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Biocatalysts: The Different Classes and Applications for Synthesis of APIs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Schrittwieser et al. (2011, 2011a) reported the chemoenzymatic synthesis of optically pure (S)-scoulerine, berbine and benzylisoquinoline alkaloids. Staring from N-methylphenethylamine and phenylacetic acid derivatives (a and b in the opposite scheme) rac-reticuline was prepared by chemical step. The subsequent enantioselective oxidative C–C bond formation, yielding (S)-scoulerine was achieved by the action of the flavin-dependent berberine bridge enzyme (BBE); (S)-scoulerine acts as a sedative and muscle-relaxing agent and is a DNA topoisomerase I inhibitor (Cheng et al., 2008). In 2014, Schrittwieser et al. developed a chemoenzymatic deracemization by means of a cascade reaction, involving two enantioselective oxidation steps and a non-stereoselective reduction reaction. For the latter they employed morpholin∙BH3 that worked better than the more often used NH3∙BH3. The enantioselective oxidations were catalyzed by a monoamine oxidase variant and BBE. The conversion of rac-benzylisochinolins to optically pure (S)-berbines was performed by stepwise or simultaneous addition of MAO, BBE and morpholino∙BH3, and yielded the products with conversions up to 98% and yields up to 88%.
Molecular Biology Tools to Boost the Production of Natural Products
Published in Luzia Valentina Modolo, Mary Ann Foglio, Brazilian Medicinal Plants, 2019
Luzia Valentina Modolo, Samuel Chaves-Silva, Thamara Ferreira da Silva, Cristiane Jovelina da-Silva
The pharmacological proprieties of plant natural products belonging to the class of benzylisoquinoline alkaloids (BIAs) have caught the attention of synthetic biologists. For instance, BIAs such as oxycodone, hydrocodone and hydromorphine are opioid analgesics supplied by pharmaceutical companies using semi-synthesis approaches. It was recently estimated that P. somniferum (opium poppy) was cultivated in approximately 100,000 hectares to obtain 800 tons of thebaine or morphine (natural precursors of semisynthetic BIAs) to meet the medical demand of analgesic opiods) (Galanie et al., 2015). Although some synthetic routes to provide morphine and derivatives are disclosed, none of them are commercially competitive or viable in large scale compared to the semisynthetic approach (Reed and Hudlicky, 2015). Efforts in synthetic biology have been made since the end of the 2000s to produce BIAs in microorganisms. S. cerevisiae was genetically modified to produce reticuline, a key intermediate of BIA's biosynthesis, from the commercially available (R,S)-norlaudanosoline (Hawkins and Smolke, 2008). A few years later, a fermentation system constituted from E. coli was developed to produce reticuline from simpler and cheaper carbon sources (Nakagawa et al., 2012). In 2014, researchers achieved the introduction of ten plant genes in S. cerevisiae, which in turn, resulted in the production of dihydrosanguinarine and sanguinarine, BIAs of notable antimicrobe and antineoplasic activities (Fossati et al., 2014). Additionally, 21 and 23 genes (of plants, mammalians and bacteria origin) were introduced to yeast strains to make them competent to produce thebaine and hydrocodone, respectively, from sugar (Galanie et al. 2015).
Catalog of Herbs
Published in James A. Duke, Handbook of Medicinal Herbs, 2018
Regarded as apertif, carminative, diuretic, emetic, emmenagogue, narcotic, nervine, stimulant, stomachic, and sudorific, bay has found its way into folk remedies for amenorrhea, colic, condylomata, hysteria, impostumes, polyps, scleroses, spasms, and wens.3238 Methyl eugenol, which constitutes 4% of bay oil, is narcotic and sedative in mice, producing sedation at low doses and reversible narcosis at higher doses. The essential oil has bactericidal and fungicidal properties. An ointment of unguent derived from the plant is said to remedy sclerosis of the spleen and liver and tumors of the uterus, spleen, parotid, testicles, liver, and stomach. The fruit, prepared in various manners, is said to help uterine fibroids, tuberosities of the face, scirrhus and scleroma of the uterus, scirrhus of the liver, indurations of the joints, spleen, and liver, internal tumors, wens, and tumors of the eye. Leaves and fruits, said to possess aromatic, stimulant, and narcotic properties, were once employed for amenorrhea, flatulent colic, cough, and hysteria. In small doses, leaves are diaphoretic; in large doses, emetic. Bay oil sometimes used as a liniment or anodyne for earache. In Lebanon the leaves and berries are extracted to a carminative liver and stomach tonic, tightly corked, and steeped in brandy in the sun for several days. The residue, after subsequent distillation, is used as a liniment for rheumatism and sprains, the distillate as an emmenagogue. Lebanese mountaineers are said to use raw berries to induce abortion. Berries macerated in flour were poulticed onto dislocations.18 Pech and Bruneton189 reported on the alkaloidal constituents, the leaves containing mostly reticuline, with some boldine, N-methylactinodaphnine, ( + )-isodomesticine, ( + ) neolitsine, actinodaphnine, nor-isodomesticine, launobine, nandigerine, and cryptodorine; actinodaphnine constituted about half of the stem alkaloids, with some reticuline and launobine; the inflorescence contained mostly actinodaphnine, with some reticuline, launobine, and nandigerine. 3,4-Dimethoxyallylbenzene produces sedation in mice at low doses; a reversible narcosis at higher doses. It prevented the death of mice treated with lethal convulsant doses of strychnine. It may have relatively specific control nervous or myoneural effects, perhaps, suggesting a clinical potential.
Tinospora Cordifolia: A review of its immunomodulatory properties
Published in Journal of Dietary Supplements, 2022
Charles R. Yates, Eugene J. Bruno, Mary E. D. Yates
Alkaloids represent another abundant class of phytoconstituents in the Tinospora genus. These include alkaloids of the berberine class (berberine (Mohan et al. 2017; Maurya et al. 1995; Srinivasan et al. 2008; Palmieri et al. 2019), palmatine (Patel and Mishra 2012; Bisset and Nwaiwu 1983) reticuline (Bala et al. 2015), and jatrorrhizine (Patel and Mishra 2012; Bala et al. 2015) as well as the aporphine class (magnoflorine (Maurya et al. 1995; Patel and Mishra 2012; Bala et al. 2015), menisperine (Maurya et al. 1995; Bala et al. 2015), tinoscorside A[8], and tinoscorside B[8]. Other chemical classes identified in T. cordifolia include steroids (derivatives of β-sitosterol (Maurya et al. 1995; Bala et al. 2015)) and polysaccharides including glucose, arabinose, xylose, galactose, rhamnose, and mannose (Jahfar and Azadi 2004; Sharma et al. 2010). A more comprehensive list of phytochemicals identified in T. cordifolia and plant parts from which they were isolated can be found in Table 1.
Limited relevance and progression of histological alterations in the liver during thioguanine therapy in inflammatory bowel disease patients
Published in Scandinavian Journal of Gastroenterology, 2019
Dirk P. van Asseldonk, Melek Simsek, Nanne K. H. de Boer, Bindia Jharap, Elisabeth Bloemena, Gijsbert den Hartog, Dik B. Westerveld, Marco C. Becx, Maurice G. Russel, Birgit I. Lissenberg-Witte, Carin M. van Nieuwkerk, Chris J. J. Mulder, Joanne Verheij, Adriaan A. van Bodegraven
Liver biopsy specimens were revised by two independent liver pathologists (JV and EB) specialized in vascular abnormalities of the liver. They were both blinded, i.e., liver biopsies were revised without information about the clinical characteristics. In case of discrepancy between the pathologists, biopsies were jointly revised and the score was decided by consensus. Evaluation of the liver specimens included presence of histopathological and vascular irregularities such as sinusoidal dilatation, nodularity, perisinusoidal fibrosis, phlebosclerosis and perivenular fibrosis and were scored in an ordinal manner (Table 1). Together with these characteristics also portal-, interface-, and lobular inflammation, fibrosis and steatosis (Brunt’s score) [17] were scored. In accordance with the definition as proposed by Wanless [11] and Jharap et al. [15], NRH was defined as grade 3 nodularity (visible on both hematoxylin-eosin and reticuline staining) in the absence of bridging fibrosis.
Cytochrome P450 in the central nervous system as a therapeutic target in neurodegenerative diseases
Published in Drug Metabolism Reviews, 2018
Cynthia Navarro-Mabarak, Rafael Camacho-Carranza, Jesús Javier Espinosa-Aguirre
Outstanding findings have also described the participation of CYP2D6 and CYP3A4 in the biosynthesis of morphine in liver and brain (Grobe et al. 2009; Kramlinger et al. 2015). CYP2D6 catalyzes three reactions in the biosynthesis of morphine, it catalyzes the 3-O-demethylation of codeine to morphine, the 3-O-demethylation of thebaine to oripavine, and the phenol coupling of (R)-reticuline to salutaridine (Figure 3) (Dayer et al. 1988; Mikus et al. 1991; Grobe et al. 2009).