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

Yeong Sang Kim, Rita Song, Hyuncheol Chung, Moo Jin Jun, Youn Soo Sohn

Research output: Contribution to journalArticle

37 Citations (Scopus)

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 1 H NMR, 195 Pt 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 (IC 50 =2.22 μM) on the human stomach cancer cells which are not responsive to cisplatin and carboplatin.

Original languageEnglish
Pages (from-to)98-104
Number of pages7
JournalJournal of Inorganic Biochemistry
Volume98
Issue number1
DOIs
Publication statusPublished - 2004 Jan 1

Fingerprint

Dicarboxylic Amino Acids
Platinum
Isomers
Isomerization
Files and rasps
Leukemia L1210
Cells
Carboplatin
Viperidae
Aspartic Acid
Cisplatin
Stomach Neoplasms
Glutamic Acid
Chelation
Magnetic Resonance Spectroscopy
Nuclear magnetic resonance spectroscopy
1,2-cyclohexanediamine
Tumors
Infrared spectroscopy
Ions

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Inorganic Chemistry

Cite this

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title = "Coordination modes vs. antitumor activity: Synthesis and antitumor activity of novel platinum(II) complexes of N-substituted amino dicarboxylic acids",
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 1 H NMR, 195 Pt 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 (IC 50 =2.22 μM) on the human stomach cancer cells which are not responsive to cisplatin and carboplatin.",
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Coordination modes vs. antitumor activity : Synthesis and antitumor activity of novel platinum(II) complexes of N-substituted amino dicarboxylic acids. / Kim, Yeong Sang; Song, Rita; Chung, Hyuncheol; Jun, Moo Jin; Sohn, Youn Soo.

In: Journal of Inorganic Biochemistry, Vol. 98, No. 1, 01.01.2004, p. 98-104.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Coordination modes vs. antitumor activity

T2 - Synthesis and antitumor activity of novel platinum(II) complexes of N-substituted amino dicarboxylic acids

AU - Kim, Yeong Sang

AU - Song, Rita

AU - Chung, Hyuncheol

AU - Jun, Moo Jin

AU - Sohn, Youn Soo

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N2 - 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 1 H NMR, 195 Pt 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 (IC 50 =2.22 μM) on the human stomach cancer cells which are not responsive to cisplatin and carboplatin.

AB - 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 1 H NMR, 195 Pt 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 (IC 50 =2.22 μM) on the human stomach cancer cells which are not responsive to cisplatin and carboplatin.

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