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Coordination modes vs. antitumor activity: synthesis and antitumor activity of novel platinum(II) complexes of N-substituted amino dicarboxylic acids

Authors
 Yeong-Sang Kim  ;  Rita Song  ;  Hyun Cheol Chung  ;  Moo Jin Jun  ;  Youn Soo Sohn 
Citation
 JOURNAL OF INORGANIC BIOCHEMISTRY, Vol.98(1) : 98-104, 2004-01 
Journal Title
 JOURNAL OF INORGANIC BIOCHEMISTRY 
ISSN
 0162-0134 
Issue Date
2004-01
MeSH
Amino Acids, Dicarboxylic / chemical synthesis ; Amino Acids, Dicarboxylic / chemistry* ; Amino Acids, Dicarboxylic / pharmacology* ; Animals ; Antineoplastic Agents / chemical synthesis ; Antineoplastic Agents / chemistry* ; Antineoplastic Agents / pharmacology* ; Cell Line, Tumor ; Drug Screening Assays, Antitumor ; Humans ; Hydrophobic and Hydrophilic Interactions ; Inhibitory Concentration 50 ; Isomerism ; Leukemia L1210 / drug therapy ; Organoplatinum Compounds / chemical synthesis ; Organoplatinum Compounds / chemistry* ; Organoplatinum Compounds / pharmacology*
Abstract
The trans-(+/-)-1,2-diaminocyclohexaneplatinum(II) complexes of multidentate L-glutamate (Glu) and L-aspartate (Asp) were prepared and their antitumor activity was examined in relation with their coordination modes. All these complexes were obtained as a mixture of (O,O')- and (O,N)-chelate isomers due to rapid isomerization of the initially formed (O,O')-isomer to the thermodynamically more stable (O,N)-isomer. The (O,O')/(O,N)-isomeric mixture with the mole ratio of 80/20 exhibited excellent antitumor activity while the pure (O,N)-isomer was only marginally active. Therefore, in order to prevent the linkage isomerization of the active (O,O')-isomer to the inactive (O,N)-isomer, we have designed N-substituted amino dicarboxylic acids as a leaving group and prepared a new series of complexes, [Pt(dach)(RGlu)] and [Pt(dach)(RAsp)] (dach=trans-(+/-)-1,2-diaminocyclohexane; R=acetyl (Ac), propionyl (Pro), pivaloyl (Piv), carbobenzyloxy (Cbz) or phthaloyl (Phth)) and characterized by means of elemental analyses, and 1H NMR, 195Pt NMR and IR spectroscopies. The N-substituted amino dicarboxylate ligands were found to coordinate to platinum(II) ion through only the (O,O')-chelation mode, and their Pt(II) complexes were chemically stable in aqueous solution. The present Pt(II) complexes of N-substituted amino dicarboxylic acids showed excellent antitumor activity against both murine leukemia L1210 and human tumor cells. Especially, the highly hydrophobic N-phthaloylglutamate complex, [Pt(dach)(PhthGlu)], exhibited an outstanding in vitro activity (IC50=2.22 microM) on the human stomach cancer cells which are not responsive to cisplatin and carboplatin.
Full Text
https://www.sciencedirect.com/science/article/pii/S0162013403003763?via%3Dihub#!
DOI
10.1016/j.jinorgbio.2003.09.004
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Chung, Hyun Cheol(정현철) ORCID logo https://orcid.org/0000-0002-0920-9471
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/178795
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