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oai:recercat.cat:2445/1648422025-12-05T14:32:04Zcom_2072_1057col_2072_478917col_2072_478923

urn:hdl:2445/164842 Neutral and ionic platinum compounds containing a cyclometalated chiral primary amine: Synthesis, antitumor activity, DNA interaction and topoisomerase I - cathepsin B inhibition 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 Platí Càncer Platinum Cancer 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. 2020-06-08T18:20:00Z 2020-06-08T18:20:00Z 2015 2020-06-08T18:20:00Z info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion Versió postprint del document publicat a: https://doi.org/10.1039/c5dt01713k Dalton Transactions, 2015, vol. 44, num. 30, p. 13602-13614 https://doi.org/10.1039/c5dt01713k (c) Albert Mach, Joan et al., 2015 info:eu-repo/semantics/openAccess Royal Society of Chemistry Articles publicats en revistes (Mineralogia, Petrologia i Geologia Aplicada)