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Halogenases with Potential Applications for the Synthesis of Halogenated Pharmaceuticals
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Georgette Rebollar-Pérez, Cynthia Romero-Guido, Antonino Baez, Eduardo Torres
Due to the tight solvation of fluoride anions in water, and the consequently reduction on their nucleophilicity, fluorination reactions are less common. Much of the mechanistic and functional understanding of fluorinases came from the knowledge about fluorinase from Streptomyces cattleya. This enzyme catalyzes the fluorination of S-adenosyl methionine to produce 5-deoxy-5-fluoroadenosine in a SN2-type reaction (Fig. 16.1e). Crystallography studies shown that fluoride ion is placed in a SN2-like trajectory to the ribose 5-C,348, consistent with the observation that introduction of fluoride occurs with inversion of stereochemistry as reported (Dong et al., 2004; Zhu et al., 2007).
Production of High Specific Activity Compounds Labeled with Short-Lived Radionuclides
Published in William C. Eckelman, Lelio G. Colombetti, Receptor-Binding Radiotracers, 2019
M.J. Welch, K.D. McElvany, T.J. Tewson
HF, NOF, C1F, and BrF have been used successfully as fluorinating agents and have the virtue of containing only one atom of fluorine. However, in the vast majority of these fluorination reactions the more electropositive species acts as an acid to generate a cation, which then reacts with the fluoride ion to give the fluoro compound. Thus, with high specific activity reagents, the cation will be formed at very low concentrations and will have to encounter a 18F−, which will also be present at very low concentrations. If a tight ion pair is formed with no possibility of ion exchange, the reaction may be successful. On the other hand, if there is any possibility of the formation of a separated ion pair, an alternative reaction pathway that does not incorporate the fluoride anion will most likely predominate.
Halogen Labeled Compounds (F, Br, At, Cl) *
Published in Garimella V. S. Rayudu, Lelio G. Colombetti, Radiotracers for Medical Applications, 2019
The synthesis by direct fluorination with F2 in the electrophilic reactions is usually rapid. F2 is not extensively employed because of its high reactivity and low selectivity. However, diluted F2 can lead to a more controllable situation. 18F-5-Fluorouracil was prepared from uracil and 18F2 in glacial acetic acid.13, 101, 10218F-5-Fluorocytosine was similarily prepared.92 Reaction of 18F2 with 3,4,6-tri-O-acetyl-D-glucal followed by subsequent acid hydrolysis leads to the formation of 18F-2-deoxy-2-fluoro-D-glucose.49, 97 Theoretically only 50% of the fluorine activity can be incorporated into the product by direct fluorination methods.
Fluorinated vectors for gene delivery
Published in Expert Opinion on Drug Delivery, 2022
Yu Wan, Yuhan Yang, Mingyu Wu, Shun Feng
PAMAM dendrimers were synthesized from an initiation core of ethylenediamine with different generations (generations G = 0 ~ 7). It is one of the cationic polymers widely used as nonviral gene vectors. However, the issues with not sufficient transfection efficacy and severe cytotoxicity hampered its application. Therefore, various surface functionalization strategies have been developed to improve transfection efficacy and reduce cytotoxicity. Among them, fluorination is a promising and commonly used method. Cheng’s group has done numerous studies on fluorinated PAMAM used for gene delivery. They first demonstrated that the substitution of primary amino groups on PAMAM with fluorocarbon chain could enhance cellular uptake, endosomal escape, serum resistance of the PAMAM/DNA polyplexes, and achieve excellent transfection efficacy at extremely low N:P ratios [28] (Figure 4a). The fluorinated PAMAM combined the features of lipid and polymer gene vectors [67]. Subsequently, they found that fluorobenzoic acid-modified PAMAM also could improve transfection efficacy and reduce cytotoxicity [42] (Figure 4b). Then a detailed study of the structure-activity relationship of fluorinated PAMAM was performed, and the results proved that G5 PAMAM dendrimer is the best choice for fluorination modification [35] (Figure 4c).
Effect of Curcumin and Its Derivates on Gastric Cancer: Molecular Mechanisms
Published in Nutrition and Cancer, 2021
Afsane Bahrami, Gordon A. Ferns
One of the synthetic modifications used in drug design is fluorination. With respect to CUR analogues, this strategy has been used for the development of EF24. Zou et al have reported that the cytotoxic activity of EF24 was caused via the induction of oxidative stress of the endoplasmic reticulum via inactivation of TrxR1 in GC cells (IC50 = 5 μmol/L) compared to normal cells (IC50 > 10 μmol/L) (144). This effect was most likely mediated by Michael addition of EF24 ketoxy group to TrxR1 selenocysteine. Since TrxR1 was found to be highly expressed in several cancer types and it has a major role in regulating intracellular redox balance; its targeting is a promising approach for the inhibition of the malignant phenotype and sensitizing tumor cells to chemotherapeutic agents (145,146).
Fluorinated scaffolds for antimalarial drug discovery
Published in Expert Opinion on Drug Discovery, 2020
Charu Upadhyay, Monika Chaudhary, Ronaldo N. De Oliveira, Aniko Borbas, Prakasha Kempaiah, Poonam S, Brijesh Rathi
Fluorination within a molecule can be accomplished by fluorinated synthon approach that includes a fluorinated building block as a source of fluorine [92]. Generally, these building blocks are hazardous reagents such as HF, F2 and SF4, and therefore are not considered as a healthy approach for drug discovery. Given that, fluorine chemistry remains challenging, particularly for pharmaceutical industry. For instance, medicinal applications of fluorides have few demerits as its excessive use leads to toxicity and affects human health [93]. These shortcomings draw an attention to an assertion that fluorination is not always a positive concept. Nevertheless, fluorine substituents are widely used in the drug industry, and it is noteworthy that large number of the prescribed drugs in the U.S. pharmaceutical market contain fluorine. As per data recorded, approximately 40% of the new synthesized drugs tested entered in phase III trials (in the year 2012 and 2013) are fluorine-containing molecules. Based on these facts and a review of the literature, we strongly suggest that the overall activity of a given drug can be boosted by selective fluorination because it can increase the compound’s half-life, extent of absorption, metabolic stability, protein-ligand binding interaction and excretion properties. Therefore, fluorine chemistry could originate a path of effective drug discovery and eventually, succeeding decades could see the emergence of many novel fluorine scaffolds as promising medicine specifically against drug resistant malaria parasites.