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)-NH₂CH(CH₃)C₁₀H₆}(L)] [L = SOMe₂ (1-R or 1-S), L = PPh₃ (2-R or 2-S), L = P(4-FC₆H₄)₃ (3-R), L = P(CH₂)₃N₃(CH₂)₃ (4-R)], cycloplatinated cationic complexes [Pt{(R)-NH₂CH(CH₃)C₁₀H₆}{L}]Cl [L = Ph₂PCH₂CH₂PPh₂ (5-R), L = (C₆F₅)₂PCH₂CH₂P(C₆F₅)₂ (6-R)] and the Pt(II) coordination compound trans-[PtCl₂{(R)-NH₂CH(CH₃)C₁₀H₆}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 (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 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.