title: Polyphosphoester conjugates of dinuclear platinum complex: synthesis and evaluation of cytotoxic and the proapoptotic activity.
abstract: Macromolecular conjugates of a dinuclear platinum complex with a spermidine bridge were synthesized using poly(oxyethylene H-phosphonate)s as precursor polymer. The complex species were attached to the polymer chain via a phosphoramide bond resulting from the reaction between the H-phosphonate groups and the middle amino group of the spermidine moiety. (1)H and (31)P{H} DOSY NMR spectral data were used to prove the conjugation reaction and to characterize the new species. The conjugates exhibited profound cytotoxicity in a panel of five chemosensitive human tumor cell lines and one cisplatin-resistant model (HL-60/CDDP), and were found to induce apoptotic cell death. A flow cytometric analysis encountered a cisplatin-dissimilar modulation of the cell cycle progression in KG-1 leukemic cells, following exposure to the dinuclear agents. Moreover, the novel compounds displayed less pronounced inhibitory activity against cultured murine renal epithelial cells, as compared to cisplatin.
authors.affiliation: Institute of Polymers, Bulgarian Academy of Sciences, Acad. Georgi Bonchev Str. Bl.103, 1113 Sofia, Bulgaria. Electronic address: mitova@polymer.bas.bg.
authors.forename: Violeta
authors.initials: V
authors.lastname: Mitova
authors.affiliation: Institute of Polymers, Bulgarian Academy of Sciences, Acad. Georgi Bonchev Str. Bl.103, 1113 Sofia, Bulgaria. Electronic address: sslavcheva@polymer.bas.bg.
authors.forename: Stoyanka
authors.initials: S
authors.lastname: Slavcheva
authors.affiliation: Laboratory of Nuclear Magnetic Resonance, Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. Georgi Bonchev Str. Bl. 9, 1113 Sofia, Bulgaria. Electronic address: psd@orgchm.bas.bg.
authors.forename: Pavletta
authors.initials: P
authors.lastname: Shestakova
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria. Electronic address: dmomekova@yahoo.com.
authors.forename: Denitsa
authors.initials: D
authors.lastname: Momekova
authors.affiliation: Laboratory of Hematopathology and Immunology, National Specialized Hospital for Active Treatment of Hematological Diseases, 6 Plovdivsko pole Str., 1756 Sofia, Bulgaria. Electronic address: nstoyanov@cetrh.org.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Stoyanov
authors.affiliation: Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria. Electronic address: gmomekov@gmail.com.
authors.forename: Georgi
authors.initials: G
authors.lastname: Momekov
authors.affiliation: Institute of Polymers, Bulgarian Academy of Sciences, Acad. Georgi Bonchev Str. Bl.103, 1113 Sofia, Bulgaria. Electronic address: ktroev@polymer.bas.bg.
authors.forename: Kolio
authors.initials: K
authors.lastname: Troev
authors.affiliation: Institute of Polymers, Bulgarian Academy of Sciences, Acad. Georgi Bonchev Str. Bl.103, 1113 Sofia, Bulgaria. Electronic address: koseva@polymer.bas.bg.
authors.forename: Neli
authors.initials: N
authors.lastname: Koseva
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D004952:Esters / Q000737:chemistry*; D018922:HL-60 Cells; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010710:Phosphates / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004952:Esters; D009944:Organoplatinum Compounds; D010710:Phosphates; D011108:Polymers; D002945:Cisplatin
keywords: Cytotoxicity; DMPh; DOSY NMR; Dinuclear platinum complex; Nephrotoxicity; Polyphosphoester conjugate; Proapoptotic activity; Renal epithelial cells; diffusion ordered NMR spectroscopy; dimethyl H-phosphonate