Platinum-based cross-linking

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. 

Oxaliplatin (Eloxatin ) is similar to other platinum analogs (e.g., cisplatin) in that it binds to the N-7 position of guanine, which results in cross-linking of DNA and double-stranded DNA breaks.26,40 Oxaliplatin differs from cisplatin in that the DNA damage induced by oxaliplatin may not be as easily recognized by DNA repair genes often seen in colorectal cancer. Oxaliplatin, in combination with 5-FU-based regimens, is indicated for the first- and second-line treatment of metastatic colon cancer, as well as the adjuvant treatment of colon cancer. 

The interstrand cross-link also induces DNA bending.72 X-ray and NMR studies on this adduct show that platinum is located in the minor groove and the cytosines of the d(GC) base pair involved in interstrand cross-link formation are flipped out of the helix stack and a localized Z-form DNA is observed.83-85 This is a highly unusual structure and very distorting—implications for differential repair of the two adducts have been addressed. Alternatively, the interstrand cross-link of the antitumor inactive trans-DDP is formed between a guanine (G) and its complementary cytosine (C) on the same base p a i r.86,87/ nms- D D P is sterically incapable of producing 1,2-intrastrand adducts and this feature has been cited as a dominant structural reason for its lack of antitumor efficacy. It is clear that the structural distortions induced on the DNA are very different and likely to induce distinctly different biological consequences. 

The polynuclear platinum compounds stand in vivid contrast to mononuclear platinum complexes because the predominant DNA lesions are long-range inter- and intrastrand cross-links where the sites of platination may be separated by up to four base pairs. The consequent structural and conformational changes in DNA are also distinct. 

This is an unusual drug in that it contains a metal atom, platinum (Pt) in this case. Cisplatin reacts with DNA to cross-link bases, disrupting normal DNA structure and function. This agent has found broad use in cancer chemotherapy, including efficacy in tumors of the testis, ovary, bladder, head and neck, thyroid, cervix, and endometrium. It is also active against neuroblastoma and osteogenic sarcoma. 

A very interesting aspect of platinum-DNA interactions concerns the nature of the resulting adducts and their relative quantities. Due to the bifunctional nature of cis-Pt, several types of adducts in the DNA can be expected to be formed, to be distinguished in (1) interstrand chelates (binding of two nucleobases that are each positioned in one of the complementary DNA strands), (2) intrastrand chelates (binding of two nucleobases within the same DNA strands), (3) intrabase chelates (binding to two different atoms in one base), and (4) DNA-protein cross-links. 

We have described a new system of polymeric snpports based on multifunctional, exceptionally sterically hindered carbosilane moieties, grafted with block poly(vinylmethyl-co-dimethyl)siloxane arms. They offer uniformly periphery-distribnted active sites (-CH = CH moieties) and can be used for preparation of novel catalysts. Platinum was thus attached to the polymers via coordination to vinyl gronps. The materials used in hydrosilylation of vinylsilanes can be considered as an alternative for traditional platinum catalysts. The utility of the catalysts seems to be dependent on the ratio [D]/[V] in the copolysiloxane arm. Those with too high amonnt of vinyl groups suffer from poor solubility and catalytic performance dne to excessive inter/intra-chain coordinative cross-linking. 

It has been demonstrated that the tran5 -[(NH3)2PtCl] adduct of 1-methylcytosine, bound via N-3, can form crosslinks with either 9-ethylguanine or 9-methyladenine as a result of Cl substitution by purine N-7 atoms. Additional H-bonds between exocyclic groups of cross-linked nucleic acid bases provide additional stabihzation of the individual complexes (Figure 13d). Binding of the related complex [(NH3)2Pt(N-3-cytosine)Cl]+ with d(GG) leads to the formation of a major product in which the platinum is bound only to N-7 of the 5 -nucleotide. ... 

Following activation via intracellular aquation reactions, cisplatin forms a variety of stable bifunctional adducts with DNA, as depicted in Figure 3. Cisplatin mainly forms 1,2-intrastrand cross-links on adjacent purine bases. It has been found that 60-65% of the platinum bound to DNA is in the form of l,2-d(GG) intrastrand cross-links and 20-25% in intrastrand l,2-d(AG) cross-links. Other adducts formed are the l,3-d(GXG) and l,4-d(GXXG) cross-links, accounting for at most 6%. Only a small percentage of cisplatin (1.5%) was found to be involved in interstrand adducts. It remains... 

The state-of-the-art silicone systems used in label stock application are normally solventless and thermal curing. Base polymers for these systems are vinyl-functionalized polydimethylsiloxanes having viscosities of around 200 - 600 mPa.s. Cross-linkers normally are hydride-functionalized polydimethylsiloxanes with a viscosity of around 25 mPa.s. These two components are cross-linked by a platinum catalyst, which can be the Karstedt catalyst. Additionally an inhibitor is added to the silicone mixture to prevent curing before it is applied on the substrate. These inhibitors ate... 

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