Small Molecule CD38 Inhibitors: Synthesis of 8-Amino-N1-inosine 5′-monophosphate, Analogues and Early Structure-Activity Relationship

Although a monoclonal antibody targeting the multifunctional ectoenzyme CD38 is an FDA-approved drug, few small molecule inhibitors exist for this enzyme that catalyzes inter alia the formation and metabolism of the N1-ribosylated, Ca2+-mobilizing, second messenger cyclic adenosine 5′-diphosphoribose (cADPR). N1-Inosine 5′-monophosphate (N1-IMP) is a fragment directly related to cADPR. 8-Substituted-N1-IMP derivatives, prepared by degradation of cyclic parent compounds, inhibit CD38-mediated cADPR hydrolysis more efficiently than related cyclic analogues, making them attractive for inhibitor development. We report a total synthesis of the N1-IMP scaffold from adenine and a small initial compound series that facilitated early delineation of structure-activity parameters, with analogues evaluated for inhibition of CD38-mediated hydrolysis of cADPR. The 5′-phosphate group proved essential for useful activity, but substitution of this group by a sulfonamide bioisostere was not fruitful. 8-NH2-N1-IMP is the most potent inhibitor (IC50 = 7.6 μM) and importantly HPLC studies showed this ligand to be cleaved at high CD38 concentrations, confirming its access to the CD38 catalytic machinery and demonstrating the potential of our fragment approach.

Electrosynthesis and characterization of lead dioxide–perfluorobutanesulfonate composite

The effect of potassium perfluorobutanesulfonate on the kinetic features of electrodeposition of lead dioxide from methanesulfonate electrolytes has been investigated. The introduction of C4F9SO3K into the lead dioxide deposition electrolyte leads to insignificant inhibition of the Pb2+ electrooxidation process, while the mechanism of the process does not change. A composite coating is formed upon deposition of coatings from electrolytes containing surfactants. The surface of a composite material consists of a mixture of clearly expressed large crystalline blocks with sharp angles and small crystals. Energy dispersive X-ray analysis revealed the satisfactory distribution of modifying elements in the entire sample bulk, and not only on the coating surface. It was shown that the electrocatalytic activity of lead dioxide–perfluorobuthanesulfonate composite differs from the undoped sample. The oxygen evolution reaction slightly decelerates on a PbO2–C4F9SO3K composite. The Tafel slopes in 1 M HClO4 calculated from these curves plotted in semilogarithmic coordinates are 136 and 145 mV dec–1 for undoped sample and lead dioxide-surfactant composite, respectively. The reaction of electrochemical oxidation of p-chlorophenol is characterized by the pseudo-first order kinetics with respect to the initial compound. The use of doped C4F9SO3K lead dioxide as an anode leads to the inhibition of the process of oxygen evolution and an almost one and a half higher rate of electrochemical conversion of 4-chlorophenol to aliphatic compounds.

Influence of the type of salt-forming acids on the antiradiation activity of T1023 analogs – salts of N-isobutanoyl-S-isopropylisothiourea

According to leading experts, the vast arsenal of radioprotective agents available in the world today does not fully meet modern practical needs, both in the field of radiation protection, and in the prevention and treatment of complications of radiotherapy. The purpose of the study was to evaluate the effect of the salt-forming acids type on the radioprotective activity of NOS inhibitor T1023. The chemical part of this study included methods of chemical synthesis, physicochemical and elemental analysis. Pharmacological part – assessment of acute toxicity using V.B. Prozorovsky express method and the study of radioprotective activity using Till and McCulloch method based on the ability of mice hematopoietic cells to form spleen colonies after irradiation. The number of endogenous hematopoietic spleen colonies were assessed on the 8th day after total exposure to gamma-irradiation at a dose of 6 Gy in six independent experiments. As a result of directed chemical synthesis, six new derivatives of T1023 – salts of N-isobutanoyl-S-isopropylisothiourea have been developed, identified and characterized. The results of studying the safety and radioprotective activity of the synthesized compounds showed that changes in the salt-forming acid don’t significantly influence the toxicity: all studied compounds are in the 3rd class of toxicity and hazard. At the same time, it was found that the replacement of the salt-forming acid significantly influenced the severity of the radioprotective effect. For some of these compounds radioprotective efficacy is comparable to or exceeds the efficacy of the initial compound T1023. It is important to note that these new compounds were used in lower, more save doses than T1023. The results suggest promising further development of NOS inhibitors – isothiourea derivatives as radioprotective agents.

Micropatterned Coculture With 3T3-J2 Fibroblasts Enhances Hepatic Functions and Drug Screening Utility of HepaRG Cells

Human liver models are useful for assessing compound metabolism/toxicity; however, primary human hepatocyte (PHH) lots are limited and highly variable in quality/viability. In contrast, cell lines, such as HepaRG, are cheaper and more reproducible surrogates for initial compound screening; however, hepatic functions and sensitivity for drug outcomes need improvement. Here, we show that HepaRGs cocultured with murine embryonic 3T3-J2 fibroblasts, previously shown to induce PHH functions, could address such limitations. We either micropatterned HepaRGs or seeded them “randomly” onto collagen-coated plates before 3T3-J2 coculture. Micropatterned cocultures (HepaRG-MPCCs) secreted 2- to 4-fold more albumin and displayed more stable cytochrome P450 activities than HepaRG conventional confluent monocultures (HepaRG-CCs) and HepaRG micropatterned hepatocytes (HepaRG-MPHs) for 4 weeks, even when excluding dimethyl sulfoxide from the medium. Furthermore, HepaRG-MPCCs had the most albumin-only positive cells (hepatic), lowest cytokeratin 19 (CK19)-only positive cells (cholangiocytic), and highest mean albumin intensity per cell than HepaRG random cocultures and monocultures; however, 80%–84% of HepaRGs remained bipotential (albumin+/CK19+) across all models. The 3T3-J2s also induced higher albumin in HepaRG spheroids than HepaRG-only spheroids. Additionally, although rifampin induced CYP3A4 in HepaRG-MPCCs and HepaRG-CCs, only HepaRG-MPCCs showed the dual omeprazole-mediated CYP1A2/3A4 induction as with PHHs. Lastly, when treated for 6 days with 47 drugs and evaluated for albumin and ATP to make binary hepatotoxicity calls, HepaRG-MPCCs displayed a sensitivity of 54% and specificity of 100% (70%/100% in PHH-MPCCs), whereas HepaRG-CCs misclassified several hepatotoxins. Ultimately, HepaRG-MPCCs could be a more cost-effective and reproducible model than PHHs for executing a tier 1 compound screen.

The Impact of Variable Selection Coverage on Detection of Ligands from a DNA-Encoded Library Screen

DNA-encoded library (DEL) technology has become a prominent screening platform in drug discovery owing to the capacity to screen billions or trillions of compounds in a single experiment. Although numerous successes with DEL technology have been reported, we are unaware of a rigorous examination of the many different variables that can influence a screen’s success. Herein, we explore the impact of variable sample sequencing depth on the detection of tool compounds with known affinities toward a given target while simultaneously probing the effect of initial compound input. Our sequencing data confirm reports that high-affinity compounds can be discovered directly from a DEL screen, but we demonstrate that a mismatch between selection output and sequencing quantity can obscure useful ligands. Our results highlight the importance of selection coverage in grasping the entire picture of a DEL screen where the signal of a weak or underrepresented ligand may be suppressed by the inherent noise of a selection. These potential missed ligands may be critical to the success or failure of a drug discovery program.

Synthesis and biological evaluation of 3-O-substituted 1-benzyl-6-oxo-1,6-dihydropyridazine derivatives

On the basis of 2-benzyl-6-hydroxypyridazin-3(2 H)-one, a series of its novel O-substituted (including 6-(1,3,5-triazin-2-yl)oxy) derivatives is prepared. It is proven that the substitution reactions in the initial compound occur mainly at the oxygen atom of the hydroxy group. On the basis of the obtained oxy-aceto(propane)hydrazides, the corresponding azides and anilides are synthesized. A series of 2-[(1-benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]- N′-(substituted benzylidene)aceto(propane)hydrazides is obtained via the reaction of various aromatic aldehydes with the same hydrazides. Heterocyclization of the latter affords compounds with a combination of pyridazine and 1,3,4-oxadiazole rings in the molecule. The reaction of oxy-acetohydrazide with potassium thiocyanate and a mixture of CS2/KOH leads to potassium salts of 2-{[(1-benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]methyl}hydrazine-1-carbothioamide and 2-{2-[(1-benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]acetyl}hydrazine-1-carbodithioic acid, respectively. Acid hydrolysis of the latter affords 2-benzyl-6-[(5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)methoxy]pyridazin-3(2 H)-one.

Synthesis of Some Novel Chalcone Derivative Via Microwave Method & It’s Antimicrobial Activity

Growing public awareness about the state of the environment, chemical product safety and new chemical regulatory policies is driving demand for leaders who are able to understand the science underlying environmental challenges and develop innovative solutions. Chalcones belong to the flavonoid family and display several pharmacological activities which are very important. They can be used as an initial compound for synthesis of a lot of compounds. In this research chalcone derivative are made via green chemistry route and analysed their physical and antimicrobial activity.

Protonation and Photocatalytic Activity of the Rb2La2Ti3O10 Layered Oxide in the Reaction of Hydrogen Production

The Rb2La2Ti3O10 layered oxide was synthesized by the solid-state method. Three phases with different protonation degrees and intercalated water contents were obtained from the initial compound by the treatment with distilled water and hydrochloric acid. The obtained samples were characterized by powder X-ray diffraction, SEM, X-ray microanalysis, BET, DRS, and TG. It was found that the complete ion exchange of Rb+ for H+ in the layered oxide Rb2La2Ti3O10 proceeds through the formation of two metastable intermediate phases with average protonation degrees of 0.5 and 0.75, which successively transform from one to another. Each of these phase transformations is accompanied not only by the contraction of the interlayer distance but also by the displacement of adjacent perovskite layers by 1/2 of the cell parameter which results in the change in the space group. The photocatalytic activity of obtained samples decreases with the increase in the protonation degree, which correlates with the decrease in the intercalated water content.

On the Allylic Oxidation of Ent-kaurenic Acid Methyl Ester with Lead Tetra-acetate

In this paper, results obtained upon treatment of the methyl ester of ent-kaur-16-en-19-oic acid (1b) with lead tetra-acetate under reflux in glacial acetic acid solution and an argon atmosphere are described. After 30 minutes reflux, GC-MS analysis of the product indicated the presence of three substances, the initial compound (1b, 7 %), the methyl ester of ent-kaur-16-en-15- O-acetyl-19-oic acid (2a, C23H30O4, 45 %), and its isomer, the methyl ester of ent-kaur-15-en-17- O-acetyl-19-oic acid (3a, 47 %). Flash chromatography over silica gel containing 20% AgNO3 yielded 2b (456 mg), which was identified by direct comparison with an authentic sample, and 3a (472 mg), whose structure was established by uni- and bi-dimensional NMR analysis. Hydrolysis of 3a with dry ammonia in MeOH yielded the methyl ester of ent-kaur-15-en-17-hydroxy-19-oic acid (3b, C21H32O3); treatment of this compound with chromic acid/pyridine complex rendered the aldehyde (4).