<i>trans</i>-Thionate Derivatives of Pt(II) and Pd(II) with Water-Soluble Phosphane PTA and DAPTA Ligands: Antiproliferative Activity against Human Ovarian Cancer Cell Lines

A series of PTA and DAPTA platinum­(II) and palladium­(II) thionate complexes of the type <i>trans</i>-[M­(SN)₂P₂] were prepared from the reaction of <i>cis</i>-[MCl₂P₂] [M = Pt, Pd; P = PTA (1,3,5-triaza-7-phosphaadamantane), DAPTA (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]­nonane)] with the <i>in situ</i> generated sodium salts of the heterocyclic thiones <i>S</i>-<i>m</i>-methylpyrimidine-2-thione, <i>S</i>-4,6-dimethylpyrimidine-2-thione, <i>S</i>-4,6-dihydroxypyrimidine-2-thione, benzothiazole-2-thione, benzoxazole-2-thione, <i>S</i>-1,3,4,-thiadiazole-2-thione, <i>S</i>-4,5-<i>H</i>-thiazolan-2-thione, and <i>S</i>-pyrimidine-4­(1<i>H</i>)-one-2-thione. The X-ray structures of six of the compounds confirm the <i>trans</i> disposition and, only in the case of [Pd₂Cl₂(<i>S</i>-pyrimidine-4­(1<i>H</i>)-one-2-thionate)₂(PTA)₂], a dinuclear structure with a Pd–Pd distance of 3.0265(14)­Å was observed. <i>In vitro</i> cytotoxicities against human ovarian cancer cell lines A2780 and A2780cisR were evaluated for ten complexes showing a high inhibition of cellular growth with a comparable inhibitory potency (IC₅₀) against A2780 cells to that of cisplatin. Notably, the compounds also show significant (up to 7-fold higher) activity in cisplatin-resistant A2780cisR cell lines

<i>trans</i>-Thionate Derivatives of Pt(II) and Pd(II) with Water-Soluble Phosphane PTA and DAPTA Ligands: Antiproliferative Activity against Human Ovarian Cancer Cell Lines

A series of PTA and DAPTA platinum­(II) and palladium­(II) thionate complexes of the type <i>trans</i>-[M­(SN)₂P₂] were prepared from the reaction of <i>cis</i>-[MCl₂P₂] [M = Pt, Pd; P = PTA (1,3,5-triaza-7-phosphaadamantane), DAPTA (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]­nonane)] with the <i>in situ</i> generated sodium salts of the heterocyclic thiones <i>S</i>-<i>m</i>-methylpyrimidine-2-thione, <i>S</i>-4,6-dimethylpyrimidine-2-thione, <i>S</i>-4,6-dihydroxypyrimidine-2-thione, benzothiazole-2-thione, benzoxazole-2-thione, <i>S</i>-1,3,4,-thiadiazole-2-thione, <i>S</i>-4,5-<i>H</i>-thiazolan-2-thione, and <i>S</i>-pyrimidine-4­(1<i>H</i>)-one-2-thione. The X-ray structures of six of the compounds confirm the <i>trans</i> disposition and, only in the case of [Pd₂Cl₂(<i>S</i>-pyrimidine-4­(1<i>H</i>)-one-2-thionate)₂(PTA)₂], a dinuclear structure with a Pd–Pd distance of 3.0265(14)­Å was observed. <i>In vitro</i> cytotoxicities against human ovarian cancer cell lines A2780 and A2780cisR were evaluated for ten complexes showing a high inhibition of cellular growth with a comparable inhibitory potency (IC₅₀) against A2780 cells to that of cisplatin. Notably, the compounds also show significant (up to 7-fold higher) activity in cisplatin-resistant A2780cisR cell lines

Characteristics of healthy volunteers (n = 20).

<p>Characteristics of healthy volunteers (n = 20).</p

DNA concentrations (ng/mL) classified by tumor types.

<p>Box and whisker plots showing 25^th, 50^th and 75^th percentiles, upper and lower adjacent values (whiskers) and Tukey outliers (•). P value is for a two-sided unpaired t-test on log10 DNA concentrations using Welch's correction for unequal variances.</p

Univariate and multivariate analysis.

<p>Univariate and multivariate analysis.</p

Patient characteristics (n = 104).^*

*<p>One patient was subsequently found to be ineligible for this study as he had not exhausted all lines of available antitumor treatments.</p>**<p>Includes non-small cell lung cancer (NSCLC), mesothelioma, sarcoma, glioblastoma, adenocarcinoma of unknown primary (ACUP), cholangiocarcinoma, and cervical, endometrial, duodenal, esophageal, pancreatic and renal cancers.</p>***<p>cpDNA was collected from 101 (97%) patients; it was not possible to draw blood from 1 patient for technical reasons and blood was not collected from 2 patients due to logistical errors.</p

cpDNA concentrations for mutational detection by Sequenom OncoCarta panel (v1.0).

<p><b>2A:</b> Nonparametric ROC analyses were used to assess the limit of the Sequenom platform to detect OncoCarta panel mutations in cpDNA. Each dot on the graph corresponds to the sensitivity and specificity at one of the observed concentrations. Mutations were considered ‘available for detection’ if they were detected in the patient's FFPE tissue. Mutations were detected in FFPE samples from 37 patients. The concentration of cpDNA with the optimal ability to detect a mutation is 29.95 ng/ml (Likelihood ratio = 7.3043). The AUC calculated is 0.8075 (95% CI 0.6552–0.9598). Patients whose FFPE was unavailable or tested negative for mutations were excluded from the analysis. The specificity reference lines for quartiles of DNA concentrations are indicated in red dashed lines. <b>2B:</b> Graph showing the types of mutations and cpDNA concentrations at which they were detected in different tumors. Mutations were detected in six oncogenes. Symbols represent different tumor types.</p

Relationship between cpDNA concentration and survival.

<p>(<b>3A</b>) Kaplan-Meier graph showing survival curves by cpDNA concentration in 101 patients with advanced solid tumors. Patients in the unfavorable category had concentrations greater than a healthy volunteer cohort maximum of 13.3 ng/ml (logrank p = 0.0383). (<b>3B</b>) Survivor function estimated from univariate Cox regression showing predicted survival curves for a range of cpDNA concentrations. A hazard ratio of 2.4 (p = 0.002) is depicted between adjacent curves.</p

Concordance in detected mutations between paired FFPE tumors and cpDNA.

<p>Concordance in detected mutations between paired FFPE tumors and cpDNA.</p

Relationship between cpDNA concentration and RMH prognostic score.

<p>Scatterplot showing the relationship between cpDNA concentration and RMH prognostic score. There was a significant positive linear trend between log₁₀(cpDNA) and RMH score (beta = 0.252, p<0.0001).</p