China
Africa
Explore chapters and articles related to this topic
Biocatalysts: The Different Classes and Applications for Synthesis of APIs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
An often-cited example is the development of an aldolase-catalyzed process for enantioselective synthesis of statin intermediates by Greenberg et al. (2004) as shown in the opposite scheme. They used a deoxyribose-5-phosphate aldolase (DERA, EC: 4.1.2.4) that they discovered via creating and screening a large genomic library generated by extracting DNA from environmental samples. Compared with an E. coli DERA, the enzyme was superior in tolerating higher substrate concentrations and reduction of the catalyst load by 10-fold. The DERA-catalyzed reaction between acetaldehyde and chloroacetaldehyde was performed as a one-pot tandem aldol reaction and led to a 6-carbon intermediate lactol (not shown oppositely) with two stereogenic centers (enantiomeric excess >99.9%; diastereomeric excess 99.8% (after recrystallization)) that was oxidized to the lactone using an aqueous sodium hypochlorite/acetic acid solution. The conversion of the chloride of the lactone to the respective statin intermediates (a nitrile moiety for atorvastatin and a hydroxy group for rosuvastatin was achieved by additional chemical means, including ring-opened and protection/deprotection sequences.
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
Statins decrease the cholesterol level and were blockbuster par excellence in affluent societies. Especially the chiral side-chain of atorvastatin (11) has been synthesized by many groups using biocatalysis with great success (Patel, 2009; Müller, 2004). The chemical company DSM was able to implement a multi-ton scale production based on the 2-deoxy-ribose-5-phosphate aldolase (DERA), which naturally cleaves the name giving substrate into acetaldehyde and glyceraldehyde-3-phosphate (Haridas et al., 2018). Since enzymes accelerate a given reaction but do not influence the thermodynamic equilibrium, the DERA can also be used in the aldol rather than the retro-aldol reaction (see Fig. 21.3). The precursor of the side-chain 9 can be produced in one reaction sequence, where DERA performs two consecutive aldol reactions: the first between acetaldehyde (7) and chloroacetaldehyde (8), and the second between previously formed aldol (8) and second molecule of acetaldehyde (7). The formed lactol 10 can be transformed into the respective pharmacophore of atorvastatin (11). This process takes advantage of DERA’s chemo- and stereoselectivity.
Therapeutics of Artemisia annua
Published in Tariq Aftab, M. Naeem, M. Masroor, A. Khan, Artemisia annua, 2017
When artemisinin is treated with borohydride, to give dihydroartemisinin (DHA), a lactol is formed in which the integrity of the peroxide group is retained and the schizonticidal activity is enhanced two-fold. In the pharmacokinetics study, DHA showed 12.5 T1/2 (half-life), 7.40 Tmax time of Cmax and 593 Cmax (peak plasma concentration) in dose of 200 mg with artemether (Benakis et al., 1993). Maggs et al. (1997) reported that the principal biliary metabolite (21 ± 9.3% of DHA dose) was the biologically inactive DHA glucuronide. The other metabolites are the product of reductive cleavage and rearrangement of the endoperoxide bridge, a process known to generate reactive radical intermediates and abolish antimalarial activity. Dimer of DHA showed the cytotoxicity to committed progenitor cells of the granulocyte monocyte lineage (CFU-GM) cells (Beekman et al.,1998). It was determined in plasma through gas chromatography–mass spectrometry by Mohamad et al. (1999). It was chemically synthesized from artemisinin by Jain et al. (2001). It may be dissolved in groundnut oil with mild heating at 80°C–90°C and cooled to room temperature. DHA, the active metabolite of the compound is known to alter the ribosomal organization and the endoplasmic reticulum as well as causing the dilation of nuclear envelope and disintegration of food vacuoles (Kakkilaya, 2002).
In vitro metabolism of alectinib, a novel potent ALK inhibitor, in human: contribution of CYP3A enzymes
Published in Xenobiotica, 2018
Toshito Nakagawa, Stephen Fowler, Kenji Takanashi, Kuresh Youdim, Tsuyoshi Yamauchi, Kosuke Kawashima, Mika Sato-Nakai, Li Yu, Masaki Ishigai
All metabolites identified in this study are considered to be oxidized at the morpholine ring to form M5 as a primary metabolism step. Many drugs have a morpholine moiety in their chemical structures, and oxidation at the morpholine ring commonly occurs as a few examples can be found (De Brabanter et al., 2013; Denissen et al., 1994; Volotinen et al., 2007). Due to the distribution of electron density, the α- or β-carbon of the morpholine is easily oxidatively metabolized to the carbinolamine or the lactol. As they are unstable and exist in equilibrium with the aldehyde, which undergoes oxidation to a stable acid metabolite or cleavage to an aminoethanol metabolite, it is not common to detect a hydroxy morpholine metabolite as a stable metabolite. Although the unstable metabolite was reported as a minor metabolite of linogliride detected only in dog urine (Wu & Mutter, 1995), the stable acid forms or the cleavage forms were reported in most cases (Denissen et al., 1994; McKillop et al., 2004a). A hydroxymorpholine metabolite of alectinib, M5, was also present at a very low concentration in hepatocyte incubates of all species investigated. The main metabolite was the cleaved aminoethanol, M4. M4 was further oxidatively dealkylated to form a minor secondary amine metabolite, M6. The stable acid metabolites, M1a and M1b, were also found, although the M1b formation was much higher than M1a. There are four possible isomers for M5, two positional isomers and the stereoisomers of each, which may have different specificity to metabolic enzymes and thus affect which stable forms become the major. It was unclear which isomer of M5 existed in the hepatocytes for two reasons: too little M5 was formed for a structural analysis by NMR, and standards could not be chemically synthesized because the products were unstable.