02518nas a2200277   4500008004100000022001400041245013400055210006900189260007500258300001400333490000700347520153500354653002101889653001501910653001201925653001901937653002601956100001601982700002101998700002102019700001802040700002002058700001702078700001702095856012802112       2015                        eng d  a0947-653900aCytostatic ruthenium(II)-platinum(II) bis(terpyridyl) anticancer complex that blocks entry into sphase by up-regulating p27(KIP1)0 aCytostatic rutheniumIIplatinumII bisterpyridyl anticancer comple  aPOSTFACH 101161, 69451 WEINHEIM, GERMANYbWILEY-V C H VERLAG GMBHcJUN  a9185-91970 v213 a<p>Cytostatic agents that interfere with specific cellular components to prevent cancer cell growth offer an attractive alternative, or complement, to traditional cytotoxic chemotherapy. Here, we describe the synthesis and characterization of a new binuclear Ru-II-Pt-II complex [Ru(tpy)(tpypma)Pt(Cl)(DMSO)](3+) (tpy=2,2:6,2-terpyridine and tpypma=4-([2,2:6,2-terpyridine]-4-yl)-N-(pyridin-2-ylmethyl)aniline), VR54, which employs the extended terpyridine tpypma ligand to link the two metal centres. In cell-free conditions, VR54 binds DNA by non-intercalative reversible mechanisms (K-b=1.3x10(5)M(-1)) and does not irreversibly bind guanosine. Cellular studies reveal that VR54 suppresses proliferation of A2780 ovarian cancer cells with no cross-resistance in the A2780CIS cisplatin-resistant cell line. Through the preparation of mononuclear Ru-II and Pt-II structural derivatives it was determined that both metal centres are required for this anti-proliferative activity. In stark contrast to cisplatin, VR54 neither activates the DNA-damage response network nor induces significant levels of cell death. Instead, VR54 is cytostatic and inhibits cell proliferation by up-regulating the cyclin-dependent kinase inhibitor p27(KIP1) and inhibiting retinoblastoma protein phosphorylation, which blocks entry into Sphase and results in G1 cell cycle arrest. Thus, VR54 inhibits cancer cell growth by a gain of function at the G1 restriction point. This is the first metal-coordination compound to demonstrate such activity.</p>10aantitumor agents10acytostatic10ap27KIP110aplatinum drugs10aruthenium terpyridine1 aRamu, Vadde1 aGill, Martin, R.1 aJarman, Paul, J.1 aTurton, David1 aThomas, Jim, A.1 aDas, Amitava1 aSmythe, Carl  uhttps://library.ncl.res.in/content/cytostatic-rutheniumii-platinumii-bisterpyridyl-anticancer-complex-blocks-entry-sphase-1