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Asymmetric Reduction of C=N Bonds by Imine Reductases and Reductive Aminases
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Matthias Höhne, Philipp Matzel, Martin Gand
Because of the high stability of cyclic imines, their biocatalytic reduction has been studied first, and reductive amination appeared to be by far more challenging, as it also requires a strict chemoselectivity of the enzymes to prevent ketone reduction to the alcohol. Early studies showed the inability of IREDs to catalyze reductive aminations (Gand et al., 2014) or yielded only small amounts of the desired amine products (Scheller et al., 2015). A first breakthrough was the discovery that a fraction of the studied IREDs can achieve reductive amination with good to excellent conversions if a high excess (10–50 fold) of the amine nucleophile is employed and the enzymes are used in high concentrations (1 mg/mL purified enzyme). On the contrary, IREDs of fungal origin have been identified that are able to catalyze imine formation in their active site. During condensation of a ketone and amine, several proton transfer steps have to occur (please see Section 14.5 for a mechanistic discussion). RedAms assist in this process by providing an additional catalytic residue acting as acid base catalyst. This allows RedAms to catalyze imine formation after the ketone and amine have been prealigned in their active site.
On Biocatalysis as Resourceful Methodology for Complex Syntheses: Selective Catalysis, Cascades and Biosynthesis
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Andreas Sebastian Klein, Thomas Classen, Jörg Pietruszka
The principle is illustrated on a cascade including three enzymes to produce tetrahydroisoquinolines (20) from inexpensive compounds (see Fig. 21.5). Besides their excellent stereoselectivity, the chemoselectivity of the enzymes is exploited. The enzymes can act within one medium because they are acting on their specific substrate. For instance, the transaminase catalyzes the reductive amination of ketone 16 but does not convert aldehyde 15 despite having the higher carbonyl activity, or the Pictet-Spenglerase uses benzyl aldehyde (19) but not meta-hydroxy benzaldehyde (15). Furthermore, the authors could show that the very last step—the Pictet-Spengler-reaction—could be carried-out using the phosphate buffer rather than the enzyme, which leads to the epimer of the newly formed stereogenic centre. This is a nice example illustrating that the combination of chemical steps and biocatalytical steps is a fruitful expansion of the synthetic methodology.
Radiochemistry for Preclinical Imaging Studies
Published in George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, Handbook of Small Animal Imaging, 2018
This protocol typically applies to radiolabeling peptides with fluorine-18. [18F]N-succinimidyl fluoro-4-benzoate ([18F]SFB) is a well-known prosthetic group with an activated ester function to primarily target lysine side chains (Vaidyanathan and Zalutsky 1992). The selectivity of the prelabeled reagent has been much improved with the use of [18F]fluoro-4-benzaldehyde ([18F]FBA) (Poethko et al. 2004). However, this approach required the coupling of an aminooxy reactive group to the vector molecule. In consequence, this labeling method allows for high chemoselectivity through the orthogonal reactant pair of an aldehyde and an aminooxy group. Although the aromatic ring introduces some lipophilicity into the vector, the aromatic fluorine-18 C-F bond is sufficiently stable as demonstrated in numerous preclinical studies. Figure 16.17 exemplifies the radiochemistry for the preparation of [18F]fluciclatide, an RGD (arginylglycylaspartic acid) receptor–binding oncology marker that has already reached clinical trials (Pettitt et al. 2010). The labeling reagent [18F]FBA can be obtained from the trifluoromethanesulfonate (triflate) precursor 5 after purification by a solid phase extraction cartridge (SPE). Following the coupling step with the aminooxy peptide precursor, [18F]fluciclatide is purified by another SPE step. The full radiochemical preparation has been implemented on the FASTlab module and provides the tracer with a non-decay-corrected radiochemical yield of 20% (Pettitt et al. 2010).
How do we address neglected sulfur pharmacophores in drug discovery?
Published in Expert Opinion on Drug Discovery, 2021
Michael J. Tilby, Michael C. Willis
Chemical probes have become a vital tool for studying biological systems. Amongst probes that feature an electrophilic functional group, sulfonyl fluorides (I) and fluorosulfates (K) have emerged as common electrophilic warheads [22]. The application of these sulfur-fluorine based molecules has provided a wealth of information on the chemoselectivity of their interactions with protein residues. One key feature of these functional groups, and also of the related sulfamoyl fluorides (L), is their relative stability toward hydrolysis [23]. This has led to recent investigations into exploiting these molecules as covalent inhibitors in drug discovery programmes. An additional attractive feature of these groups is that they can be installed into known pharmaceuticals with relative ease. Molecule 11 is a good example of this [24]. In this case, the fluorosulfate displayed increased potency compared to the known phenol derivative, which is itself an anti-cancer drug candidate.
An overview of late-stage functionalization in today’s drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Michael Moir, Jonathan J. Danon, Tristan A. Reekie, Michael Kassiou
The practicality (tolerant to air and moisture), high reactivity, and chemoselectivity of radical reactions allow for rapid access to biologically relevant molecules. Radicals are generally inert to a range of reactive functionalities present in most drug-like compounds such as alcohols and amines. This has motivated their application to the LSF of complex molecules.
Effect of gal/GalNAc regioisomerism in galactosylated liposomes on asialoglycoprotein receptor-mediated hepatocyte-selective targeting in vivo
Published in Journal of Liposome Research, 2021
Hua Nie, Bo Qiu, Qi-Xuan Yang, Ying Zhao, Xiao-Min Liu, Ying-Ting Zhang, Fu-Lin Liao, Sheng-Yuan Zhang
The majority of galactosylated CHS in previous studies was synthesized with the glycosidic linkage at the 1-Gal or 1-GalNAc site (Hattori et al.2000; Khorev et al.2008; Dube et al.2010). Few studies were performed utilizing the glycosidic linkage at the 6-Gal (Sun et al.2014) or 6-GalNAc loci. Frequently in these studies, the Gal and CHS groups were coupled via chemical reactions to produce the glycolipid ( Managit et al. 2005a; Wang et al.2006; Yu et al.2007). However, these chemical methods require complicated and controlled multi-step reactions, making it is difficult to transform them into industrial-scale glycolipid products. Compared with the chemical synthesis method, lipase catalysis has advantages in the esterification of sugar, such as high efficiency, high regioselectivity, and low toxicity. Recently, we reported a novel galactosylated CHS (5-cholesten-3b-yl) [(4-O-b-d-galactopyranosyl) d-glucitol-6] sebacate (CHS-1-Gal) that was synthesized by lipase-catalysis with a high yield of 90% (Nie et al. 2015a, 2015b). We showed it had excellent characteristics for liver-targeting in vivo (Luo et al.2016). In our current work, we employed this same strategy to synthesize two kinds of galactosyl-CHS: CHS-6-Gal and CHS-6-GalNAc, via a two-step lipase-catalyzed, transesterification in non-aqueous phase. As there are several hydroxyl groups in monosaccharide sugar, chemoselective esterification is necessary before complexation with the lipid. After the resultant compound was purified, chemoselectivity was confirmed by 13C NMR, in which the chemical shifts of esterified carbon have been reported to show a downfield shift, while neighbouring carbons show an upfield shift (Chopineau et al.1988; Miura et al.2003). Thus, the 13C signals for C-6′ of Gal in CHS-6-Gal, C-6′ of GalNAc in CHS-6-GalNAc, and C-6′ of lactitol in CHS-1-Gal shifted to a lower magnetic field from 63.34, 63.26, and 64.87 ppm down to 65.65, 65.68, and 67.08 ppm, respectively (Figure 1). 13C signals for C-5′, on the other hand, shifted to higher magnetic field from 72.59, 72.48, and 73.46 ppm up to 69.63, 69.56, and 72.05 ppm, respectively. These spectra indicate that the chemoselective esterification by selective lipases only proceeds at the C-6′of these sugars. In addition, we used Heteronuclear Multiple Bond Correlation (HMBC) as an experimental method for rapid assignment of proton chemical shifts in the Gal, GalNAc and Lac substrates before and after enzymatic synthesis (Figure 1) The HMBC correlations between H-6′a, H-6′b and C-37 further confirmed that the esterification of Gal, GalNAc, and Lac only occurs at C-6′ position. Di-substituted compounds were not obtained using lipase catalyzed esterfications.