In-Hospital Preparation Of Radiotracers Garimella
Garimella V. S. Rayudu, Lelio G. Colombetti in Radiotracers for Medical Applications, 2019
D. 131I, 125I, 123I-Labeling (for details refer to text of Chapter 1, Volume II)Chloramine-TICIElectrolyticHypochloritePeroxidase + H2O2 (mild method)TriiodideIsotopie exchangeDiazotization and iodinationBolton and Hunter Reagent N-Succinimidyl 3-[4-Hydroxy 5-(125I) Iodophenyl] propionateOthers: (a) hydroboration + iodination, (b) electrophilic radioiodo destannyla-tion, and (c) microdiffusion of fresh I2 vapor, (d) iodobeads and iodogen
Methods of Protein Iodination
Erwin Regoeczi in Iodine-Labeled Plasma Proteins, 2019
The labile I held by a thiol protein as sulfenyl periodide (R-SI3) is a potential tyrosine substituent.210 Hydroboration can be used to attach B to the least substituted C of organic compounds, and I can then be substituted for B by mild oxidation.211 Both approaches may have a future with proteins after further developmental work.
Chemoenzymatic Approaches towards (S)-Duloxetine
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Samik Nanda et al. reported an efficient but general synthetic strategy for the enantiopure chemoenzymatic synthesis of duloxetine 2 (Schwartz et al., 2000). The chemical construction commenced with the commercially available benzaldehyde (Scheme 5.17). An asymmetric hydrocyanation reaction with Prunus armeniaca hydroxynitrile lyase (ParsHNL) and hydrogen cyanide in diisopropyl ether (DIPE) solvent furnished the respective 2-thiophene-carboxaldehyde 41 in 90% yield (ee = 97%). With the enantiopure cyanohydrins in hand, 41 is protected as its TBS (tert-butyldimethyl silyl) ether through reaction with imidazole and tert-Butyldimethylsilyl chloride at 25°C to give the protected cyanohydrin 42 in 92% yield. Compound 42 is not purified further, and so the crude mixture of 42 is subjected to DIBAL-H treatment at −78°C for 2 h, which yielded the corresponding aldehyde 43 in almost quantitative yield. The aldehyde after usual workup (no chromatographic separation is needed) is subjected to one carbon Wittig olefination with Ph3P=CH2 to afford olefin 44 in 75% yield. Compound 44 upon hydroboration with BH3. SMe2 afforded the corresponding alcohol 45 in 84% yield (no chromatographic separation is needed). Alcohol 45 is then treated with methanesulfonyl chloride (Ms-Cl) and Et3N to furnish the respective mesylate 46 in 88% yield (no chromatographic separation is needed) (Scheme 5.17). Mesylate 46 upon treatment with an aq. solution of 40% MeNH2 in refluxing THF afforded the corresponding amine 47 in 72% yield. Cleavage of silyl ether in compound 47 is accomplished by reaction with TBAF/THF to deliver aminoalcohol 12 in 90% yield (no chromatographic separation is needed). At the end, the Mitsunobu reaction of compound 12 with 1-naphthol afforded the (R)-duloxetine in 21% overall yield from 41. It is also noteworthy that out of the nine synthetic steps employed, they used chromatographic purification methods in only three steps. The synthesis is cost effective and green also, as chromatographic separation in some steps is avoided. By applying the same chemoenzymatic hydrocyanation protocol, the asymmetric fabrication of other familiar anti-depressant drugs, fluoxetine, nisoxetine, atomoxetine can be accomplished (Rej et al., 2013). Synthesis through enzyme catalyzed enantioselective hydrocyanation reaction.
Selected strategies to fight pathogenic bacteria
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Aiva Plotniece, Arkadij Sobolev, Claudiu T. Supuran, Fabrizio Carta, Fredrik Björkling, Henrik Franzyk, Jari Yli-Kauhaluoma, Koen Augustyns, Paul Cos, Linda De Vooght, Matthias Govaerts, Juliana Aizawa, Päivi Tammela, Raivis Žalubovskis
Vaborbactam (Scheme 2) is an example of a synthetic β-lactamase inhibitor that is used in combination with meropenem, an intravenous β-lactam antibiotic susceptible to degradation by metallo-β-lactamases. The FDA-approved meropenem-vaborbactam combination complements other β-lactamase inhibitors, such as clavulanic acid, a secondary metabolite of Streptomyces clavuligerus. The Klebsiella pneumoniae β-lactamase is only weakly inhibited by clavulanic acid, which therefore has no clinically relevant use against infections caused by K. pneumoniae7. Vaporbactam is a potent inhibitor of K. pneumonia carbapenemase with no observable concomitant off-target inhibition of mammalian serine proteases. However, vaborbactam does not inhibit class B metallo-β-lactamases, thus, further search for compounds with even wider β-lactamase spectrum is warranted. The key steps in the vaborbactam synthesis involve iridium (I)-catalyzed regioselective hydroboration of an allyl precursor, stereoselective chloromethylation of pinanediol boronate, and a stereospecific substitution of the chloro substituent with lithium hexamethylsilazide8.
Multicomponent reactions (MCR) in medicinal chemistry: a patent review (2010-2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Hafiza Amna Younus, Mariya Al-Rashida, Abdul Hameed, Maliha Uroos, Uzma Salar, Sobia Rana, Khalid Mohammed Khan
In the first step vinylation of a ketone using an appropriate vinyl metal nucleophile leads to a racemic piperidone. This is followed by 1,4-conjugated vinyl addition using metal salts of vinyl trifluoroborates, vinyl alkoxysilanes, or vinyl boronic acid/ester. A racemic amino acid derivative is prepared from the piperidone using multicomponent reactions such as the Ugi reaction, the Bucherer-Bergs reaction, or the Strecker reaction. With the help of column chromatography using a chiral stationary phase, the racemic amino acid derivatives can be resolved into enantiomerically pure isomers. The piperidine derivative is obtained by deprotection which is then benzylated. Hydroboration is done using pinacol borane or bis(pinacolato) diboron in the presence of a suitable catalyst. Hydrolysis of the amide to the amino acid derivative is done, followed by protection to form Boc-amino acid, subsequent deprotection, and amidation leads to the preparation of the final compound as shown in Scheme 10.
Tablet formulation of Famotidine-loaded P-gp inhibiting nanoparticles using PLA-g-PEG grafted polymer
Published in Pharmaceutical Development and Technology, 2019
Mohamed Mokhtar, Patrick M. Gosselin, Lacasse François-Xavier, Patrice Hildgen
Poly(ethylene glycol) (PEG) grafted randomly on poly(D,L)-lactide was synthesized in the laboratory. Detailed procedure is described in previous work (Nadeau et al. 2005; Shilpa et al. 2005; Essa et al. 2010). PEG grafting of two molecular weights (750 and 2000 Da) was performed at 5% density ratio (mol/mol of lactic acid). In brief, a polyester-co-ether copolymer of D,L-lactide (21.5 g, 99 mmol or 95 mmol) and allyl glycidyl ether (AGE) (0.343 g, 2 mmol or 10 mmol) were first synthesized by ring-opening polymerization using tetraphenyl tin as catalyst (1:10 000 molar ratios with regard to lactide) under argon. The reaction was maintained at 180 °C for 6 h. The synthesized polymers with allyl group were oxidized to hydroxyl group by hydroboration then to carboxylic acid groups by Jones reagent. Finally, methoxy poly(ethylene glycol) (MePEG) was grafted onto the polymers. 1H NMR spectra were recorded using a Bruker ARX 400 spectrometer (Bruker, Germany). 10–20 mg samples of each polymer were dissolved in CDCl3 and chemical shift (d) was measured in ppm using tetramethylsilane (TMS) as an internal reference. The number (Mn) and the weight average molecular weights (Mw) of synthesized polymers were determined by gel permeation chromatography (GPC) using a Waters Associate chromatography system model 717 (Waters, Milford, MA) equipped with a refractive index detector model 410 and a Phenogel 5 µm column (Phenomenex, Torrance, CA). Polystyrene standards were used for calibration with chloroform as a mobile phase at a flow rate of 0.6 mL/min. Fourier transform infrared (FTIR) spectroscopy was used to characterize the functional groups of PLA, PEG, and grafted PEG-g-PLA polymers. The spectra of polymers were recorded using a Nicolet iS10spectrometer (Madison, WI). All spectra were recorded at ambient temperature at a resolution of 2 cm−1 and 64 times scanning for each measurement to obtain an adequate signal-to-noise ratio. The FTIR spectra were recorded in transmission mode with dry powder of polymers, which were spread on a sample holder stage and scanned from 4000 cm−1 to 400 cm−1.
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