000221787 001__ 221787
000221787 005__ 20181203024350.0
000221787 0247_ $$2doi$$a10.1007/s00775-016-1353-z
000221787 022__ $$a0949-8257
000221787 02470 $$2ISI$$a000378819300002
000221787 037__ $$aARTICLE
000221787 245__ $$aChlorambucil conjugates of dinuclear p-cymene ruthenium trithiolato complexes: synthesis, characterization and cytotoxicity study in vitro and in vivo
000221787 260__ $$bSpringer Verlag$$c2016$$aNew York
000221787 269__ $$a2016
000221787 300__ $$a10
000221787 336__ $$aJournal Articles
000221787 520__ $$aFour diruthenium trithiolato chlorambucil conjugates have been prepared via Steglich esterification from chlorambucil and the corresponding trithiolato precursors. All conjugates are highly cytotoxic towards human ovarian A2780 and A2780cisR cancer cell lines with IC50 values in the nanomolar range. The conjugates exhibit selectivity towards A2780 cells as compared to non-cancerous HEK293 cells, while being only slightly selective for RF24 and A2780cisR cells. In vivo, the conjugate [10]BF4 suppressed the growth of a solid Ehrlich tumor in immunocompetent NMRI mice but did not prolong their overall survival. The reactivity of the chlorambucil conjugates with glutathione, a potential target of the dinuclear ruthenium motive, and with the 2-deoxyguanosine 5'-monophosphate (dGMP-a model target of chlorambucil) was studied by mass spectrometry and NMR spectroscopy. The conjugates did not show catalytic activity for the oxidation of glutathione nor binding to nucleotides, indicating that glutathione oxidation and DNA alkylation are not key mechanisms of action. Four highly cytotoxic diruthenium trithiolato chlorambucil conjugates have been prepared. All conjugates exhibit selectivity towards A2780 cells as compared to HEK293 cells, while being only slightly active in RF24 and A2780cisR cells. In vivo, the best candidate suppressed the growth of a solid Ehrlich tumor in immunocompetent NMRI mice but did not prolong their overall survival. [GRAPHICS] .
000221787 6531_ $$aArene ruthenium
000221787 6531_ $$aChlorambucil
000221787 6531_ $$aDinuclear complexes
000221787 6531_ $$aAnticancer activity
000221787 6531_ $$aIn vivo study
000221787 700__ $$uUniv Neuchatel, Inst Chim, Neuchatel, Switzerland$$aStibal, David
000221787 700__ $$uUniv Neuchatel, Inst Chim, Neuchatel, Switzerland$$aTherrien, Bruno
000221787 700__ $$uUniv Neuchatel, Inst Chim, Neuchatel, Switzerland$$aSuss-Fink, Georg
000221787 700__ $$0245027$$g168504$$uEcole Polytech Fed Lausanne, Inst Sci & Ingn Chim, Lausanne, Switzerland$$aNowak-Sliwinska, Patrycja
000221787 700__ $$0240015$$g149418$$uEcole Polytech Fed Lausanne, Inst Sci & Ingn Chim, Lausanne, Switzerland$$aDyson, Paul J.
000221787 700__ $$aCermakova, Eva
000221787 700__ $$uCharles Univ Prague, Fac Med Hradec Kralove, Dept Med Biochem, Hradec Kralove, Czech Republic$$aRezacova, Martina
000221787 700__ $$aTomsik, Pavel$$uCharles Univ Prague, Fac Med Hradec Kralove, Dept Med Biochem, Hradec Kralove, Czech Republic
000221787 773__ $$j21$$tJournal Of Biological Inorganic Chemistry$$k4$$q443-452
000221787 909C0 $$xU9$$0252010$$pLCOM
000221787 909CO $$pSB$$particle$$ooai:infoscience.tind.io:221787
000221787 917Z8 $$x135992
000221787 937__ $$aEPFL-ARTICLE-221787
000221787 973__ $$rREVIEWED$$sPUBLISHED$$aEPFL
000221787 980__ $$aARTICLE