Royal Society of Chemistry, Dalton Transactions, 30(44), p. 13602-13614
DOI: 10.1039/c5dt01713k
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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)-NH2CH(CH3)C10H6}(L)] [L = SOMe2 ( or ), L = PPh3 ( or ), L = P(4-FC6H4)3 (), L = P(CH2)3N3(CH2)3 ()], cycloplatinated cationic complexes [Pt{(R)-NH2CH(CH3)C10H6}{L}]Cl [L = Ph2PCH2CH2PPh2 (), L = (C6F5)2PCH2CH2P(C6F5)2 ()] and the Pt(ii) coordination compound trans-[PtCl2{(R)-NH2CH(CH3)C10H6}2] (). The X-ray molecular structure of 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 (IC50 = 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 and , modify the DNA migration as cisplatin, cationic platinacycle was able to inhibit topoisomerase I-promoted DNA supercoiling, and Pt(ii) coordination compound turned out to be the most potent inhibitor of cathepsin B. Induction of G-1 phase ( and ), and S and G-2 phases () arrests are related to the antiproliferative activity of some representative compounds upon A-549 cells. Induction of apoptosis is also observed for and .