Dinuclear CuI complexes of pyridyl-diazadiphosphetidines and aminobis(phosphonite) ligands: synthesis, structural studies and antiproliferative activity towards human cervical, colon carcinoma and breast cancer cells

Abstract

The copper(I) complexes containing phosphorus donor ligands such as diazadiphosphetidine, cis-{(o-OCH₂C₅H₄N)P(μ-N^tBu)}₂ (1) and aminobis(phosphonite), C₆H₅N{P(OC₆H₃(OMe-o)(C₃H₅-p))₂}₂ (2, PNP), have been synthesized. Treatment of 1 with copper iodide afforded the 1D coordination polymer [{Cu(μ-I)}₂{(o-OCH₂C₅H₄N)P(μ-N^tBu)}₂]_n (3). Treatment of 3 with 2,2′-bipyridine (bpy) and 1,10-phenanthroline (phen) produced mixed-ligand complexes [(L)₂Cu₂{(o-OCH₂C₅H₄N)P(μ-N^tBu)}₂][I]₂ (4 L = bpy; 5 L = phen) in good yields. The reaction of 2 with copper iodide yielded a rare tetranuclear copper complex [(CuI)₂C₆H₅N(PR₂)₂]₂ (6), which on subsequent treatment with various pyridyl ligands produced binuclear complexes [{Cu(μ-I)(py)}₂(μ-PNP)] (7), [Cu₂(μ-I)(bpy)₂(μ-PNP)]I (8), [Cu₂(μ-I)I(bpy)(μ-PNP)] (9), [Cu₂(phen)(bpy)(μ-PNP)](OTf)₂ (10), [Cu₂(μ-I)I(phen)(μ-PNP)] (11) and [Cu₂(μ-I)(phen)₂(μ-PNP)]I (12), in an almost quantitative yield. The new copper(I) complexes (4, 5 and 7–12) were tested for anti-cancer activity against three human tumor cell lines. Compounds 5, 10 and 12 showed in vitro antitumor activity 5–7 fold higher than cisplatin, the most used anticancer drug. These three most potent compounds (5, 10 and 12) were chosen for detailed study to understand their mechanism of action. The copper(I) compounds studied in the present investigation were found to inhibit tumor cell growth by arresting cells at the S-phase of the cell cycle. The characteristic nuclear morphology of treated cells showed signs of DNA damage. The experimental evidence clearly indicated that these compounds initiated apoptosis, which is mediated through the p53 pathway.