title: Chemical and cellular investigations of trans-ammine-pyridine-dichlorido-platinum(II), the likely metabolite of the antitumor active cis-diammine-pyridine-chorido-platinum(II).
abstract: It has been proposed that the well-studied monofunctional platinum complex cis-[PtCl(NH3)2(py)](+) (cDPCP) forms DNA adducts similar to those of the trans platinum complex trans-[PtCl2(NH3)(py)] (ampyplatin, py=pyridine). Thus this latter could be the active form of cDPCP. Detailed studies on the mechanism of ampyplatin action were performed in this work. Results indicate that ampyplatin has significantly higher antiproliferative activity than cDPCP and is comparable to cisplatin. Cellular uptake experiments indicate that ampyplatin can be efficiently accumulated in A549 cancer cells. Binding of ampyplatin to DNA mainly produces monofunctional adducts; remarkably, these adducts can be recognized by the HMGB1 protein. Kinetic studies on the reaction with GMP indicate that the reactivity of ampyplatin is much lower than that of transplatin and is more similar to that of trans-[PtCl2{E-HN=C(Me)OMe}2] (trans-EE), a widely investigated antitumor active trans-oriented platinum complex. In addition, the hydrolysis of ampyplatin is significantly suppressed, whereas the hydrolysis of the mono-GMP adduct is highly enhanced. These results indicate that the mechanism of ampyplatin differs not only from that of antitumor inactive transplatin but also from that of antitumor active trans-EE and this could account for the remarkable activity of parent cDPCP.
authors.affiliation: CAS Key Laboratory of Soft Matter Chemistry, Department of Chemistry, University of Science and Technology of China, Hefei Anhui 230026, China.
authors.forename: Dechen
authors.initials: D
authors.lastname: Xu
authors.forename: Yuanzeng
authors.initials: Y
authors.lastname: Min
authors.forename: Qinqin
authors.initials: Q
authors.lastname: Cheng
authors.forename: Hongdong
authors.initials: H
authors.lastname: Shi
authors.forename: Kaiju
authors.initials: K
authors.lastname: Wei
authors.forename: Fabio
authors.initials: F
authors.lastname: Arnesano
authors.forename: Giovanni
authors.initials: G
authors.lastname: Natile
authors.forename: Yangzhong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018736:DNA Adducts / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010984:Platinum / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D004273:DNA, Neoplasm; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D009363:Neoplasm Proteins; D011725:Pyridines; D010984:Platinum
keywords: Antitumor; DNA; HMGB1; Kinetics; Trans Platinum Complexes