis in A/J mice (Mimoto et al. 2000). 

The structures and properties of these non-canonical DNA are closely related to their biological functions. Due to their unique three-dimensional structures, small molecules can bind to them to stabilize or alter their structures, and are eventually able to regulate their biological functions. One of the most successful such small molecules is ds-diamminedichloroplat-inum(ii), or cisplatin, a commonly used anti-cancer drug. It can covalently bind to DNA molecules, forming a DNA-cisplatin adduct that eventually inhibits DNA synthesis. Therefore, exploring the small molecules that can interact with DNA, especially with non-canonical DNA molecules, is an effective route to anti-cancer drug discovery. 

Structure, recognition, and processing of cisplatin-DNA adducts 99CRV2467. 

The only prominent antitumor tetravalent platinum complex so far is iproplatin (102). In vitro it has been shown to cause interstrand DNA-breaking and cross linking. Free radical scavengers inhibit these effects. The complex is less neurotoxic and less nephrotoxic than cisplatin. Its synthesis begins with hydrogen peroxide oxidation of cis-dichlorobis(isopropvlamine) platinum (100) to the dimethylacetamide complex 101. The latter is heated in vacuum to liberate iproplatin [25]. 

Cisplatin, Pt (NH3)2Cl2, is a chemotherapeutic agent that disrupts die growth of DNA. If die current cost of Pt is 1118.0/troy ounce (1 troy oz = 31.10 g), how many grams of cisplatin can you make with three thousand dollars worth of platinum How many pounds ... 

The cis isomer ( cisplatin ) is an effective anticancer drug. This reflects the ability of the two Cl atoms to interact with the nitrogen atoms of DNA, a molecule responsible for cell reproduction. The trans isomer is ineffective in chemotherapy, presumably because the Q atoms are too far apart to react with a DNA molecule. 

Dimeric complexes like [Cl(NH3)Pt H2N(CH2)4NH2 Pt(NH3)Cl]Cl2 are also being investigated as they bind to DNA in a different way to that involved in cisplatin binding and are active in cisplatin-resistant human tumour cells. They are more potent than cisplatin in lung cancer models in vivo and are likely to go on clinical trials in the near future [204],... 

The ability of cisplatin to be toxic to tumour cells is believed to relate to its binding to DNA, but since trans- [Pt (NH3) 2 Cl2 ] also binds to DNA, the reason for the inactivity of the trans-form is more complex. 

Figure 3.118 Possible modes of cisplatin binding to DNA strands. (Reproduced from J.J.R. Frausto da Silva and R.J.P. Williams, The Biological Chemistry of the Elements, 1994, p. 539, by permission of Oxford University Press.)...

Figure 3.119 cis-Pt(NH3)2[d(pGpG)], model compound for the binding of cisplatin to DNA. (Reprinted with permission from Science, 1985,230,430. Copyright (1985) American Association for the Advancement of Science.)... 

Binding of cisplatin to the neighbouring bases in the DNA disrupts the orderly stacking of the purine bases when it forms a 1,2-intrastrand crosslink, it bends the DNA helix by some 34° towards the major groove and unwinds the helix by 13°. These cross-links are believed to block DNA replication. 

Cisplatin was discovered fortuitously by observing that bacteria present in electrolysis solutions could not divide. It is hypothesized that in the intracellular environment, a chloride is lost and replaced by a water molecule. The resulting species is an efficient bifunctional interactor with DNA, forming platinum-based cross-links similar to that formed by alkylating agents. 

Bloemink, M. Reedijk, J. In Sigel, A. Sigel, H. (Eds.), Metal Ions in Biological Systems Cisplatin and Derived Anticancer Drugs. Mechanism and Current Status of DNA Binding, Marcel Dekker, New York, 1996 Vol. 32, p. 641. 

Eloxatin ) (cisplatin) in that it binds to the N-7 position of guanine, which results in cross-linking of DNA and double-stranded DNA breaks. Acute (within first 2 days) and persistent (greater than 14 days) neuropathies Additional toxicites Anaphylactic-like reactions, dyspnea... 

Hambley and co-workers have reported the synthesis, DNA cross-linking, and in vitro anticancer properties of a platinum(II) complex that was designed to bind the macromolecule in an interstrand rather than intrastrand manner,162 the latter being the dominant mode of DNA-binding by platinum anticancer drugs such as cisplatin. The complex [PtCl2(hpip)] ((46) ... 

Cisplatin is a platinum complex (platinum dichloride and two ammonia molecules) used as a cytostatic agent against cancer. The molecule cross-links DNA strands, thus leading to cell death. 

ABT-888 (22) shows limited activity as monotherapy however, it strongly potentiates the activity of multiple DNA-damaging agents in preclinical models [39]. ABT-888 potentiated TMZ in a glioma model in a dose-dependent manner, with maximal efficacy achieved at 50 mg/ kg, which reduced tumor volume by 63%, 44% better than TMZ alone. In the MX-1 breast xenograft model, ABT-888, at 5 mg/ kg/ day in combination with cisplatin, caused sustained regressions in 8/9 mice compared to 3/9 for cisplatin monotherapy. 

Figure 2 Double-stranded oligonucleotide photoprobes that simulate modified DNA and intended to cross-link to DNA-binding proteins. (A) Probe modeling interstrand cross-linking by cisplatin Source From Ref. [63], with permission from the American Chemical Society via the Rightslink service (license number 2458870278307 granted June 30, 2010). The benzophenone probe prior to reaction with DNA is shown in the lower part of the panel. (B) Photoaffinity probe for bacterial DNA repair proteins. TT is a simulated thymine dimer intended to be recognized as a site of damage in DNA, and T (two instances) is the diazirine thymine derivative T Source From Ref. [64], with permission from Wiley.

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