Platinum(II) Complexes with Diglycine:  X-ray Crystal Structure, ¹⁵N NMR Spectra, and Growth-Inhibitory Activity against Mouse Meth A Solid Tumor in Vivo

Abstract

Two new dipeptide complexes of the form H[Pt(digly)Cl] (2) (H2digly = glycylglycine) and H[Pt(Hdigly)Cl2] (4) were newly prepared, and K[Pt(Hdigly)Cl2] (3) was isolated. Complex 1, K[Pt(digly)Cl], crystallizes in the monoclinic space group C2/c with unit cell dimensions a = 25.77(1) Å, b = 4.09(2) Å, c = 16.432(9) Å, β = 103.74(4)°, and Z = 8. Complex 3 crystallizes in the monoclinic space group P21/c with unit cell dimensions a = 8.892(5) Å, b = 11.387(4) Å, c = 9.974(4) Å, β = 105.45(4)°, Z = 4. Complex 4 crystallizes in the monoclinic space group P21/c with unit cell dimensions a = 9.311(6) Å, b = 7.737(8), c = 15.627(4) Å, β = 105.92(3)°, Z = 4. Complex 4 has the rare iminol type H2digly coordinating to Pt. The 15N chemical shifts and the coupling constants of the deprotonated coordinated amide N were obtained for the first time for these complexes. These amide peaks showed almost no coordination shift compared with the large coordination shift of the amine nitrogen. The coupling constants between Pt and deprotonated nitrogen for K[Pt(Hdipep)Cl2] were larger than those for K[Pt(dipep)Cl]. The growth inhibition assays of K[Pt(digly)Cl], K[Pt(Hdigly)Cl2], and cis-diamminedichloroplatinum(II) (cisplatin) against methylcholanthrene-induced Meth A fibrosarcoma (Meth A) solid tumor transplanted in BALB/c mice were measured. In mice, 35.9% of slight growth inhibition was observed in the group administered with K[Pt(digly)Cl] (dose of 26 mg/kg/day), and 40.6% in the group administered with K[Pt(Hdigly)Cl2] (dose of 52 mg/kg/day), and 45.3% cisplatin (dose of 10 mg/kg/day). The side effects related to the decrease in body weight are milder than that of cisplatin. Their toxicity against normal mouse bone marrow cells was measured. All of them exhibited toxicity against bone marrow cells, but K[Pt(digly)Cl] and K[Pt(Hdigly)Cl2] had only 1/10 the toxicity of cisplatin.

Protonation and coordination ability of small peptides – theoretical and experimental approaches for elucidation

“…These binding sites were fused in five-and six-membered chelate rings (figures 5 and 6). Interaction of H-(Gly) 2 -OH with Pt II led to the formation of mononuclear complexes with bidentate coordination (figure 4(B) and figure 5) as potassium dichloro-((Gly) 2 -N,N 0 )-Pt II (NOJKUS) and dichloro-((Gly) 2 -N,N 0 )-Pt II dihydrate (NOJLAZ) [119]. Depending on the reaction conditions H-(Gly) 2 -OH could interact tridentately through NH 2 , N À1 , and OCO À -centers, as observed in the potassium ((Gly) 2 -trichloro-Pt IV monohydrate (XEVYIG) [120] (figure 5) or ammonium bis((Gly) 2 -N,N 0 ,O)-Co III dihydrate (AGGLCO) [121].…”

“…The protonation of the peptide led to a shift of corresponding amide vibrations The new band at 1749 cm À1 corresponds to the C¼O of the -COOH fragment. The data for the higher Gly-analogs revealed that the values for NH are typical of trans-amide fragments where the frequency of the IR band corresponding to NH is observed within the range of 1560-1530 cm À1 (table 1) [116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132][133][134][135]. However, the strong overlapping of the spectroscopic patterns requires the application of other physical methods, such as NMR and MS.…”

Kinetics and mechanism of the reactions of platinum(II)‐dipicolinate and platinum(II)‐glycylglycine with oxalate ion

“…The Xray structural data [10] of K[Pt(digly)Cl] shows that the platinum atom is in an approximate square-planar environment but is displaced by 0.051Å from the plane which accommodates Cl, O, and the two N atoms. The principal distortion in the PtN 2 OCl coordination geometry is a non-linearity in the diglyO Pt N angle [O2 Pt N1 = 166.8 (3) • ] and the magnitude of [O2 Pt N2] bite angle is 82.6(3)Å.…”

“…The antitumor activity of only a few peptide-platinum(II) complexes has recently been reported in which di-and tri-peptides are coordinated to platinum(II) [8,9]. The study with [Pt(digly)(H 2 O)] assumes great significance in view of the recent report of reasonable antitumor activity of its parent complex, [Pt(digly)Cl] [10]. The present kinetic study has been extended over a wide range of pH to distinguish between the reactivity of the protonated and deprotonated forms of all the reacting species.…”

Anti- Candida Activity of a New Platinum Derivative

“…Since cisplatin is associated with side effects such as nephrotoxicity, nausea, and vomiting, many platinum complexes have been prepared in the hope of developing new derivatives with more potent activity and less toxicity. These trials indicated that the toxicity of platinum could be regulated by addition of imino ether, functional amines, and amino acid esters (5,6,14). Conversion of platinum(II) complexes to platinum(IV) analogs is another approach for preparation of new types of cytotoxic platinum complexes and moderating the toxicity of platinum(II) complexes.…”