A novel series of organometallic antitumour agents based on Ru II and Os II complexes containing N-substituted 2-pyridinecarbothioamides (PCAs) has been synthesized and characterized. To the best of our knowledge, this is the first report of organometallic anticancer compounds with an S,N-bidentate ligand system. While the ligands showed activity as gastric mucosal protectants and low acute toxicity in vivo (J. Med. Chem., 1990, 33, 327-336), coordination leads to highly antiproliferative metallodrugs, depending on lipophilicity and steric demand, in colon carcinoma and non-small lung cancer cell lines with intrinsic chemoresistances. The most lipophilic and smallest congeners are the most effective with IC 50 values in the low micromolar range. This new family of potential metallodrugs features exceptional stability in hydrochloric acid (60 mM), characterized by complete suppression of hydrolysis and low reactivity towards biological nucleophiles. Therefore, their unexpected aqueous chemistry renders this family of antiproliferative agents suitable for oral administration. An unprecedented feature is their ability to form transient thioketone-bridged dimers in aqueous solution upon hydrolysis, which is believed to minimize deactivation by biological nucleophiles. However, the biological effect seems to be caused by the monomer as observed with crystallographic studies of the nucleosome core particle (NCP), which revealed that [chlorido(h 6 -p-cymene)(N-phenyl-2-pyridinecarbothioamide)osmium(II)] chloride and [chlorido(h 6 -p-cymene)(N-fluorophenyl-2-pyridinecarbothioamide)osmium(II)] chloride react at two types of binding sites on the histone proteins. The adducts form at histidine side chains located on the nucleosome surface and the inner cleft of the nucleosome in the midst of an extensive histonehistone interface, suggesting interference with chromatin activity as a possible mode of action of these compounds. Additionally, ligand-based S / O exchange allows for a potential dual-mode of action by targeting DNA (J. Med. Chem., 2009, 52, 7753-7764). The quantitative estimates of drug-likeness (QED) for this family of compounds revealed a similar drug-likeness compared to erlotinib, tamoxifen, imatinib and sorafenib.

The ability to solve cognitive tasks depends upon adaptive changes in the organization of whole-brain functional networks. However, the link between task-induced network reconfigurations and their underlying energy demands is poorly understood. We address this by multimodal network analyses integrating functional and molecular neuroimaging acquired concurrently during a complex cognitive task. Task engagement elicited a marked increase in the association between glucose consumption and functional brain network reorganization. This convergence between metabolic and neural processes was specific to feedforward connections linking the visual and dorsal attention networks, in accordance with task requirements of visuo-spatial reasoning. Further increases in cognitive load above initial task engagement did not affect the relationship between metabolism and network reorganization but only modulated existing interactions. Our findings show how the upregulation of key computational mechanisms to support cognitive performance unveils the complex, interdependent changes in neural metabolism and neuro-vascular responses.

Maleimide-functionalised Pt(IV) complexes with highly selective binding properties to thiol groups were synthesised as precursors for binding of thiol-containing tumour-targeting molecules like human serum albumin.

PET with avid substrates of P-glycoprotein (ABCB1) provided evidence of the role of this efflux transporter in effectively restricting the brain penetration of its substrates across the human blood-brain barrier (BBB). This may not reflect the situation for weak ABCB1 substrates including several antidepressants, antiepileptic drugs, and neuroleptics, which exert central nervous system effects despite being transported by ABCB1. We performed PET with the weak ABCB1 substrate 11 C-metoclopramide in humans to elucidate the impact of ABCB1 function on its brain kinetics. Methods: Ten healthy male subjects underwent 2 consecutive 11 C-metoclopramide PET scans without and with ABCB1 inhibition using cyclosporine A (CsA). Pharmacokinetic modeling was performed to estimate the total volume of distribution (V T) and the influx (K 1) and efflux (k 2) rate constants between plasma and selected brain regions. Furthermore, 11 C-metoclopramide washout from the brain was estimated by determining the elimination slope (k E,brain) of the brain time-activity curves. Results: In baseline scans, 11 C-metoclopramide showed appreciable brain distribution (V T 5 2.11 ± 0.33 mL/cm 3). During CsA infusion, whole-brain gray matter V T and K 1 were increased by 29% ± 17% and 9% ± 12%, respectively. K 2 was decreased by 15% ± 5%, consistent with a decrease in k E,brain (−32% ± 18%). The impact of CsA on outcome parameters was significant and similar across brain regions except for the pituitary gland, which is not protected by the BBB. Conclusion: Our results show for the first time that ABCB1 does not solely account for the "barrier" property of the BBB but also acts as a detoxifying system to limit the overall brain exposure to its substrates at the human blood-brain interface.

The development of receptor tyrosine‐kinase inhibitors (TKIs) was a major step forward in cancer treatment. However, the therapy with TKIs is limited by strong side effects and drug resistance. The aim of this study was the design of novel epidermal growth factor receptor (EGFR) inhibitors that are specifically activated in malignant tissue. Thus, a CoIII‐based prodrug strategy for the targeted release of an EGFR inhibitor triggered by hypoxia in the solid tumor was used. New inhibitors with chelating moieties were prepared and tested for their EGFR‐inhibitory potential. The most promising candidate was coupled to CoIII and the biological activity tested in cell culture. Indeed, hypoxic activation and subsequent EGFR inhibition was proven. Finally, the compound was tested in vivo, also revealing potent anticancer activity.

Background: In recent years, molecular imaging adressing the C-X-C motif chemokine receptor 4 (CXCR4) has increasingly been utilized in various clinical settings. Here, we aimed to assess radiopharmaceutical uptake and image contrast to determine the most relevant clinical applications for CXCR4-directed imaging. We also investigated the impact of specific activity on scan contrast. Methods: 690 patients with a variety of neoplasms underwent a total of 777 PET/CT scans with 68 Ga-PentixaFor, serving as CXCR4-specific radioligand. A semiquantitative target lesion (TL) analysis was conducted [providing maximum standardized uptake values (SUVmax) and target-to-blood pool ratio (TBR), defined as SUVmax (from TL) divided by mean SUV (from blood pool)]. The applied specific activity (in MBq/µg) was compared to semi-quantitative assessments.Results: Of the 777 scans, 242 did not show discernible uptake in disease sites, leaving 535 PET scans (68.9%) for further analysis. Very high tracer uptake (SUVmax > 12) was found in multiple myeloma (MM; n=113), followed by adrenocortical carcinoma (n=30), mantle cell lymphoma (MCL; n=20), adrenocortical adenoma (n=6) and small cell lung cancer (SCLC; n=12). Providing information on image contrast, comparable results for TBR were recorded, with TBR (>8) in MM, MCL and acute lymphoblastoid leukemia (n=6). When comparing specific activity with semiquantitative parameters, no significant correlation was found for SUVmax or TBR (P ≥ 0.612).Conclusions: In this large cohort, 68 Ga-PentixaFor demonstrated high image contrast in a variety of neoplasms, particularly for hematologic malignancies, SCLC and adrenocortical neoplasms.The present analysis may provide a roadmap to detect patients who may benefit from CXCR4targeted therapies.

Thiomaltol, a potential S,O-coordinating molecule, has been utilized for the complexation of four different organometallic fragments, yielding the desired Ru , Os , Rh , and Ir complexes having a "piano-stool" configuration. In addition to the synthesis of these compounds with a chlorido leaving group, the analogous 1-methylimidazole derivatives have been prepared, giving rise to thiomaltol-based organometallics with enhanced stability under physiological conditions. The organometallic compounds have been characterized by NMR spectroscopy, elemental analysis, and X-ray diffraction analysis. Their behavior in aqueous solution and their interactions with certain amino acids have been studied by ESI mass spectrometry. Their pH-dependent stability has been investigated by H NMR in aqueous solution, and their cytotoxicity against three different cancer cell lines has been investigated. Furthermore, their capacity as topoisomerase IIα inhibitors as well as their effect on the cell cycle distribution and reactive oxygen species (ROS) generation have been elucidated.

(OC-6-43)-Dichlorido(N,N-dimethyl-ethane-1,2-diamine)dihydroxidoplatinum(IV) could selectively be mono-carboxylated with succinic anhydride based on the steric hindrance caused by the two methyl groups of the equatorial ligand. Subsequent esterification of the uncoordinated carboxylic acid with alcohols of different lengths (methanol, butanol, hexanol and octanol) afforded the corresponding esters. The synthesized complexes were characterized in detail by elemental analysis, ESI-MS, multinuclear ((1)H, (13)C, (15)N and (195)Pt) NMR spectroscopy and in two cases by X-ray crystallography. Cytotoxicity of novel platinum(IV) compounds was investigated in four human cancer cell lines (CH1, A549, SW480 and SK-OV-3). Remarkably, the most lipophilic complexes showed IC(50) values down to the low micromolar or even nanomolar range.