TY - JOUR
T1 - Facile entry to germanate and stannate complexes [(η6-arene)RuCl(η2-dppm)]+[ECl3]- (E = Ge, Sn) as potent anti-cancer agents
AU - Aldeghi, Niccolo
AU - Romano, Dario
AU - Marschner, Christoph
AU - Biswas, Supratim
AU - Chakraborty, Suparna
AU - Prince, Sharon
AU - Ngubane, Siyabonga
AU - Blom, Burgert
N1 - Funding Information:
The authors wish to thank the Maastricht Science Programme, and the Faculty of Science and Engineering (FSE) at Maastricht University (UM) for financial support of this research. This work was supported by grants from the South Africa Medical Research Council (SA MRC), the South Africa National Research Foundation (NRF) (CPRR #120815), Cancer Association of South Africa (CANSA) and the University of Cape Town (UCT). We also thank Maarten Honing and Darya Hadavi (M4I, FHML (Maastricht MultiModal Molecular Imaging; Faculty Health, Medicine & Life Sciences, Maastricht University) for measuring and interpreting the HRMS of all the compounds.
Funding Information:
The authors wish to thank the Maastricht Science Programme, and the Faculty of Science and Engineering (FSE) at Maastricht University (UM) for financial support of this research. This work was supported by grants from the South Africa Medical Research Council (SA MRC) , the South Africa National Research Foundation (NRF) ( CPRR #120815 ), Cancer Association of South Africa (CANSA) and the University of Cape Town (UCT) .
Publisher Copyright:
© 2020 The Authors
PY - 2020/6/14
Y1 - 2020/6/14
N2 - A series of arene Ru(II) salt complexes of the type [(eta(6)-arene)RuCl(eta(2)-dppm)](+)[ECl3](-) (arene = C6H6, p-cymene, 1,3,5-Me3C6H3; E = Ge, Sn) bearing trichlorogermanate and trichlorostannate anions are reported. Starting from the known complexes: [(eta(6)-C6H6)RuCl2(eta(1)-dppm)] (1), [(eta(6)-p-cymene)RuCl2(eta(1)-dppm)] (3) and the novel complex [(eta(6)-1,3,5-Me3C6H3)RuCl2(eta(1)-dppm)] (7) (dppm = 1,1-bis(diphenylphosphino)methane), reactions with SnCl2 or GeCl2(dioxane) respectively afforded, by halide abstraction at the ruthenium(II) centres in 1, 3 or 7 the salts: [(eta(6)-C6H6)RuCl(eta(2)-dppm)](+) SnCl3- (2), [(eta(6)-p-cymene)RuCl(eta(2)-dppm)](+) SnCl3- (4), [(eta(6)-C6H6)RuCl(eta(2)-dppm)](+) GeCl3- (5), [(eta(6)-p-cymene) RuCl(eta(2)-dppm)](+) GeCl3- (6), [(eta(6)-1,3,5-Me3C6H3)RuCl(eta(2)-dppm)](+) SnCl3- (8) and [(eta(6)-1,3,5-Me3C6H3) RuCl(eta(2)-dppm)](+) GeCl3- (9). The trichlorostannate complexes 2, 4 and 8 are extremely rare examples of ruthenium complexes bearing the SnCl3- counter anion, and the complexes 5, 6 and 9 are the first examples of ruthenium trichlorogermanate complexes to be reported. All compounds were isolated in high yields as air stable materials and were spectroscopically characterized by multinuclear NMR: (H-1, P-31 {H-1}, C-13{H-1}), Infra-red (IR), UV-Vis, and high resolution electrospray ionization mass spectrometry (HR-ESI-MS), the latter both in (+) and (-) mode. Additionally, single crystal X-ray diffraction analyses of salts 4 and 6 are reported, revealing pseudotetrahedral Ru(II) centres with eta(6) bound p-cymene ligands and eta(2)-bound dppm ligands with statistical disorder on the ECl3- anions (E = Ge (6), Sn (4)). Density functional theory calculations (B3LYP with the basis set 6-31 + G(d,p) for H, C, P and Cl atoms; while for Ru, Ge, and Sn atoms DGDZVP basis set) are reported for salts 4 and 6 revealing localization of the LUMOs on the ruthenium-arene rings and some localization on the chloride atom. Finally, MTT in vitro cytotoxicity assays for the MCF-7 and MDA-MB-231 breast cancer cell lines are reported for all complexes and compared to cisplatin. All complexes show remarkable in vitro cytotoxic activity and most are considerably more cytotoxic than cisplatin in both breast cancer cell lines: IC50 values range from 2.25 mu M (compound 2) to 5.97 mu M (compound 9) (cisplatin = 5.74 mu M) in MCF-7 cells; 2.20 mu M (compound 2) to 6.39 mu M (compound 5) (cisplatin = 13.98 mu M) in MDA-MB-231. Moreover, when compared to nonmalignant breast epithelial cells (MCF12A), all complexes exhibit promising selectivity indices (SI) with compound 5 having the highest SI in MCF-7 cells at 4.8; and compound 6 at 3.65 in MDA-MB-231, with most of the other compounds also being considerably more selective than cisplatin on both celllines (SI = 2.26 on MCF-7 and 0.93 on MDA-MB-231). A clonogenic assay was conducted for salts 5 and 6 and the results reveal that both compounds inhibited long-term (14 days) survival in both breast cancer cell lines tested indicating these drugs are very promising candidates for pre-clinical studies. (C) 2020 The Authors. Published by Elsevier B.V.
AB - A series of arene Ru(II) salt complexes of the type [(eta(6)-arene)RuCl(eta(2)-dppm)](+)[ECl3](-) (arene = C6H6, p-cymene, 1,3,5-Me3C6H3; E = Ge, Sn) bearing trichlorogermanate and trichlorostannate anions are reported. Starting from the known complexes: [(eta(6)-C6H6)RuCl2(eta(1)-dppm)] (1), [(eta(6)-p-cymene)RuCl2(eta(1)-dppm)] (3) and the novel complex [(eta(6)-1,3,5-Me3C6H3)RuCl2(eta(1)-dppm)] (7) (dppm = 1,1-bis(diphenylphosphino)methane), reactions with SnCl2 or GeCl2(dioxane) respectively afforded, by halide abstraction at the ruthenium(II) centres in 1, 3 or 7 the salts: [(eta(6)-C6H6)RuCl(eta(2)-dppm)](+) SnCl3- (2), [(eta(6)-p-cymene)RuCl(eta(2)-dppm)](+) SnCl3- (4), [(eta(6)-C6H6)RuCl(eta(2)-dppm)](+) GeCl3- (5), [(eta(6)-p-cymene) RuCl(eta(2)-dppm)](+) GeCl3- (6), [(eta(6)-1,3,5-Me3C6H3)RuCl(eta(2)-dppm)](+) SnCl3- (8) and [(eta(6)-1,3,5-Me3C6H3) RuCl(eta(2)-dppm)](+) GeCl3- (9). The trichlorostannate complexes 2, 4 and 8 are extremely rare examples of ruthenium complexes bearing the SnCl3- counter anion, and the complexes 5, 6 and 9 are the first examples of ruthenium trichlorogermanate complexes to be reported. All compounds were isolated in high yields as air stable materials and were spectroscopically characterized by multinuclear NMR: (H-1, P-31 {H-1}, C-13{H-1}), Infra-red (IR), UV-Vis, and high resolution electrospray ionization mass spectrometry (HR-ESI-MS), the latter both in (+) and (-) mode. Additionally, single crystal X-ray diffraction analyses of salts 4 and 6 are reported, revealing pseudotetrahedral Ru(II) centres with eta(6) bound p-cymene ligands and eta(2)-bound dppm ligands with statistical disorder on the ECl3- anions (E = Ge (6), Sn (4)). Density functional theory calculations (B3LYP with the basis set 6-31 + G(d,p) for H, C, P and Cl atoms; while for Ru, Ge, and Sn atoms DGDZVP basis set) are reported for salts 4 and 6 revealing localization of the LUMOs on the ruthenium-arene rings and some localization on the chloride atom. Finally, MTT in vitro cytotoxicity assays for the MCF-7 and MDA-MB-231 breast cancer cell lines are reported for all complexes and compared to cisplatin. All complexes show remarkable in vitro cytotoxic activity and most are considerably more cytotoxic than cisplatin in both breast cancer cell lines: IC50 values range from 2.25 mu M (compound 2) to 5.97 mu M (compound 9) (cisplatin = 5.74 mu M) in MCF-7 cells; 2.20 mu M (compound 2) to 6.39 mu M (compound 5) (cisplatin = 13.98 mu M) in MDA-MB-231. Moreover, when compared to nonmalignant breast epithelial cells (MCF12A), all complexes exhibit promising selectivity indices (SI) with compound 5 having the highest SI in MCF-7 cells at 4.8; and compound 6 at 3.65 in MDA-MB-231, with most of the other compounds also being considerably more selective than cisplatin on both celllines (SI = 2.26 on MCF-7 and 0.93 on MDA-MB-231). A clonogenic assay was conducted for salts 5 and 6 and the results reveal that both compounds inhibited long-term (14 days) survival in both breast cancer cell lines tested indicating these drugs are very promising candidates for pre-clinical studies. (C) 2020 The Authors. Published by Elsevier B.V.
KW - Ruthenium anti-cancer agents
KW - Ionic complexes
KW - Germanate and stannate complexes
KW - CANCER STEM-CELLS
KW - RUTHENIUM COMPLEXES
KW - RUTHENIUM(II)-ARENE COMPOUND
KW - PLATINUM COMPOUNDS
KW - METAL-COMPLEXES
KW - NAMI-A
KW - CISPLATIN
KW - ANTITUMOR
KW - CYTOTOXICITY
KW - CHEMOTHERAPY
U2 - 10.1016/j.jorganchem.2020.121214
DO - 10.1016/j.jorganchem.2020.121214
M3 - Article
SN - 0022-328X
VL - 916
JO - Journal of Organometallic Chemistry
JF - Journal of Organometallic Chemistry
M1 - 121214
ER -