Occurrence, Distribution, and Environmental Behavior of Persistent, Mobile, and Toxic (PMT) and Very Persistent and Very Mobile (vPvM) Substances in the Sources of German Drinking Water.

Persistent, mobile, and toxic (PMT) and very persistent and very mobile (vPvM) substances have been recognized as a threat to both the aquatic environment and to drinking water resources. These substances are currently prioritized for regulatory action by the European Commission, whereby a proposal for the inclusion of hazard classes for PMT and vPvM substances has been put forward. Comprehensive monitoring data for many PMT/vPvM substances in drinking water sources are scarce. Herein, we analyze 34 PMT/vPvM substances in 46 surface water, groundwater, bank filtrate, and raw water samples taken throughout Germany. Results of the sampling campaign demonstrated that known PMT/vPvM substances such as 1H-benzotriazole, melamine, cyanuric acid, and 1,4-dioxane are responsible for substantial contamination in the sources of German drinking water. In addition, the results revealed the widespread presence of the emerging substances 2-acrylamido-2-methylpropanesulfonic acid (AMPS) and diphenylguanidine (DPG). A correlation analysis showed a pronounced co-occurrence of PMT/vPvM substances associated predominantly with consumer or professional uses and also demonstrated an inhomogeneous co-occurrence for substances associated mainly with industrial use. These data were used to test the hypothesis that most PMT/vPvM substances pass bank filtration without significant concentration reduction, which is one of the main reasons for introducing PMT/vPvM as a hazard class within Europe.

Ultra-Short-Chain PFASs in the Sources of German Drinking Water: Prevalent, Overlooked, Difficult to Remove, and Unregulated.

Per- and polyfluoroalkyl substances (PFASs) have been a focal point of environmental chemistry and chemical regulation in recent years, culminating in a shift from individual PFAS regulation toward a PFAS group regulatory approach in Europe. PFASs are a highly diverse group of substances, and knowledge about this group is still scarce beyond the well-studied, legacy long-chain, and short-chain perfluorocarboxylates (PFCAs) and perfluorosulfonates (PFSAs). Herein, quantitative and semiquantitative data for 43 legacy short-chain and ultra-short-chain PFASs (≤2 perfluorocarbon atoms for PFCAs, ≤3 for PFSAs and other PFASs) in 46 water samples collected from 13 different sources of German drinking water are presented. The PFASs considered include novel compounds like hexafluoroisopropanol, bis(trifluoromethylsulfonyl)imide, and tris(pentafluoroethyl)trifluorophosphate. The ultra-short-chain PFASs trifluoroacetate, perfluoropropanoate, and trifluoromethanesulfonate were ubiquitous and present at the highest concentrations (98% of sum target PFAS concentrations). "PFAS total" parameters like the adsorbable organic fluorine (AOF) and total oxidizable precursor (TOP) assay were found to provide only an incomplete picture of PFAS contamination in these water samples by not capturing these highly prevalent ultra-short-chain PFASs. These ultra-short-chain PFASs represent a major challenge for drinking water production and show that regulation in the form of preventive measures is required to manage them.

Synthesis and biological testing of novel pyridoisothiazolones as histone acetyltransferase inhibitors.

We present a combination of database screening, synthesis and in vitro testing to identify novel histone acetyltransferase (HAT) inhibitors. The National Cancer Institute compound collection (NCI) and several commercial databases were filtered by similarity-based virtual screening to find new HAT inhibitors. Employing the recombinant HAT p300/CBP-associated factor (PCAF) and two different histone substrates for screening, pyridoisothiazolones were identified as inhibitors of human PCAF. Due to the limited solubility of the initial hits, we synthesized and tested them on PCAF. The compounds inhibit the proliferation of cancer cells. In summary, valuable chemical tools and potential lead candidates for new anticancer agents directed against HATs as new targets have been identified.

Pyridylalanine-containing hydroxamic acids as selective HDAC6 inhibitors.

We synthesized hydroxamic acids with a pyridylalanine substructure and identified them as selective inhibitors of human recombinant HDAC6. The in vitro selectivity was up to 25-fold for HDAC6 over HDAC1 and was confirmed by Western blotting to assess tubulin versus histone acetylation in cancer cells. Docking studies with an HDAC6 homology model suggested that the hydrophobic cap group of the inhibitors interacts with aromatic residues that form a sub-pocket near the entrance of the substrate binding channel. The HDAC6-selective compounds have less cytotoxicity toward cancer cells than do pan-HDAC inhibitors. The synergistic antiproliferative activity we showed with the proteasome inhibitor bortezomib suggests the potential for combination anticancer therapy with less general toxicity.

Structure-activity studies on splitomicin derivatives as sirtuin inhibitors and computational prediction of binding mode.

NAD (+)-dependent histone deacetylases (sirtuins) are enzymes that cleave acetyl groups from lysines in histones and other proteins. Potent selective sirtuin inhibitors are interesting tools for the investigation of the biological functions of those enzymes and may be future drugs for the treatment of cancer. Splitomicin was among the first two inhibitors that were discovered for yeast sirtuins but showed rather weak inhibition on human enzymes. We present detailed structure-activity relationships on splitomicin derivatives and their inhibition of recombinant Sirt2. To rationalize our experimental results, ligand docking followed by molecular mechanics Poisson-Boltzmann/surface area (MM-PBSA) calculations were carried out. These analyses suggested a molecular basis for the interaction of the beta-phenylsplitomicins with human Sirt2. Protein-based virtual screening resulted in the identification of a novel Sirt2 inhibitor chemotype. Selected inhibitors showed antiproliferative properties and tubulin hyperacetylation in MCF7 breast cancer cells and are promising candidates for further optimization as potential anticancer drugs.

Characterization of novel inhibitors of histone acetyltransferases.

Modification of proteins by histone acetyltransferases (HAT) or histone deacetylases plays an important role in the control of gene expression, and its dysregulation has been linked to malignant transformation and other diseases. Although histone deacetylase inhibitors have been extensively studied and several are currently in clinical trials, there is little information available on inhibitors of HATs (HATi). Starting from the natural product lead HATi anacardic acid, a series of 28 analogues was synthesized and investigated for HAT-inhibitory properties and effects on cancer cell growth. The compounds inhibited up to 95% HAT activity in vitro, and there was a clear correlation between their inhibitory potency and cytotoxicity toward a broad panel of cancer cells. Interestingly, all tested compounds were relatively nontoxic to nonmalignant human cell lines. Western blot analysis of MCF7 breast carcinoma cells treated with HATi showed significant reduction in acetylation levels of histone H4. To directly show effect of the new compounds on HAT activity in vivo, MCF7 cells were cotransfected with the p21 promoter fused to firefly luciferase and a full-length p300 acetyltransferase, and luciferase activity was determined following treatment with HATi. Significant inhibition of p300 activity was detected after treatment with all tested compounds except one. Effects of the new HATi on protein acetylation and HAT activity in vivo make them a suitable tool for discovery of molecular targets of HATs and, potentially, for development of new anticancer therapeutics.