Synthesis of a novel nitrogen mustard–conjugated bis-terpyridine ruthenium(II) complex as a potent anticancer agent that induces cell cycle arrest and apoptosis

Abstract

A fairly small-sized aryl nitrogen mustard–conjugated terpyridine is synthesized in only two steps as a ligand to chelate with RuCl3 to afford a [Ru(tpy-CM)2]Cl2 complex. This complex exhibits prominent antiproliferative activity toward several tumor cells. Further studies conclusively show that the complex suppresses human renal clear cell carcinoma cells (786-O cells) by inducing G1 phase cell cycle arrest and apoptosis. This work provides a synthetic and therapeutic model for nitrogen mustard-containing metal complexes.

Minimal Functionalization of Ruthenium Compounds with Enhanced Photoreactivity against Hard-to-Treat Cancer Cells and Resistant Bacteria

“…In another case, a ruthenium biphosphine complex, [Ru­(GA)­(dppe) 2 ]­PF 6 (where GA is gallic acid and dppe is 1,2-bis­(diphenylphosphino)­ethane) exhibited an IC 50 of 0.84 μmol L –1 without any light irradiation (after 48 h of cellular incubation) . Similarly, a terpyridine-based ruthenium compound, [Ru­(tpy-CM) 2 ]­Cl 2 (where tpy-CM is [2,2’:6′,2″-terpyridine]-4′-il)- N , N -bis­(2-chloroethyl)­aniline)), showed IC 50 of 2.6 μmol L –1 , also without light irradiation, but with a longer cellular incubation time of 72 h. By combining a bipyridine-based ruthenium compound, Δ-[Ru­(bpy) 2 (HPIP)]­(ClO 4 ) 2 (where HPIP is (2-hydroxyphenyl)­imidazo­[4,5- f ]­[1,10]­phenanthroline), with a known anticancer drug, doxorubicin, these authors obtained an IC 50 of 1.2 μmol L –1 , without light and with cellular incubation time of 24 h . One of the best ruthenium compounds for the elimination of MDA-MB-231 cells was ct -[RuCl­(CO)­(dppb)­(dpqQX)]­PF 6 (where dppb is (1,4-bis­(diphenylphosphino)­butane) and dpqQX is dipyrido­[3,2-a:2′,3′-c]­quinoxaline­[2,3- b ]­quinoxaline), where an IC 50 of 0.1 μmol L –1 was measured without any light irradiation and after a cellular incubation time of 48 h .…”

“…This compound showed IC 50 of 0.74 μmol L −1 upon 30 min of blue light irradiation with cell incubation of 72 h. 82 In another case, a ruthenium biphosphine complex, [Ru(GA)(dppe) 2 ]PF 6 (where GA is gallic acid and dppe is 1,2bis(diphenylphosphino)ethane) exhibited an IC 50 of 0.84 μmol L −1 without any light irradiation (after 48 h of cellular incubation). 83 Similarly, a terpyridine-based ruthenium compound, [Ru(tpy-CM) 2 ]Cl 2 (where tpy-CM is [2,2':6′,2″terpyridine]-4′-il)-N,N-bis(2-chloroethyl)aniline)), 84 showed IC 50 of 2.6 μmol L −1 , also without light irradiation, but with a longer cellular incubation time of 72 h. By combining a bipyridine-based ruthenium compound, Δ-[Ru(bpy) 2 (HPIP)]-(ClO 4 ) 2 (where HPIP is (2-hydroxyphenyl)imidazo[4,5-f ]-[1,10]phenanthroline), with a known anticancer drug, doxorubicin, these authors obtained an IC 50 of 1.2 μmol L −1 , without light and with cellular incubation time of 24 h. 85 One of the best ruthenium compounds for the elimination of MDA-MB-231 cells was ct-[RuCl(CO)(dppb)(dpqQX)]PF 6 (where dppb is (1,4-bis(diphenylphosphino)butane) and dpqQX is dipyrido-[3,2-a:2′,3′-c]quinoxaline[2,3-b]quinoxaline), where an IC 50 of 0.1 μmol L −1 was measured without any light irradiation and after a cellular incubation time of 48 h. 86 In our case, GRBA has exhibited some very exciting features, where potent cytotoxicity can be achieved upon light irradiation (43 nmol L −1 ), while without light only modest cytotoxicity is noticed making it appealing for phototherapy. The selectivity index (SI) was also calculated for these experiments, which is an important parameter for assessing the selectivity of an anticancer compound, indicating the difference in toxicity between cancerous and healthy cells.…”

“…IC 50 Values (μM) for the GRPA and GRBA Complexes in the MDA-MB-231 (Human Triple-Negative Breast Adenocarcinoma of Mesenchymal Phenotype), A2780 (Human Ovarian Adenocarcinoma), A549 (Human Lung Alveolar Epithelial Basal Cell Adenocarcinoma), and MRC-5 (Human Nontumorous Lung) Cell Lines in the Dark and upon Light Irradiation (460 nm, 10 min, 10.8 J cm −2 ) 83. Similarly, a terpyridine-based ruthenium compound, [Ru(tpy-CM) 2 ]Cl 2 (where tpy-CM is [2,2':6′,2″terpyridine]-4′-il)-N,N-bis(2-chloroethyl)aniline)),84 showed IC 50 of 2.6 μmol L −1 , also without light irradiation, but with a longer cellular incubation time of 72 h. By combining a bipyridine-based ruthenium compound, Δ-[Ru(bpy) 2 (HPIP)]-(ClO 4 ) 2 (where HPIP is (2-hydroxyphenyl)imidazo[4,5-f ]-[1,10]phenanthroline), with a known anticancer drug, doxorubicin, these authors obtained an IC 50 of 1.2 μmol L −1 , without light and with cellular incubation time of 24 h 85. One of the best ruthenium compounds for the elimination of MDA-MB-231 cells was ct-[RuCl(CO)(dppb)(dpqQX)]PF 6 (where dppb is (1,4-bis(diphenylphosphino)butane) and dpqQX is dipyrido-[3,2-a:2′,3′-c]quinoxaline[2,3-b]quinoxaline)…”