The contrasting catalytic efficiency and cancer cell antiproliferative activity of stereoselective organoruthenium transfer hydrogenation catalysts.
The rapidly growing area of catalytic ruthenium chemistry has provided new complexes with potential as organometallic anticancer agents with novel mechanisms of action. Here we report the anticancer activity of four neutral organometallic Ru(II) arene N-tosyl-1,2-diphenylethane-1,2-diamine (TsDPEN) tethered transfer hydrogenation catalysts. The enantiomers (R,R)-[Ru(η(6)-C6H5(CH2)3-TsDPEN-N-Me)Cl] (8) and (S,S)-[Ru(η(6)-C6H5(CH2)3-TsDPEN-N-Me)Cl] (8a) exhibited higher potency than cisplatin against A2780 human ovarian cancer cells. When the N-methyl was replaced by N-H, i.e. to give (R,R)-[Ru(η(6)-Ph(CH2)3-TsDPEN-NH)Cl] (7) and (S,S)-[Ru(η(6)-Ph(CH2)3-TsDPEN-NH)Cl] (7a), respectively, anticancer activity decreased >5-fold. Their antiproliferative activity appears to be linked to their ability to accumulate in cells, and their mechanism of action might involve inhibition of tubulin polymerisation. This appears to be the first report of the potent anticancer activity of tethered Ru(II) arene complexes, and the structure-activity relationship suggests that the N-methyl substituents are important for potency. In the National Cancer Institute 60-cancer-cell-line screen, complexes 8 and 8a exhibited higher activity than cisplatin towards a broad range of cancer cell lines. Intriguingly, in contrast to their potent anticancer properties, complexes 8/8a are poor catalysts for asymmetric transfer hydrogenation, whereas complexes 7/7a are effective asymmetric hydrogenation catalysts.
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK. p.j.sadler@warwick.ac.uk.
Ying
Y
Fu
Carlos
C
Sanchez-Cano
Rina
R
Soni
Isolda
I
Romero-Canelon
Jessica M
JM
Hearn
Zhe
Z
Liu
Martin
M
Wills
Peter J
PJ
Sadler
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D002384:Catalysis; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006859:Hydrogen / Q000737:chemistry*; D006865:Hydrogenation; D012428:Ruthenium / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D014404:Tubulin; D012428:Ruthenium; D006859:Hydrogen