The antitumor complex ethylenediamine platinum (II) malonate: X-ray structure analysis, and studies of its stability in solution

Cutbush, S.; Kuroda, Reiko; Neidle, Stephen; Robins, A. B.

doi:10.1016/0162-0134(83)85003-x

Cited by 26 publications

(7 citation statements)

References 4 publications

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“…Bidentate ligands bound to Pt are much more stable than chlorido ligands as leaving ligands. While the half-life for displacement of the chlorido ligands in an aquous solution of cisplatin is approximately 2 h at 37 °C, the half-life for the displacement of the malonato ligand in ethylenediamine platinum(II) malonate approaches 5 days . Similar stabilities were reported for other bidentate ligands, such as oxalate, ethylmalonate and 1,1-cyclobutane dicarboxylate. , Hence, given their stability in aqueous solutions, Pt compounds containing bidentate ligands have been shown to react slowly with DNA in vitro . , In fact, most available evidence suggests that the displacement of the bidentate ligand in Pt complexes to form the monoaquated species is rate-limiting for their reaction with DNA.…”

Section: Resultsmentioning

confidence: 67%

Valuable Insight into the Anticancer Activity of the Platinum-Histone Deacetylase Inhibitor Conjugate, cis-[Pt(NH₃)₂malSAHA_–2H)]

et al. 2012

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cis-[Pt(II)(NH3)2(malSAHA-2H)], a cisplatin adduct conjugated to a potent histone deacetylase inhibitor (HDACi), suberoylanilide hydroxamic acid (SAHA), was previously developed as a potential anticancer agent. This Pt-HDACi conjugate was demonstrated to have comparable cytotoxicity to cisplatin against A2780 ovarian cancer cells but significantly reduced cytotoxicity against a representative normal cell line, NHDF. Thus, with a view to (i) understanding more deeply the effects that may play an important role in the biological (pharmacological) properties of this new conjugate against cancer cells and (ii) developing the next generation of Pt-HDACi conjugates, the cytotoxicity, DNA binding, cellular accumulation and HDAC inhibitory activity of cis-[Pt(II)(NH3)2(malSAHA-2H)] were investigated and are reported herein. cis-[Pt(II)(NH3)2(malSAHA-2H)] was found to have marginally lower cytotoxicity against a panel of cancer cell lines as compared to cisplatin and SAHA. cis-[Pt(II)(NH3)2(malSAHA-2H)] was also found to accumulate better in cancer cells but bind DNA less readily as compared to cisplatin. DNA binding experiments indicated that cis-[Pt(II)(NH3)2(malSAHA-2H)] bound DNA more effectively in cellulo as compared to in cell-free media. Activation of the Pt-HDACi conjugate was therefore investigated. The binding of cis-[Pt(II)(NH3)2(malSAHA-2H)] to DNA was found to be enhanced by the presence of thiol-containing molecules such as glutathione and thiourea, and activation occurred in cytosolic but not nuclear extract of human cancer cells. The activity of cis-[Pt(NH3)2(malSAHA-2H)] as a HDAC inhibitor was also examined; the conjugate exhibited no inhibition of HDAC activity in CH1 cells. In light of these results, novel Pt-HDACi conjugates are currently being developed, with particular emphasis, through subtle structural modifications, on enhancing the rate of DNA binding and enhancing HDAC inhibitory activity.

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Section: Resultsmentioning

confidence: 67%

Valuable Insight into the Anticancer Activity of the Platinum-Histone Deacetylase Inhibitor Conjugate, cis-[Pt(NH₃)₂malSAHA_–2H)]

et al. 2012

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“…Compound (I) contains two six-membered chelate rings. The tn ring adopts a chair conformation while the mal ring is in a boat conformation, as in the structures of other M II complexes with mal (Baker et al, 1993;Brown & Lock, 1989;Rochon et al, 1985;Cutbush et al, 1983;van Kralingen et al, 1980). In the tn ring, the dihedral angles of the planes Pd1/N1/N2 and C1/C2/C3 with respect to the plane N1/ C1/C3/N2 are 32.2 (1) and 60.5 (2) , respectively, which shows a less flattened conformation than those in [M II Cl 2 (tn)] {24.3 (2) and 62.1 (5) in [Pt II Cl 2 (tn)], 22.2 (1) and 62.1 (3) in [Pd II Cl 2 (tn)]}.…”

Section: Commentmentioning

confidence: 85%

(Malonato-κ²O,O′)(propane-1,3-diamine-κ²N,N′)palladium(II)

Odoko

Okabe

2007

Acta Cryst E

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“…Malopen (JM-40). This complex is ethylenediamine(malonato)platinum(II) and is of particular interest because there is a difference between the structure in the crystallographic database and the literature reference ( 24 ). From the 50 random configurations for malopen one obtains two geometries.…”

Section: Resultsmentioning

confidence: 99%

Molecular Mechanics Force Field for Platinum Coordination Complexes

Cundari

Moody

et al. 1996

J. Phys. Chem.

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A molecular mechanics study of square planar Pt(II) coordination complexes is reported. Three new ligating atom types which are representative of the σ-donor ligands prevalent in Pt(II) coordination chemistryschloride, carboxylate oxygen, and amine nitrogensare developed to extend the MM2 force field. The newly derived MM force field accurately describes the geometry of both the inner and outer coordination sphere of Pt(II) complexes. Quick and efficient modeling is obtained despite simplifications used in constructing the force field, e.g., neglect of anharmonic corrections to the bond-stretching and angle-bending potentials. The simplifications used in construction of the force field allow accurate structural prediction in a timely manner using readily available software and hardware. Additionally, the new MM force field shows the ability to predict structures, in the absence of a starting guess of the geometry from X-ray crystallography, that are subsequently found to be in good agreement with experimental geometries.

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The antitumor complex ethylenediamine platinum (II) malonate: X-ray structure analysis, and studies of its stability in solution

Cited by 26 publications

References 4 publications

Valuable Insight into the Anticancer Activity of the Platinum-Histone Deacetylase Inhibitor Conjugate, cis-[Pt(NH₃)₂malSAHA_–2H)]

Valuable Insight into the Anticancer Activity of the Platinum-Histone Deacetylase Inhibitor Conjugate, cis-[Pt(NH₃)₂malSAHA_–2H)]

(Malonato-κ²O,O′)(propane-1,3-diamine-κ²N,N′)palladium(II)

Molecular Mechanics Force Field for Platinum Coordination Complexes

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The antitumor complex ethylenediamine platinum (II) malonate: X-ray structure analysis, and studies of its stability in solution

Cited by 26 publications

References 4 publications

Valuable Insight into the Anticancer Activity of the Platinum-Histone Deacetylase Inhibitor Conjugate, cis-[Pt(NH3)2malSAHA–2H)]

Valuable Insight into the Anticancer Activity of the Platinum-Histone Deacetylase Inhibitor Conjugate, cis-[Pt(NH3)2malSAHA–2H)]

(Malonato-κ2O,O′)(propane-1,3-diamine-κ2N,N′)palladium(II)

Molecular Mechanics Force Field for Platinum Coordination Complexes

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Product

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About

Valuable Insight into the Anticancer Activity of the Platinum-Histone Deacetylase Inhibitor Conjugate, cis-[Pt(NH₃)₂malSAHA_–2H)]

Valuable Insight into the Anticancer Activity of the Platinum-Histone Deacetylase Inhibitor Conjugate, cis-[Pt(NH₃)₂malSAHA_–2H)]

(Malonato-κ²O,O′)(propane-1,3-diamine-κ²N,N′)palladium(II)