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Title: Neutral and ionic platinum compounds containing a cyclometalated chiral primary amine: Synthesis, antitumor activity, DNA interaction and topoisomerase I - cathepsin B inhibition
Author: Albert Mach, Joan
Bosque Pueyo, Ramón
Crespo, M.
Granell Sanvicente, Jaime Ramón
López Martínez, Ma. Concepción
Martín, Raquel
González, A.
Jayaraman, A.
Quirante Serrano, Josefina
Calvis, Carme
Badía Palacín, Josefa
Baldomà Llavinés, Laura
Font Bardia, Ma. Mercedes
Cascante i Serratosa, Marta
Messeguer i Peypoch, Ramon
Keywords: Platí
Issue Date: 2015
Publisher: Royal Society of Chemistry
Abstract: The synthesis and preliminary biological evaluation of neutral and cationic platinum derivatives of chiral 1-(1-naphthyl)ethylamine are reported, namely cycloplatinated neutral complexes [PtCl{(R or S)-NH(2)CH(CH(3))C(10)H(6)}(L)] [L = SOMe(2) ( 1-R or 1-S ), L = PPh(3) (2-R or 2-S), L = P(4-FC(6)H(4))(3) (3-R), L = P(CH(2))(3)N(3)(CH(2))(3) (4-R)], cycloplatinated cationic complexes [Pt{(R)-NH(2)CH(CH(3))C(10)H(6)}{L}]Cl [L = Ph(2)PCH(2)CH(2)PPh(2) (5-R), L = (C(6)F(5))(2)PCH(2)CH(2)P(C(6)F(5))(2) (6-R)] and the Pt(ii) coordination compound trans-[PtCl(2){(R)-NH(2)CH(CH(3))C(10)H(6)}(2)] (7-R). The X-ray molecular structure of 7-R is reported. The cytotoxic activity against a panel of human adenocarcinoma cell lines (A-549 lung, MDA-MB-231 and MCF-7 breast, and HCT-116 colon), cell cycle arrest and apoptosis, DNA interaction, topoisomerase I and cathepsin B inhibition, and Pt cell uptake of the studied compounds are presented. Remarkable cytotoxicity was observed for most of the synthesized Pt(ii) compounds regardless of (i) the absolute configuration R or S, and (ii) the coordinated/cyclometallated (neutral or cationic) nature of the complexes. The most potent compound 2-R (IC(50) = 270 nM) showed a 148-fold increase in potency with regard to cisplatin in HCT-116 colon cancer cells. Preliminary biological results point out to different biomolecular targets for the investigated compounds. Neutral cyclometallated complexes 1-R and 2-R, modify the DNA migration as cisplatin, cationic platinacycle 5-R was able to inhibit topoisomerase I-promoted DNA supercoiling, and Pt(ii) coordination compound 7-R turned out to be the most potent inhibitor of cathepsin B. Induction of G-1 phase ( 2-R and 5-R ), and S and G-2 phases (6-R) arrests are related to the antiproliferative activity of some representative compounds upon A-549 cells. Induction of apoptosis is also observed for 2-R and 6-R.
Note: Versió postprint del document publicat a:
It is part of: Dalton Transactions, 2015, vol. 44, num. 30, p. 13602-13614
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ISSN: 1477-9226
Appears in Collections:Articles publicats en revistes (Mineralogia, Petrologia i Geologia Aplicada)

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