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Panax quinquefolium (American Ginseng) and Physostigma venenosum (Calabar Bean)
Published in Azamal Husen, Herbs, Shrubs, and Trees of Potential Medicinal Benefits, 2022
Sushweta Mahalanobish, Noyel Ghosh, Parames C. Sil
The bioactive compounds that are present in AG and exert various beneficial effects on human health are known to be ginsenosides or panaxosides. They are basically glycosides in nature consisting of sugar chain along with non-sugar (aglycone) moiety. The chemical structure of ginsenosides contains three types of aglycone – dammarane-type tetracyclic triterpene, pentacyclic oleanolic acid, and tetracyclic ocotillol type. The sugar part of ginsenosides comprises hexoses (glucose, galactose), 6-deoxyhexoses (furanose, rhamnose), pentoses (arabinose, xylose), and uronic acids (glucuronic acid). They are cyclic in nature and connected with aglycone part by hemiacetal bonds (Kochan et al., 2017; Nag et al., 2012). The nomenclature of ginsenosides is designed as “Rx”, where “R” indicates root and “x” indicates the polarity of the molecule in alphabetical order from “a” to “h” index.
Genetics and Biosynthesis of Lipopolysaccharide O-Antigens
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Wendy J. Keenleyside, Chris Whitfield
The structural diversity of O-PSs is tremendous (Table 1). A review of the compositional data reveals greater than 60 monosaccharides that may be present as well as more than 30 different noncarbohydrate substituents (3). The O-PSs possess repeating unit structures and the O units vary among different serotypes based on the nature of the sugar constituents, the position and anomeric configuration (α or β(3) of the O-glycosidic linkages, the ring form of the substituent sugars (pyranose or furanose), as well as the presence or absence of noncarbohydrate “decorations” and the types of linkages by which these substituents are attached. The O units may comprise anywhere from one to eight monosaccharides, may be linear or branched, and may be homopolymers (i.e., a single monosaccharide component) or, more frequently, heteropolymers. In some cases, the precise O unit may be masked by nonstoichiometric modifications (e.g., O-acetylation or glycosylation).
FLT3: A Receptor Tyrosine Kinase Target in Adult and Pediatric AML
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Mark Levis, Patrick Brown, Donald Small
The two FLT3 inhibitors in this class, CEP-701 and PKC412, are alkaloids derived from parent compounds of microbial origin. This class of alkaloids is probably the oldest to be recognized as kinase inhibitors. The parent compounds, staurosporine (the precursor of PKC412) and K252α (the precursor of CEP-701), are highly nonselective, with activity against a broad variety of tyrosine and serine/threonine kinases (149–152). They differ only by the sugar moiety linked to the indolocarbazole scaffold; staurosporine contains a pyranose group, while K252α has a furanose residue. Crystal structure studies of staurosporine bound to different kinases reveal that the indolocarbazole inserts into the ATP-binding pocket, while the pyranose group interacts with residues outside the cleft (139). Modification of the sugar residue of either staurosporine or K252α would therefore be expected to influence the selectivity of the derivative.
Investigation of the enantioselectivity of acetylcholinesterase and butyrylcholinesterase upon inhibition by tacrine-iminosugar heterodimers
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
I. Caroline Vaaland, Óscar López, Adrián Puerta, Miguel X. Fernandes, José M. Padrón, José G. Fernández-Bolaños, Magne O. Sydnes, Emil Lindbäck
The synthesis of heterodimers 9a, 10a, and 11a commenced from L-xylose (14a), which was converted into 2,3,5-tri-O-benzyl-L-xylofuranose (15a) by following a reported three step procedure (Scheme 2)40. The obtained furanose underwent three subsequent chemical modifications including: (1) aldoxime formation, (2) selective O-silylation of the oxime oxygen atom, and (3) mesylation to provide compound 16a41 in 78% yield after purification by silica gel chromatography. When 16a was treated with F- ions it cyclized into nitrone 17a42,43 upon loss of the O-silyl group. Tetra-O-benzylated DAB 18a was obtained in 82% yield when nitrone 17a was reduced first by sodium borohydride and followed by zinc in acetic acid44. In the following step, 18a underwent N-propargylation to form alkyne 19a when it was treated with propargyl bromide. This alkyne underwent copper-catalysed azide – alkyne cycloaddition45 with azides 13a46, 13b32, and 13c32 to form heterodimers 20a, 21a, and 22a, respectively. In the final step, heterodimers 20a, 21a, and 22a underwent BCl3 promoted de-O-benzylation to generate target compounds 9a, 10a, and 11a, respectively.
Advances in biocatalytic and chemoenzymatic synthesis of nucleoside analogues
Published in Expert Opinion on Drug Discovery, 2022
Sebastian C. Cosgrove, Gavin J. Miller
We focus here on approaches that deliver nucleoside analogue targets using chemoenzymatic or biocatalytic cascade transformations as the key steps. Enzymatic transformations that have found significant application within other, largely synthetic routes, or for the production of key precursors [8,9], will not be discussed, as they have been reviewed elsewhere [10]. Two key aspects are covered. The first surrounds methodology concepts, effectively using enzymes to access diverse nucleoside analogue space and also for producing key building blocks, for wider use in enzymatic synthesis cascades (e.g., furanose 1-phosphates). The second aspect focuses on the use of biocatalytic enzyme cascades for the synthesis of nucleoside analogue drugs that are either approved (e.g., molnupiravir and didanosine) or in current clinical trials (e.g., islatravir). We also consider important technology improvements for enacting enzymatic nucleoside synthesis, including enzyme immobilization and flow systems.
Chemistry of ROS-mediated oxidation to the guanine base in DNA and its biological consequences
Published in International Journal of Radiation Biology, 2022
Aaron M. Fleming, Cynthia J. Burrows
Another potential outcome of the unstable intermediate (8-OH-G•) is one-electron reduction and protonation, which after ring opening to a more stable carbonyl compound would produce the formamidopyrimidine product derived from dG, or Fapy-G (Figure 1; Cadet et al. 2008; Dizdaroglu 2015). This type of reduction can only occur under strongly anoxic conditions, achieved in very hypoxic tumors, or when ionizing radiation generates both HO• and H• that add sequentially to the G heterocycle without the radical intermediate (8-OH-G•) being intercepted by O2 or O2•− (Douki et al. 1997). Fapy-G has been found in quantities nearly equal to that of OG under conditions of ionizing radiation (Frelon et al. 2000). Analysis of Fapy-G as a nucleoside is complicated by ribose ring opening and reclosure that can generate both α and β anomers at C1’ as well as both furanose (5-membered) and pyranose (6-membered) rings (Berger and Cadet 1985), as well as the glycosidic bond being labile toward hydrolysis to yield the free base. Thus, Fapy-G is a good example of a G lesion that has represented challenges for consistent detection and quantification between laboratories (Swarts et al. 1996; Douki et al. 1997; Frelon et al. 2000; Cui et al. 2013; Alshykhly et al. 2015b).