15N and 195Pt NMR-Study of the Effect of Chain-Length, n, on the Reactions of Amino-Acids, +NH3(CH2)NCO2 (N = 1, 2, 3), With Platinum(II) Ammine Complexes

Abstract

15N and 195Pt n.m.r. have been used to study the reactions in solution of cis -Pt(15NH3)2(H2O)22+ (1), cis -Pt(15NH3)2(OH)2 (2), cis -Pt(15NH3)2Cl2 (3), Pt(15NH3)3(H2O)2+ (4) and Pt(15NH3)3(OH)+ (5) with the amino acids +NH3(CH2)nCO2- (LH) [n = 1 ( glycine, glyH ); n = 2 (β- alanine , βalaH ), n = 3 (γ- aminobutyric acid, abaH )]. While glycine with (1) gives initially cis -Pt(NH3)2( glyH -O)(H2O)2+, with facile ring closure to Pt(NH3)2( gly - N,O)+, β- alanine and γ- aminobutyric acid with (1) give solutions containing a mixture of cis -Pt(NH3)2(LH-O)(H2O)2+, cis -Pt(NH3)2(LH.O)22+, and {Pt(NH3)2}2(μO,O-LH)(μ-OH)3+, which are quite stable kinetically under mildly acid conditions. Ring closure to Pt(NH3)2(L-N,O)+ becomes increasingly difficult as n increases. At 37°C and initial pH 7, (3) with glycine gives Pt(NH3)2( gly -N,O)+, but β- alanine and γ- aminobutyric acid give predominantly cis -Pt(NH3)2Cl(LH-O)+. Compound (4) with glycine gives initially Pt(NH3)3( glyH -O)2+, which then isomerizes to Pt(NH3)3( glyH -N)2+. In corresponding reactions with β- alanine and γ- aminobutyric acid, Pt(NH3)3(LH-O)2+ is stable indefinitely under mildly acid conditions. Differences in reactivity of the amino acids with (2) and (5) in alkaline solutions may be correlated with decreasing nucleophilicity of the amine group of NH2(CH2)nCO2- as n increases.

Platinum-Based Antitumor Drugs Containing Enantiomerically Pure α-Trifluoromethyl Alanine as Ligand

“…Anal. (C4H5-NCl2F3KNO2Pt) C, H, N. MS MALDI-TOF: M -(% relative abundance) ) 420 (22), 421 (22), 422 (28), 423 (15), 424 (13). NMR data: 1 H, δ ) 1.89 ppm (3H, s); 19 F, δ ) -77.26 ppm; 195 Pt, δ ) -1627 ppm (br) (D2O; pH* 6.00).…”

“…Amino acids can coordinate to platinum in different ways. They can be monodentate (coordinated only through the amino group or only through the carboxylic functionality) or bidentate (coordinated through both the amino and the carboxylic groups). − If the amino acid contains a sulfur atom in a side chain, there is also the possibility of S coordination . In this context it is worth mentioning that sulfur-containing amino acids have been extensively studied as models for platinum interaction with glutathione (GSH) and metallothioneines.…”

Reactions of platinum(II) dipicolinate complex with amino acids—chelation and isomerization

“…Under the reaction condition (pH 7.0), the glycine nitrogen (p K a = 9.6) is protonated and the carboxyl group is fully deprotonated causing the carboxylate oxygen more available for bonding than the amine nitrogen. This has been proved in the reaction of [Pt(NH 3 ) 3 (H 2 O)] 2+ with glycine at pH 3 where even the partially deprotonated carboxyl group is favored for bonding leading to [Pt(NH 3 ) 3 (gly‐ O )] 2+ as a sufficiently stable product 15. The coordination occurs first, followed by a fast ring closure to form the chelate, [Pt(dipic bi )(gly‐N,O)].…”

“…2+ with glycine at pH 3 as a sufficiently stable product [15]. The coordination occurs first, followed by a fast ring closure to form the chelate, [Pt(dipic bi )(gly-N ,O)].…”

Biological relevance of interaction of platinum drugs with O-donor ligands

“…ESI-Mass Spectrometry has helped elucidate donor atom preferences in amino acids, where generally there is a preference for α-NH2 over the α-COOH groups [15]. Appleton used 195 Pt and 15 N NMR to study the reaction of cisplatin with a series of amino acids + NH3(CH2)nCOO -, with variable chain length: n = 1, (glycine), n = 2 (β-alanine) and n = 3 (γ-aminobutyric acid) [17]. Initially glycine forms an O-bound complex with cisplatin, which ring closes to form an N,O chelated species, which is thermodynamically more stable.…”