E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity

A strategy for creating potent and pan-genotypic stimulator of interferon genes (STING) agonists is described. Locking a bioactive U-shaped conformation of cyclic dinucleotides by introducing a transannular macrocyclic bridge between the nucleic acid bases leads to a topologically novel macrocycle-bridged STING agonist (MBSA). In addition to substantially enhanced potency, the newly designed MBSAs, exemplified by clinical candidate E7766 , exhibit broad pan-genotypic activity in all major human STING variants. E7766 is shown to have potent antitumor activity with long lasting immune memory response in a mouse liver metastatic tumor model. Two complementary stereoselective synthetic routes to E7766 are also described.     

In Vivo Albumin-Binding of a C-Functionalized Cyclam Platform for 64Cu-PET/CT Imaging in Breast Cancer Model

An improved glucose-chelator-albumin bioconjugate (GluCAB) derivative, GluCAB-2^Mal, has been synthesized and studied for in vivo ⁶⁴Cu-PET/CT imaging in breast cancer mice models together with its first-generation analogue GluCAB-1^Mal. The radioligand works on the principle of tumor targeting through the enhanced permeability and retention (EPR) effect with a supportive role played by glucose metabolism. [⁶⁴Cu]Cu-GluCAB-2^Mal (99 % RCP) exhibited high serum stability with immediate binding to serum proteins. In vivo experiments for comparison between tumor targeting of [⁶⁴Cu]Cu-GluCAB-2^Mal and previous-generation [⁶⁴Cu]Cu-GluCAB-1^Mal encompassed microPET/CT imaging and biodistribution analysis in an allograft E0771 breast cancer mouse model. Tumor uptake of [⁶⁴Cu]Cu-GluCAB-2^Mal was clearly evident with twice as much accumulation as compared to its predecessor and a tumor/muscle ratio of up to 5 after 24 h. Further comparison indicated a decrease in liver accumulation for [⁶⁴Cu]Cu-Glu-CAB-2^Mal.     

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.     

A Novel Approach for Bolted T-Stub Connections

This paper reports an investigation into new connection types and their behaviors determined using full-scale experiments. T-shaped connections were created using the IPE standard profile. The aim of this study was to analyze the influence of T connections based on the IPE standard profile, height of beam to height of T-stub joint (H) of T-stub joints, and lengths (X) of T-stub joints on the behavior of steel connections, in order to provide the necessary data for improving Eurocode 3 and enable efficient use of residue IPE standard profiles and back to the consumption cycle. While the moment resistance values increased with an increase in H from H_min to H_max in model groups with X of 126 mm, and the energy dissipation increased with an increase in H from H_min to H_max and also with an increase in the lengths (X) of T-stub joints from 54 to 126 mm.     

Physicochemical Properties of Zwitterionic Drugs in Therapy

In solution, amphoteric compounds exist in anionic, uncharged, zwitterionic and cationic forms. The importance of zwitterionic drugs is currently under-represented in the literature. Herein, the acid-base parameters, lipophilicity and solubility of such compounds are discussed to deepen the molecular-level understanding of their pharmacokinetic and pharmacodynamic behaviour. Our recent studies show there are many drug molecules, including thyroid hormones and 5-hydroxytryptophan, the precursor of the neurotransmitter serotonin, for which the contribution of the zwitterionic microspecies to the overall lipophilicity exceeds that of the uncharged one, which is of higher individual lipophilicity, but occurs in much lower concentration. The second part of the minireview highlights the most important zwitterionic compounds in therapy, grouped into therapeutic classes. The importance of the charge of the molecules is emphasized in their binding to the target molecules.     

A model of energy management analysis,case study of a sugar factory in Turkey

This study presents a case study of energy management in a sugar factory in Turkey. The main idea of the study is to analyse energy consumption, the quantity of material production, and figure out a suitable energy efficiency for the case study of a sugar factory subsequently. Firstly, a material production and energy consumption audit were performed for the sugar factory. Secondly, energy efficiency was calculated from the energy data. The SPSS (Statistical Package for the Social Sciences) statistical software was used to ensure the accuracy of the data. The factory’s energy consumption was calculated as 43,590.25 toe (tons of oil equivalent) over the last year. These results were used for CUSUM (Cumulative Sum Deviation Method) graphics. This research poses the consumption of energy, cost of energy and the relationship between energy usage and material production of sugar. The unit of energy cost was 688.22 [$/toe] for the last year. This result showed that the factory decreased the unit of energy by optimisation. The results indicated that the investigated sugar factory should pay attention to the energy management issue in order to comply with the Energy Efficiency of Turkish Law and Directives.