Oxorhenium(V) complexes with pyridinedicarboxylic ligands: Synthesis, density functional theory calculations, and drug combination study

Three oxorhenium(V) complexes [ReOLCl₂(PPh₃)] (C1–C3) were synthesized in the reaction of 2,3-pyridinedicarboxylic acid (HL1), 2,5-pyridinedicarboxylic acid (HL2), and 2,6-pyridinedicarboxylic acid (HL3) with [ReOCl₃(PPh₃)₂]. Chemical structures of synthesized compounds were confirmed using standard analytical techniques. The most stable geometry of complexes was proposed using density functional theory calculations. The antiproliferative activity of the synthesized complexes was evaluated in a panel of human tumor cell lines (A549, PANC-1, OVCAR-3, and MDA-MB-231) and in one nontumor cell line (MRC-5), in comparison with the activity of cisplatin as a reference drug. The complex C3 exhibited the highest antiproliferative potential in PANC-1 cells, with IC₅₀ 48.73 ± 0.31 μM. Our previous research of oxorhenium(V) complexes suggested the involvement of drug-efflux transporter P-glycoprotein (Pgp) in the detoxification of rhenium complexes in pancreatic adenocarcinoma cells. In the present study, the effect of verapamil hydrochloride, the specific pharmacological blocker of Pgp, was tested in combination with novel rhenium complexes C1–C3 or cisplatin (CDDP), in PANC-1 cells. The verapamil enhanced the antiproliferative activity of complex C3, indicating again the role of Pgp in detoxification of oxorhenium(V) complexes in highly invasive and resistant PANC-1 cells.