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Eight rhenium(I) tricarbonyl aqua complexes with the general formula fac-[Re(CO)3(N,N′-bid)(H2O)][NO3] (1–8), where N,N′-bid is (2,6-dimethoxypyridyl)imidazo[4,5-f]1,10-phenanthroline (L1), (indole)imidazo[4,5-f]1,10-phenanthroline (L2), (5-methoxyindole)-imidazo[4,5-f]1,10-phenanthroline (L3), (biphenyl)imidazo[4,5-f]1,10-phenanthroline (L4), (fluorene)imidazo[4,5-f]1,10-phenanthroline (L5), (benzo[b]thiophene)imidazo[4,5-f]1,10-phenanthroline (L6), (5-bromothiazole)imidazo[4,5-f]1,10-phenanthroline (L7), and (4,5-dimethylthiophene)imidazo[4,5-f]1,10-phenanthroline (L8), were synthesized and characterized using 1H and 13C{1H} NMR, FT-IR, UV/Vis absorption spectroscopy, and ESI-mass spectrometry, and their purity was confirmed by elemental analysis. The stability of the complexes in aqueous buffer solution (pH 7.4) was confirmed by UV/Vis spectroscopy. The cytotoxicity of the complexes (1–8) was then evaluated on prostate cancer cells (PC3), showing a low nanomolar to low micromolar in vitrocytotoxicity. Worthy of note, three of the Re(I) tricarbonyl complexes showed very low (IC50= 30–50 nM) cytotoxic activity against PC3 cells and up to 26-fold selectivity over normal human retinal pigment epithelial-1 (RPE-1) cells. The cytotoxicity of both complexes 3and 6was lowered under hypoxic conditions in PC3 cells. However, the compounds were still 10 times more active than cisplatin in these conditions. Additional biological experiments were then performed on the most selective complexes (complexes 3and 6). Cell fractioning experiments followed by ICP-MS studies revealed that 3and 6accumulate mostly in the mitochondria and nucleus, respectively. Despite the respective mitochondrial and nuclear localization of 3and 6, 3did not trigger the apoptosis pathways for cell killing, whereas 6can trigger apoptosis but not as a major pathway. Complex 3induced a paraptosis pathway for cell killing while 6did not induce any of our other tested pathways, namely, necrosis, paraptosis, and autophagy. Both complexes 3and 6were found to be involved in mitochondrial dysfunction and downregulated the ATP production of PC3 cells. To the best of our knowledge, this report presents some of the most cytotoxic Re(I) carbonyl complexes with exceptionally low nanomolar cytotoxic activity toward prostate cancer cells, demonstrating further the future viability of utilizing rhenium in the fight against cancer.

The aquation reactions of four rhenium(I) dicarbonyl complexes, [Re(CO)2(NN)(PR3)(Cl)], where NN = 1,10-phenanthroline (Phen) and 2,9-dimethyl-1,10-phenanthroline (DMPhen) and PR3= 1,3,5-triaza-7-phosphaadamantane (PTA) and 1,4-diacetyl-1,3,7-triaza-5-phosphabicylco[3.3.1]nonane (DAPTA). Additionally, the anation reactions of the corresponding aqua complexes with Cl–were investigated. Single crystals of [Re(CO)2(DMPhen)(PTA)(Cl)]·DMF and [Re(CO)2(DMPhen)(DAPTA)(Cl)] were obtained, and their structures were determined using X-ray diffraction. The Re–Cl interatomic distances are 2.4991(13) and 2.4922(6) Å, respectively, indicating a mild trans influence effect of the phosphine ligands. The rate constants, kaq, for the aquation reactions of these complexes spanned a range of (3.7 ± 0.3) × 10–4to (15.7 ± 0.3) × 10–4s–1with the two Phen complexes having rate constants that are 2.5 times greater than those of the DMPhen complexes at 298 K. Similarly, the second-order anation rate constants (kCl) of the resulting aqua complexes, [Re(CO)2(NN)(PR3)(H2O)]+, with Cl–ions at 298 K varied between (2.99 ± 0.05) × 10–3and (6.79 ± 0.09) × 10–3M–1s–1. Likewise, these rate constants for the Phen complexes were almost 2 times faster than those of the DMPhen complexes. The pKavalues of the four aqua complexes were determined to be greater than 9.0 for all of the complexes with [Re(CO)2(Phen)(PTA)(H2O)]+having the highest pKavalue of 9.28 ± 0.03. From the pKavalues and the ratios of the aquation and anation rate contants, which give thermodynamic Cl–binding constants, the speciation of the rhenium(I) complexes in blood plasma, the cytoplasm, and the cell nucleus were estimated. The data suggest that the aqua complexes would be the dominant species in all three environments. This result may have important implications on the potential biological activity of these complexes.

C29H28O5PRe, triclinic, P1̄ (no. 2), a= 12.733(7) Å, b= 18.668(11) Å, c= 24.779(15) Å, α= 101.442(20)°, β= 100.844(18)°, γ= 104.240(19)°, V= 5419(9) Å3, Z= 8, Rgt(F) = 0.0307, wRref(F2) = 0.0772, T= 100 K.

C22H33N3O5·0.67H2O, monoclinic, P21/c, a= 11.9915(6) Å, b= 18.9934(10) Å, c= 10.5332(5) Å, β= 112.155(2)°, V= 2221.91(19) Å3, Z= 4, Rgt(F) = 0.0417, wRref(F2) = 0.1139, T= 100(2) K.

C43H34NO8PS2Re2, monoclinic, P21/c(no. 14), a= 12.165(8) Å, b= 19.027(11) Å, c= 18.848(14) Å, β= 108.735(2)°, V= 4131(5) Å3, Z= 4, Rgt(F)= 0.0308, wRref(F2)= 0.0683, T= 100(2) K.

C30H22N4O18Re2, monoclinic, P21/c(no. 14), a= 10.167(7) Å, b= 17.57(1) Å, c= 19.95(1) Å, β= 98.75(1)°, V= 3522(9) Å3, Z= 4, Rgt(F)= 0.0275, wRref(F2)= 0.0633, T= 100(2) K.

C16H21O8N2F6Re, triclinic, P1̅, a= 9.161(5) Å, b= 10.283(5) Å, c= 12.974(5) Å, α= 87.739(5)°, β= 78.339(5)°, γ= 75.047(5)°, V= 1156.3(10) Å3, Z= 2, Rgt(F)= 0.037, wRref(F2)= 0.1012, T= 100(2) K.

C29H28O5PRe, monoclinic, P21/n(no. 14), a= 10.548(5) Å, b= 22.996(5) Å, c= 11.022(5) Å, β= 98.011(5)°, V= 2647.4(18) Å3, Z= 4, Rgt(F) = 0.0306, wRref(F2) = 0.0911, T= 100 K.

C27H24O5PRe, triclinic, P1̄ (no. 2), a= 9.0305(17) Å, b= 12.084(2) Å, c= 12.403(2) Å, α= 89.688(6)°, β= 70.083(6)°, γ= 76.315(6)°, V= 1232.2(4) Å3, Z= 2, Rgt(F) = 0.0180, wRref(F2) = 0.0432, T= 100(2) K.

C7H3N2O7, C8H20N, monoclinic, P21/n, a= 11.477(3) Å, b= 6.858(1) Å, c= 21.254(5) Å, β= 92.96(1)°, V= 1670.6(9) Å3, Z= 4, Rgt(F)= 0.0432, wRref(F2)= 0.1279, T= 100(2) K.