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 language | English |
|---|---|
| Pages (from-to) | 98-104 |
| Number of pages | 7 |
| Journal | Journal of Inorganic Biochemistry |
| Volume | 98 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2004 Jan 1 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Inorganic Chemistry
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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 journal › Article
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
PY - 2004/1/1
Y1 - 2004/1/1
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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UR - http://www.scopus.com/inward/citedby.url?scp=0344687281&partnerID=8YFLogxK
U2 - 10.1016/j.jinorgbio.2003.09.004
DO - 10.1016/j.jinorgbio.2003.09.004
M3 - Article
C2 - 14659638
AN - SCOPUS:0344687281
VL - 98
SP - 98
EP - 104
JO - Journal of Inorganic Biochemistry
JF - Journal of Inorganic Biochemistry
SN - 0162-0134
IS - 1
ER -