Synthesis and Characterization of New Ethylenediamine Platinum(IV) Complexes Containing Lipophilic Carboxylate Ligands

A series of new ethylenediamine (en) platinum(IV) complexes of the type Pt(IV)enX2A2, with X2  = cyclobutane-1,1-dicarboxylato (CBDCA), dichloro or bis(decanoato) and A = acetato, dodecanoato, tetradecanoato, hexadecanoato, octadecanoato, adamantanecarboxylato (Ad) or 3α, 12α-diformoxy-5β-cholato (DFCA) were synthesized and characterized by elemental analysis, infrared and NMR (1H  and  13C) spectroscopic techniques. Previous platinum(IV) compounds were usually restricted to trans-dihydroxo or trans-dichloro platinum(IV) complexes. Recently trans-dicarboxylato platinum(IV) complexes with mainly acetate, trifluoracetate or short-chain carboxylate groups (<11 carbons) in the axial position have been described in the literature[1,2,3]. In this paper we report on the synthesis and characterization of a new class of ethylenediamine platinum(IV) compounds that have high lipophilic long-chain carboxylate ligands either in the axial or equatorial position. The platinum(IV) compounds with the lipophilic trans-carboxylate ligands in the axial position were prepared by acylation of the trans-dihydroxo platinum(IV) species using an acyl halide in the presence of pyridine. In contrast to previous publications[1] the yields were excellent (up to 94%!)

Synthesis of (N,N'-Bis(2-Hydroxyethyl)Ethane-1,2-Diamine)Malonatoplatinum(II) and X-Ray Crystal Structure of the Cis-R,S-Isomer

Hydroxyethyl substituted amineplatinum(II) and (IV) complexes are an interesting class of platinum based antitumour compounds due to their uncoordinated hydroxy groups. These hydroxy groups could play an important role in the mode of action of such complexes with respect to their ability to act as donor or acceptor for hydrogen bonds. Moreover, their chemistry in solution is of interest because it was found that there is the possibility of an intramolecular attack to form ethanolatoamine chelated species which are responsible for very stable monoadducts with 5'-GMP. Furthermore, there is the possibility of derivatisation at the OH site to form a new series of platinum compounds which may be used for a carrier mediated transport to tumour tissues. In this context a series of (N,N'-bis(2-hydroxyethyl)ethane-l,2-diamine)-platinum(II) complexes has been synthesised. During purification of one of the platinum based compounds, it was possible to isolate (SP-4-3)-R,S-(N,N'-bis(2-hydroxyethyl)ethane-l,2-diamine)malonatoplatinum(ll) and to resolve the structure by single crystal structure analysis. Intra- and intermolecular hydrogen bonds have been found which may explain the spontaneous crystallisation of the cis-R,S isomer and the stabilisation of the boat conformation of the malonatoplatinum(II) six-membered ring

Synthesis, structural characterization, antimicrobial and cytotoxic effects of aziridine, 2-aminoethylaziridine and azirine complexes of copper(II) and palladium(II).

The synthesis, spectroscopic and X-ray structural characterization of copper(II) and palladium(II) complexes with aziridine ligands as 2-dimethylaziridine HNCH2CMe2 (a), the bidentate N-(2-aminoethyl)aziridines C2H4NC2H4NH2 (b) or CH2CMe2NCH2CMe2NH2 (c) as well as the unsaturated azirine NCH2CPh (d) are reported. Cleavage of the cyclometallated Pd(II) dimer [μ-Cl(C6H4CHMeNMe2-C,N)Pd]2 with ligand a yielded compound [Cl(NHCH2CMe2)(C6H4CHMe2NMe2-C,N)Pd] (1a). The reaction of the aziridine complex trans-[Cl2Pd(HNC2H4)2] with an excess of aziridine in the presence of AgOTf gave the ionic chelate complex trans-[(C2H4NC2H4NH2-N,N′)2Pd](OTf)2 (2b) which contains the new ligand b formed by an unexpected insertion and ring opening reaction of two aziridines (“aziridine dimerization”). CuCl2 reacted in pure HNC2H4 or HNCH2CMe2 (b) again by “dimerization” to give the tris-chelated ionic complex [Cu(C2H4NC2H4NH2-N,N′)3]Cl2 (3b) or the bis-chelated complex [CuCl(C2H2Me2NC2H2Me2NH2-N,N′)2]Cl (4c). By addition of 2H-3-phenylazirine (d) to PdCl2, trans-[Cl2Pd(NCH2CPh)2] (5d) was formed. All new compounds were characterized by NMR, IR and mass spectra and also by X-ray structure analyses (except 3b). Additionally the cytotoxic effects of these complexes were examined on HL-60 and NALM-6 human leukemia cells and melanoma WM-115 cells. The antimicrobial activity was also determined. The growth of Gram-positive bacterial strains (S. aureus, S. epidermidis, E. faecalis) was inhibited by almost all tested complexes at the concentrations of 37.5–300.0 μg mL−1. However, MIC values of complexes obtained for Gram-negative E. coli and P. aeruginosa, as well as for C. albicans yeast, mostly exceeded 300 μg mL−1. The highest antibacterial activity was achieved by complexes 1a and 2b. Complex 2b also inhibited the growth of Gram-negative bacteria. Graphical abstract: Synthesis, structural characterization, antimicrobial and cytotoxic effects of aziridine, 2-aminoethylaziridine and azirine complexes of copper(ii) and palladium(ii

Paediatric CT scan usage and referrals of children to computed tomography in Germany-a cross-sectional survey of medical practice and awareness of radiation related health risks among physicians

<p>Abstract</p> <p>Background</p> <p>Computed tomography (CT) is a major source of ionizing radiation exposure in medical diagnostic. Compared to adults, children are supposed to be more susceptible to health risks related to radiation. The purpose of a cross-sectional survey among office-based physicians in Germany was the assessment of medical practice in paediatric CT referrals and to investigate physicians' knowledge of radiation doses and potential health risks of radiation exposure from CT in children.</p> <p>Methods</p> <p>A standardized questionnaire was distributed to all paediatricians and surgeons in two defined study areas. Furthermore, the study population included a random sample of general practitioners in the two areas. The questionnaire covered the frequency of referrals for paediatric CT examinations, the medical diagnoses leading to paediatric CT referrals, physicians' knowledge of radiation doses and potential health risks of radiation exposure from CT in children.</p> <p>Results</p> <p>A total of 295 (36.4%) physicians responded. 59% of the doctors had not referred a child to CT in the past year, and approximately 30% referred only 1-5 children annually. The most frequent indications for a CT examination in children were trauma or a suspected cancer. 42% of the referrals were related to minor diagnoses or unspecific symptoms. The participants underestimated the radiation exposure due to CT and they overestimated the radiation exposure due to conventional X-ray examinations.</p> <p>Conclusions</p> <p>In Germany, the frequency of referrals of children to computed tomography is moderate. The knowledge on the risks from radiation exposure among office-based physicians in our sample varied, but there was a tendency to underestimate potential CT risks. Advanced radiological training might lead to considerable amendments in terms of knowledge and practice of CT referral.</p

Survival rate in patients with hepatocellular carcinoma: a retrospective analysis of 389 patients

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. However, treatment options are limited and often inefficient. The aim of this study was to determine current survival rates for patients diagnosed with HCC and to identify prognostic factors, which will help in choosing optimal therapies for individual patients. A retrospective analysis of medical records was performed on 389 patients who were identified through the central tumour registry at our institution from 1998 to 2003. Clinical parameters, treatments received and survival curves from time of diagnosis were analysed. Overall median survival was 11 months. Liver cirrhosis was diagnosed in 80.5% of all patients. A total of 170 patients received transarterial chemoembolisation (TACE) and/or percutaneous ethanol injections (PEI) with a median survival rate of 16 months for patients receiving TACE, 11 months for patients receiving PEI and 24 months for patients receiving TACE followed by PEI. Independent negative prognostic parameters for survival were the presence of portal vein thrombosis, advanced liver cirrhosis (Child–Pugh score B or C) and a score of >2. This study will help to estimate survival rates for patients with HCC according to their clinical status at diagnosis and the treatments received

Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

Indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (KP1019) and its Na+ analogue (KP1339) are two of the most prominent non-platinum antitumor metal complexes currently undergoing clinical trials. After intravenous administration, they are known to bind to human serum albumin (HSA) in a noncovalent manner. To elucidate their HSA binding sites, displacement reactions with the established site markers warfarin and dansylglycine as well as bilirubin were monitored by spectrofluorimetry, ultrafiltration-UV-vis spectrophotometry, and/or capillary zone electrophoresis. Conditional stability constants for the binding of KP1019 and KP1339 to sites I and II of HSA were determined, indicating that both Ru(III) compounds bind to both sites with moderately strong affinity (log K (1)' = 5.3-5.8). No preference for either binding site was found, and similar results were obtained for both metal complexes, demonstrating low influence of the counter ion on the binding event

Comparison of 1.0 M gadobutrol and 0.5 M gadopentate dimeglumine-enhanced MRI in 471 patients with known or suspected renal lesions: Results of a multicenter, single-blind, interindividual, randomized clinical phase III trial

The purpose of this phase III clinical trial was to compare two different extracellular contrast agents, 1.0 M gadobutrol and 0.5 M gadopentate dimeglumine, for magnetic resonance imaging (MRI) in patients with known or suspected focal renal lesions. Using a multicenter, single-blind, interindividual, randomized study design, both contrast agents were compared in a total of 471 patients regarding their diagnostic accuracy, sensitivity, and specificity to correctly classify focal lesions of the kidney. To test for noninferiority the diagnostic accuracy rates for both contrast agents were compared with CT results based on a blinded reading. The average diagnostic accuracy across the three blinded readers ('average reader') was 83.7% for gadobutrol and 87.3% for gadopentate dimeglumine. The increase in accuracy from precontrast to combined precontrast and postcontrast MRI was 8.0% for gadobutrol and 6.9% for gadopentate dimeglumine. Sensitivity of the average reader was 85.2% for gadobutrol and 88.7% for gadopentate dimeglumine. Specificity of the average reader was 82.1% for gadobutrol and 86.1% for gadopentate dimeglumine. In conclusion, this study documents evidence for the noninferiority of a single i.v. bolus injection of 1.0 M gadobutrol compared with 0.5 M gadopentate dimeglumine in the diagnostic assessment of renal lesions with CE-MRI

PET/CT Imaging of c-Myc Transgenic Mice Identifies the Genotoxic N-Nitroso-Diethylamine as Carcinogen in a Short-Term Cancer Bioassay

Background: More than 100,000 chemicals are in use but have not been tested for their safety. To overcome limitations in the cancer bioassay several alternative testing strategies are explored. The inability to monitor non-invasively onset and progression of disease limits, however, the value of current testing strategies. Here, we report the application of in vivo imaging to a c-Myc transgenic mouse model of liver cancer for the development of a short-term cancer bioassay. Methodology/Principal Findings: mCT and 18 F-FDG mPET were used to detect and quantify tumor lesions after treatment with the genotoxic carcinogen NDEA, the tumor promoting agent BHT or the hepatotoxin paracetamol. Tumor growth was investigated between the ages of 4 to 8.5 months and contrast-enhanced mCT imaging detected liver lesions as well as metastatic spread with high sensitivity and accuracy as confirmed by histopathology. Significant differences in the onset of tumor growth, tumor load and glucose metabolism were observed when the NDEA treatment group was compared with any of the other treatment groups. NDEA treatment of c-Myc transgenic mice significantly accelerated tumor growth and caused metastatic spread of HCC in to lung but this treatment also induced primary lung cancer growth. In contrast, BHT and paracetamol did not promote hepatocarcinogenesis. Conclusions/Significance: The present study evidences the accuracy of in vivo imaging in defining tumor growth, tumor load, lesion number and metastatic spread. Consequently, the application of in vivo imaging techniques to transgeni