Abstract:
:Previous studies of platinum(II) compounds with bidentate leaving ligands have emphasized the contrast between the stability of the bidentate leaving ligand in vitro (T1/2 greater than 11 days in water) and the apparent reactivity of these bidentate platinum compounds in vivo. However, none of these studies actually measured the stability of these compounds in tissue culture medium (or in any other reaction mixture resembling in vivo conditions). The experiments described in this paper were designed to measure the stability and fate of (d,l-trans-1,2-diaminocyclohexane)malonatoplatinum(II) [Pt(mal)(trans-dach)] in RPMI-1640 tissue culture medium. The T1/2 for displacement of the malonate ligand in this medium was 9.5 hr at 37 degrees. Of the inorganic anions present in the medium, chloride accounted for the greatest displacement of the malonate ligand. However, at the concentrations with which it is found in tissue culture medium and in blood, bicarbonate was nearly as effective as chloride at displacing the malonate ligand. This observation is of particular significance because the bicarbonatoplatinum complex is unstable and the bicarbonate displacement reaction appears to represent a major non-enzymatic pathway for the formation of the biologically active aquated platinum complexes. At the concentrations with which they occur inside the cell, phosphates may play a similar role. Of the amino acids present in the medium, glutathione and the sulfur-containing amino acids were 50- to 400-fold more effective at displacing the malonate ligand than the other amino acids in RPMI-1640 medium. In the case of methionine, the reaction with Pt(mal)(trans-dach) was shown to be a direct displacement (SN2) reaction at physiological methionine concentrations. When Pt(mal)(trans-dach) was incubated at 37 degrees for 24 hr in RPMI-1640 medium, the major transformation products formed were (d,l-trans-1,2-diaminocyclohexane)methionineplatinum(II) (38%), other amino acid-platinum complexes (19%), and (d,l,-trans-1,2-diaminocyclohexane)dichloroplatinum(II) (14%). Eleven percent of the Pt(mal)(trans-dach) remained intact. Mass spectrometry and 1H-NMR indicated that the (d,l-trans-1,2-diaminocyclohexane)methionineplatinum(II) complexes that formed in RPMI-1640 medium consisted of approximately 60% of the bidentate mono-methionine complex coordinated to platinum at the sulfur and alpha-amino positions and 40% of the bis-methionine complex, presumably coordinated at the sulfurs.(ABSTRACT TRUNCATED AT 400 WORDS)
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Mauldin SK,Plescia M,Richard FA,Wyrick SD,Voyksner RD,Chaney SGdoi
10.1016/0006-2952(88)90646-6subject
Has Abstractpub_date
1988-09-01 00:00:00pages
3321-33issue
17eissn
0006-2952issn
1873-2968pii
0006-2952(88)90646-6journal_volume
37pub_type
杂志文章abstract::Anticholinesterases (anti-ChE) have some effects on biological properties including behavior, vision, and electroencephalograms, which are often long lasting and which do not appear to be due to cholinesterase (ChE; EC 3.1.1.7) inhibition, but which may be due to alterations in the organization and/or functioning of t...
journal_title:Biochemical pharmacology
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pub_type: 杂志文章,评审
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pub_type: 杂志文章
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更新日期:1984-02-15 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Biochemical pharmacology
pub_type: 杂志文章
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更新日期:1988-04-01 00:00:00
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