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Host-Parasite Interactions With Macrophages In Culture
Published in Hans H. Gadebusch, Phagocytes and Cellular Immunity, 2020
Lee S. F. Soderberg, Morris Solotorovsky
Coenzymes, such as nicotinamide adenine dinucleotide (NAD) and adenosine triphosphate (ATP), regulate carbohydrate metabolism and oxidative phosphorylation among other activities. Because of this correlation with energy-generating pathways, coenzymes have been measured in normal and activated macrophages. The presence of NAD, measured by fluorescence with ethyl methyl ketone, revealed no difference in concentrations of this coenzyme in macrophages from tuberculous guinea pigs and normal macrophages.114 However, NADase activity increased sevenfold in immune macrophages. Cellular ATPase activity, indicated by the release of inorganic phosphate, was similar in macrophages from mice immunized with Corynebacterium ovis or normal macrophages, but assays of ATP revealed a 5.2-fold increase in ATP content in immune cells as compared with normal cells.115 Likewise, macrophages activated by intraperitoneal Listeria infections showed ATPase levels similar to uninduced macrophages.46 Macrophages induced with thioglycollate, however, showed considerably reduced ATPase levels. Uninduced macrophages were found to have high AMPase levels than Listeria-activated cells and essentially no AMPase was found in thioglycollate-induced cells.
Synthesis of Important Chiral Building Blocks for Pharmaceuticals Using Lactobacillus and Rhodococcus Alcohol Dehydrogenases
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Marion Rauter, Simon Krebs, Gotthard Kunze
Pękala and coworkers studied the reduction of xanthine derivatives with a methyl ketone moiety by isolated L. kefir ADH as well as by biotransformation using L. kefir whole cells (Pękala et al., 2007; Pękala and Zelaszczyk, 2009). The water soluble substrates pentoxifylline and propentofylline (2.5 mM) were successfully converted to the corresponding secondary (R)-alcohols using the free enzyme with an ee >99% and yields of 96 and 98% with 8% isopropanol for cofactor regeneration. Whole cell L. kefir biotransformation of the substrates gave similar yields with lower costs due to enzyme purification and addition of cofactor not being required, but ee decreased to 98% and 96%. Thus, highly enantiopure substances for pharmacokinetic and pharmacodynamic studies should be produced using free enzymes.
Drug Targeting to the Lung: Chemical and Biochemical Considerations
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Peter A. Crooks, Narsimha R. Penthala, Abeer M. Al-Ghananeem
In a structure-activity correlation study, a number of N-substituted derivatives of rolipram (52) were prepared and evaluated (Tanaka et al. 1995). A carbamate ester of rolipram was found to be approximately 10-fold more potent than rolipram itself at inhibiting human PDE IV. A methyl ketone derivative of rolipram showed more potent inhibition of PDE IV compared to rolipram or its carbamate ester. Based on proton NMR spectroscopy and computer modeling studies, a pharmacophore model of the methyl ketone derivative was proposed (Stafford et al. 1995). This model showed that the ketone carbonyl oxygen atom is involved in an important interaction within the PDE IV active site. Sodium orthovanadate, a phosphotyrosine phosphate inhibitor, exhibits dose- and time-dependent suppression of Lewis lung carcinoma A11 cell spreading. Protein tyrosine phosphorylation levels in A11 cells were elevated after treatment with ortho vanadate; this increase was partially diminished by the tyrosine kinase inhibitor ST 638, concomitantly with restoration of the suppressed cell spreading, as well as invasive and metastatic ability (Takenaga 1996). These results suggest tyrosine phosphorylation influences adhesion of cancer cells to lung surface endothelia, and that a valid approach in treating cancer is inhibition of phosphotyrosine phosphatase.
Clinical toxicology of exposures to chemicals from clandestine drug laboratories: a literature review
Published in Clinical Toxicology, 2022
Arjen Koppen, Anja P. G. Wijnands-Kleukers, Femke M. J. Gresnigt, Dylan W. de Lange
Drug synthesis potentially involves exposure to hazardous chemicals which could result in serious health effects. Hazardous chemicals used in bulk in clandestine drug laboratories include toxic alcohols, organic solvents, acidic and alkaline solutions [2–4]. For instance, methanol is used as a solvent during the synthesis of MDMA (3,4-methylenedioxymetamfetamine), including the Wacker oxidation from safrole to piperonyl methyl ketone [37]. During these processes, methanol evaporates, and without adequate ventilation, harmful airborne concentrations may be reached. Organic solvents, including heptane and toluene, are used for extraction of intermediate or end products [2,5]. Anhydrous ammonia is another hazardous chemical commonly used in the synthesis of illicit drugs. This chemical is used, together with an alkali metal (usually lithium or sodium), to reduce ephedrine or pseudoephedrine to form metamfetamine in the so-called Birch reduction [6].
Comprehensive overview of the recently FDA-approved contraceptive vaginal ring releasing segesterone acetate and ethinylestradiol: A new year-long, patient controlled, reversible birth control method
Published in Expert Review of Clinical Pharmacology, 2019
By contrast, the binding affinity of SA to the androgen receptor (AR) is 500-600-fold less than testosterone [12]. SA does not stimulate growth of ventral prostate (androgenic target) or the levator ani (anabolic target) in castrate immature rats. In fact, SA has shown some antiandrogenic activity. Similarly, SA has potent progestational and antiestrogenic action on the uterus, utilizing a 17 β-methyl ketone function [14]. SA has significant binding to glucocorticoid receptors (GR) in vitro, but in vivo, SA has no glucocorticoid activity. It has minimal binding to SHBG [12]. By contrast, all progestins in the first three generations of oral contraceptives (norethindrone, 3-keto-desogestrel, and levonorgestrel) have a 17β-hydroxyl group, have estrogenic, androgenic, and anabolic activity and also bind to SHBG.
Spectrum of candidate molecules against Chikungunya virus - an insight into the antiviral screening platforms
Published in Expert Review of Anti-infective Therapy, 2019
Shree Madhu Bhat, Piya Paul Mudgal, Sudheesh n, Govindakarnavar Arunkumar
Structure-activity relationship studies of a series of inhibitors that selectively blocked CHIKV replication revealed that the [1,2,3] triazolo [4, 5-d] pyrimidin-7(6H)-one structure and the meta-substituted aryl ring linked at position 3 of the triazole (Figure 4a) were critical for anti-CHIKV activity [74]. Substitution with an ethyl group at position 5 of triazolo pyrimidine (Figure 4b) was found to improve anti-CHIKV activity significantly in terms of both steric [74] and electronic properties (Figure 4b). The synthesis and evaluation of novel analogues in this series indicated that among the newly synthesized oximes, functionalization of the methyl ketone at position 3 of the aryl ring through oxime derivatization (Figure 4c) (EC50: 3.6 µM) and incorporation of distal amines improved the antiviral activity against CHIKV (Figure 4d) (EC50: 5–7 µM) [74]. Virtual screening of a large compound databases led to the identification of a few CHIKV nsP2 inhibitors, which upon in vitro validation revealed the importance of the central cyclopropyl ring (EC50: 5 µM) (Figure 5 a (i) for the anti-CHIKV activity. Replacement with a trans-ethenylic group (Figure 5 a (ii) however, slightly improved the antiviral activity (EC50: 3.2 µM) [75].