title: Neutral and ionic platinum compounds containing a cyclometallated chiral primary amine: synthesis, antitumor activity, DNA interaction and topoisomerase I-cathepsin B inhibition.
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.
authors.affiliation: Departament de Química Inorgànica, Facultat de Química, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain. margarita.crespo@qi.ub.es.
authors.forename: Joan
authors.initials: J
authors.lastname: Albert
authors.forename: Ramon
authors.initials: R
authors.lastname: Bosque
authors.forename: Margarita
authors.initials: M
authors.lastname: Crespo
authors.forename: Jaume
authors.initials: J
authors.lastname: Granell
authors.forename: Concepción
authors.initials: C
authors.lastname: López
authors.forename: Raquel
authors.initials: R
authors.lastname: Martín
authors.forename: Asensio
authors.initials: A
authors.lastname: González
authors.forename: Anusha
authors.initials: A
authors.lastname: Jayaraman
authors.forename: Josefina
authors.initials: J
authors.lastname: Quirante
authors.forename: Carme
authors.initials: C
authors.lastname: Calvis
authors.forename: Josefa
authors.initials: J
authors.lastname: Badía
authors.forename: Laura
authors.initials: L
authors.lastname: Baldomà
authors.forename: Mercè
authors.initials: M
authors.lastname: Font-Bardia
authors.forename: Marta
authors.initials: M
authors.lastname: Cascante
authors.forename: Ramon
authors.initials: R
authors.lastname: Messeguer
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002412:Cations / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism*; D005021:Ethylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002412:Cations; D005021:Ethylamines; D009281:Naphthalenes; D009944:Organoplatinum Compounds; D059004:Topoisomerase I Inhibitors; C055450:1-(1-naphthyl)ethylamine; D004247:DNA; D002401:Cathepsin B