Replacement of an NH3by an Iminoether in Transplatin Makes an Antitumor Drug from an Inactive Compound
| Autor: | Daniel Locker, Angelina Boccarelli, Mauro Coluccia, Francesco P. Intini, Marc Leng, Annie Schwartz, Giovanni Natile, Marie-Josèphe Giraud-Panis, Domenico Giordano, Claudio Pisano |
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| Rok vydání: | 2000 |
| Předmět: |
Stereochemistry
Guanine DNA Footprinting Oligonucleotides Antineoplastic Agents Adduct DNA Adducts Mice chemistry.chemical_compound In vivo Tumor Cells Cultured medicine Animals Humans Pharmacology Cisplatin Leukemia P388 Chemistry High Mobility Group Proteins Thiourea DNA DNA Restriction Enzymes DNA-Directed RNA Polymerases Rats Disease Models Animal Cross-Linking Reagents Naked DNA Nucleic Acid Conformation Molecular Medicine Drug Screening Assays Antitumor Cytosine medicine.drug |
| Zdroj: | Scopus-Elsevier Europe PubMed Central |
| ISSN: | 1521-0111 0026-895X |
| Popis: | To investigate the modifications of antitumor activity and DNA binding mode of transplatin after replacement of one nonleaving group NH(3) by an iminoether group, trans-[PtCl(2)(Z-HN=C(OMe)Me)(NH(3)] and trans-[PtCl(2)(E-HN=C(OMe)Me)(NH(3)] complexes (differing in the Z or E configuration of iminoether, and abbreviated mixed Z and mixed E, respectively), have been synthesized. In a panel of human tumor cell lines, both mixed Z and mixed E show a cytotoxic potency higher than that of transplatin, the mean IC(50) values being 103, 37, and 215 microM, respectively. In vivo mixed Z is more active and less toxic than mixed E in murine P388 leukemia and retains its efficacy against SK-OV-3 human cancer cell xenograft in nude mice. In the reaction with naked DNA, mixed Z forms monofunctional adducts that do not evolve into intrastrand cross-links but close slowly into interstrand cross-links between complementary guanine and cytosine residues. The monofunctional mixed Z adducts are removed by thiourea and glutathione. The interstrand cross-links behave as hinge joints, increasing the flexibility of DNA double helix. The mixed Z, transplatin, and cisplatin interstrand cross-links, as well as mixed Z monofunctional adducts are not specifically recognized by HMG1 protein, which was confirmed to be able to specifically recognize cisplatin d(GpG) intrastrand cross-links. These data demonstrate that the DNA interaction properties of the antitumor-active mixed Z are very similar to those of transplatin, thus suggesting that clinical inactivity of transplatin could not depend upon its peculiar DNA binding mode. |
| Databáze: | OpenAIRE |
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