Strategies To Design Selective Histone Deacetylase Inhibitors

This review classifies drug-design strategies successfully implemented in the development of histone deacetylase (HDAC) inhibitors, which have many applications including cancer treatment. Our focus is on especially demanded selective HDAC inhibitors and their structure-activity relationships in relation to corresponding protein structures. The main part of the paper is divided into six subsections each narrating how optimization of one of six structural features can influence inhibitor selectivity. It starts with the impact of the zinc binding group on selectivity, continues with the optimization of the linker placed in the substrate binding tunnel as well as the adjustment of the cap group interacting with the surface of the protein, and ends with the addition of groups targeting class-specific sub-pockets: the side-pocket-, lower-pocket- and foot-pocket-targeting groups. The review is rounded off with a conclusion and an outlook on the future of HDAC inhibitor design.     

From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs

The orexin system is responsible for regulating the sleep-wake cycle. Suvorexant, a dual orexin receptor antagonist (DORA) is approved by the FDA for the treatment of insomnia disorders. Herein, we report the optimization efforts toward a DORA, where our starting point was (5-methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-[5-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrrolidin-1-yl}methanone ( 6 ), a compound which emerged from our in-house research program. Compound 6 was shown to be a potent, brain-penetrating DORA with in vivo efficacy similar to suvorexant in rats. However, shortcomings from low metabolic stability, high plasma protein binding (PPB), low brain free fraction (f_u brain), and low aqueous solubility, were identified and hence, compound 6 was not an ideal candidate for further development. Our optimization efforts addressing the above-mentioned shortcomings resulted in the identification of (4-chloro-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-methyl-2-[5-(2-trifluoromethoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-pyrrolidin-1-yl}l-methanone ( 42 ), a DORA with improved in vivo efficacy compared to 6 .     

The Alkylquinolone Repertoire of Pseudomonas aeruginosa is Linked to Structural Flexibility of the FabH‐like 2‐Heptyl‐3‐hydroxy‐4(1H)‐quinolone (PQS) Biosynthesis Enzyme PqsBC

Pseudomonas aeruginosa is a bacterial pathogen that causes life‐threatening infections in immunocompromised patients. It produces a large armory of saturated and mono‐unsaturated 2‐alkyl‐4(1H)‐quinolones (AQs) and AQ N‐oxides (AQNOs) that serve as signaling molecules to control the production of virulence factors and that are involved in membrane vesicle formation and iron chelation; furthermore, they also have, for example, antibiotic properties. It has been shown that the β‐ketoacyl‐acyl‐carrier protein synthase III (FabH)‐like heterodimeric enzyme PqsBC catalyzes the last step in the biosynthesis of the most abundant AQ congener, 2‐heptyl‐4(1H)‐quinolone (HHQ), by condensing octanoyl‐coenzyme A (CoA) with 2‐aminobenzoylacetate (2‐ABA), but the basis for the large number of other AQs/AQNOs produced by P. aeruginosa is not known. Here, we demonstrate that PqsBC uses different medium‐chain acyl‐CoAs to produce various saturated AQs/AQNOs and that it also biosynthesizes mono‐unsaturated congeners. Further, we determined the structures of PqsBC in four different crystal forms at 1.5 to 2.7 Å resolution. Together with a previous report, the data reveal that PqsBC adopts open, intermediate, and closed conformations that alter the shape of the acyl‐binding cavity and explain the promiscuity of PqsBC. The different conformations also allow us to propose a model for structural transitions that accompany the catalytic cycle of PqsBC that might have broader implications for other FabH‐enzymes, for which such structural transitions have been postulated but have never been observed.     

Alternating Cationic-Hydrophobic Peptide/Peptoid Hybrids: Influence of Hydrophobicity on Antibacterial Activity and Cell Selectivity

The influence of hydrophobicity on antibacterial activity versus the effect on the viability of mammalian cells for peptide/peptoid hybrids was examined for oligomers based on the cationic Lys-like peptoid residue combined with each of 28 hydrophobic amino acids in an alternating sequence. Their relative hydrophobicity was correlated to activity against both Gram-negative and Gram-positive species, human red blood cells, and HepG2 cells. This identified hydrophobic side chains that confer potent antibacterial activity (e. g., MICs of 2–8 μg/mL against E. coli) and low toxicity toward mammalian cells (<10 % hemolysis at 400 μg/mL and IC₅₀>800 μg/mL for HepG2 viability). Most peptidomimetics retained activity against drug-resistant strains. These findings corroborate the hypothesis that for related peptidomimetics two hydrophobicity thresholds may be identified: i) it should exceed a certain level in order to confer antibacterial activity, and ii) there is an upper limit, beyond which cell selectivity is lost. It is envisioned that once identified for a given subclass of peptide-like antibacterials such thresholds can guide further optimisation.     

Adaptive neuro-fuzzy algorithm applied to predict and control multi-phase flow rates through wellhead chokes

A Takagi-Sugeno adaptive neuro-fuzzy inference system (TSFIS) model is developed and applied to a dataset of wellhead flow-test data for the Resalat oil field located offshore southern Iran, the objective is to assist in the prediction and control of multi-phase flow rates of oil and gas through the wellhead chokes. For this purpose, 182 test data points (Appendix 1) related to the Resalat field are evaluated. In order to predict production flow rate (Q_L) expressed as stock-tank barrels per day (STB/D), this dataset includes four selected input variables: upstream pressure (Pwh); wellhead choke sizes (D64); gas to liquid ratio (GLR); and, base solids and water including some water-soluble oil emulsion (BS&W). The test data points evaluated include a wide range of oil flow rate conditions and values for the four input variables recorded. The TSFIS algorithm applied involves five data processing steps: a) pre-processing, b) fuzzification, c) rules base and adaptive neuro-fuzzy inference engine, d) defuzzification, and e) post-processing of the fuzzy model. The developed TSFIS model for the Resalat oil field database predicted oil flow rate to a high degree of accuracy (root mean square error = 247 STB/D, correlation coefficient = 0.9987), which improves substantially on the commonly used empirical algorithms used for such predictions. TSFIS can potentially be applied in wellhead choke fuzzy controllers to stabilize flow in specific wells based on real-time input data records.     

Hydrolysis-resistant polyurethane elastomers synthesized from hydrophobic bio-based polyfarnesene diol

Hydrolytic stability is an essential requirement for polyurethanes (PUs) that are used in highly humid and aqueous environments. In this study, hydrolysis-resistant PU elastomers (PUEs) are synthesized based on hydrophobic bio-based polyfarnesene diol (PFD), which contains unique “bottle brushes” structure (with long branched hydrocarbon side chains). The effect of hard segment (HS) content, ranging from 30 to 50%, on the morphology and properties of PUEs is investigated by Fourier transform infrared spectroscopy, thermogravimetric analysis, differential scanning calorimetry, X-ray diffraction, scanning electron microscopy, tensile, water absorption, and contact angle measurements. The results show that there are prominent phase separations in the synthesized PUEs. The PUEs show a three-stage degradation process and two T_g, one is at about −66 °C and the other 61 °C, which are related to the soft segment and HS, respectively. Water contact angles of PUEs increase from 98.6 to 105.2° with the increasing of PFD structural unit fraction. After being immersed in deionized water for 30 days, PUEs show no significant degradation of both tensile strength and elongation at break, and mass changes of all samples are less than 0.5%. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47673.     

Protection through property: from private to river-held rights

ABSTRACT

This article explores how private owners can protect bodies of water through private property rights. It compares the use of conventional property rights in the Netherlands and New Zealand with a novel approach whereby a New Zealand river owns itself.     

Synthesis,Anticancer Activity,Structure-Activity Relationship and Mechanistic Investigations of Falcarindiol Analogues

Forty samples of optically active falcarindiol analogues are synthesized by using the easily available C2 symmetric (R)- and (S)-1,1’-binaphth-2-ol (BINOL) in combination with Ti(OⁱPr)₄, Zn powder and EtI. Their anticancer activities on Hccc-9810, HepG2, MDA-MB-231, Hela, MG-63 and H460 cells are assayed to elucidate their structure-activity relationships. These results showed that the falcarindiol analogue (3R,8S)- 2 i with the terminal double bond has the most potent anti-proliferation effect on Hccc-9810 cells with IC₅₀ value of 0.46 μM. The falcarindiol analogue (3R,8S)- 2 i can induce obvious Hccc-9810 cell apoptosis in a concentration-dependent manner by Hoechst staining and flow cytometry analysis. The proposed mechanism suggests that the falcarindiol analogue (3R,8S)- 2 i increases LDH release and MDA content, and reduces the levels of SOD activity, which lead to the accumulation of oxidative stress and induce apoptosis in Hccc-9810 cells.     

Fluidizing effects of polymers with various anchoring groups in cement pastes and their sensitivity to environmental temperatures

We synthesized various polymers with different functional groups of ─COO⁻, ─SO₃⁻, and ≡N⁺─ to study the impact of the environmental temperature (25, 50, and 80 °C) on the dispersing capability by measuring the fluidity of fresh cement paste, total organic carbon, ζ potential, and isothermal calorimetry. The results show that no adsorption was observed for the cement pastes containing acrylic acid, 2-acrylamido-2-methyl propane sulfonic acid, and [3-(methacryloylamino)propyl] trimethyl ammonium chloride, probably because of the trace amount of adsorption, whereas the fluidity of the pastes was indeed improved by the addition of these chemicals. Generally, for the polymers containing various functional groups, the adsorption capability was in the order ─COO⁻ > ─SO₃⁻ > ≡N⁺─. The dispersing capability for the carboxylate superplasticizer was robust to the change in the temperature, whereas it was dramatically weakened by the increase in temperature for sulfonate superplasticizer, although the adsorption amount increased along with the temperature rise. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47494.     

Structure−Activity Relationships of Cinnamate Ester Analogues as Potent Antiprotozoal Agents

Protozoal infections are still a global health problem, threatening the lives of millions of people around the world, mainly in impoverished tropical and sub-tropical regions. Thus, in view of the lack of efficient therapies and increasing resistances against existing drugs, this study describes the antiprotozoal potential of synthetic cinnamate ester analogues and their structure-activity relationships. In general, Leishmania donovani and Trypanosoma brucei were quite susceptible to the compounds in a structure-dependent manner. Detailed analysis revealed a key role of the substitution pattern on the aromatic ring and a marked effect of the side chain on the activity against these two parasites. The high antileishmanial potency and remarkable selectivity of the nitro-aromatic derivatives suggested them as promising candidates for further studies. On the other hand, the high in vitro potency of catechol-type compounds against T. brucei could not be extrapolated to an in vivo mouse model.