scholarly journals The Synthesis of Carbohydrates for the Treatment of Disease

2021 ◽  
Author(s):  
◽  
Emma Marie Dangerfield
Keyword(s):  
Cell Activity ◽  
Protecting Groups ◽  
Inkt Cell ◽  
Primary Amines ◽  
Alamar Blue ◽  
Glycosidase Inhibitors ◽  
Protecting Group ◽  
Comparable Activity ◽  
Species Specific ◽  
Reduced Activity

<p>In this thesis I investigated two aspects of glycobiology. In the first, I investigated the potential of α-GalCer analogues to be used in cancer immunotherapy. Two 4-deoxy α-GalCer analogues, with either a sphinganine or a sphingosine base, were synthesised using a convergent strategy. The α-GalCer sphinganine derivative was synthesised in 14 steps from D-arabinose, and in an overall 13% yield. The α-GalCer sphingosine analogue was synthesised in 13 steps also in 13% yield. Biological analysis revealed that both 4-deoxy analogues possessed comparable activity to α-GalCer in mice, however demonstrated significantly reduced hNKT cell activity. The reduced activity was attributed to species-specific differences in iNKT cell glycolipid recognition rather than reduced CD1d presentation. From these results we suggest that glycolipids developed for potent CD1d-iNKT cell activity in humans should contain a ceramide base with the 4-hydroxyl present. The second part of this thesis focused on protecting group free methodology for the synthesis of sugar mimetics that have proven potential as glycosidase inhibitors. In this work I developed an efficient, high yielding and diastereoselective strategy for the synthesis of a number of five and six membered azasugars. This strategy utilises two novel reaction methodologies. The first enabled the stereoselective formation of cyclic carbamates from olefinic amines, the transition states controlling the stereoselectivity during this reaction are discussed. The second reaction facilitated the synthesis of primary amines without the need for protecting groups, the scope of this reductive amination methodology is also investigated. The five membered azasugars 1,4-dideoxy-1,4-imino-Dxylitol, 1,4-dideoxy-1,4-imino-L-lyxitol, 1,4-dideoxy-1,4-imino-L-xylitol and 1,2,4-trideoxy-1,4-imino-L-xylitol were prepared in 5 steps, in good overall yields (57%, 55%, 54% and 48% respectively), and without the need for protecting groups. The six membered azasugar DGJ was prepared over six steps in 33% yield using similar methodology. The synthesised compounds were also tested for anti-tubercular activity using a BCG alamar blue assay.</p>

scholarly journals The Synthesis of Carbohydrates for the Treatment of Disease

2021 ◽  
Author(s):  
◽  
Emma Marie Dangerfield
Keyword(s):  
Cell Activity ◽  
Protecting Groups ◽  
Inkt Cell ◽  
Primary Amines ◽  
Alamar Blue ◽  
Glycosidase Inhibitors ◽  
Protecting Group ◽  
Comparable Activity ◽  
Species Specific ◽  
Reduced Activity

<p>In this thesis I investigated two aspects of glycobiology. In the first, I investigated the potential of α-GalCer analogues to be used in cancer immunotherapy. Two 4-deoxy α-GalCer analogues, with either a sphinganine or a sphingosine base, were synthesised using a convergent strategy. The α-GalCer sphinganine derivative was synthesised in 14 steps from D-arabinose, and in an overall 13% yield. The α-GalCer sphingosine analogue was synthesised in 13 steps also in 13% yield. Biological analysis revealed that both 4-deoxy analogues possessed comparable activity to α-GalCer in mice, however demonstrated significantly reduced hNKT cell activity. The reduced activity was attributed to species-specific differences in iNKT cell glycolipid recognition rather than reduced CD1d presentation. From these results we suggest that glycolipids developed for potent CD1d-iNKT cell activity in humans should contain a ceramide base with the 4-hydroxyl present. The second part of this thesis focused on protecting group free methodology for the synthesis of sugar mimetics that have proven potential as glycosidase inhibitors. In this work I developed an efficient, high yielding and diastereoselective strategy for the synthesis of a number of five and six membered azasugars. This strategy utilises two novel reaction methodologies. The first enabled the stereoselective formation of cyclic carbamates from olefinic amines, the transition states controlling the stereoselectivity during this reaction are discussed. The second reaction facilitated the synthesis of primary amines without the need for protecting groups, the scope of this reductive amination methodology is also investigated. The five membered azasugars 1,4-dideoxy-1,4-imino-Dxylitol, 1,4-dideoxy-1,4-imino-L-lyxitol, 1,4-dideoxy-1,4-imino-L-xylitol and 1,2,4-trideoxy-1,4-imino-L-xylitol were prepared in 5 steps, in good overall yields (57%, 55%, 54% and 48% respectively), and without the need for protecting groups. The six membered azasugar DGJ was prepared over six steps in 33% yield using similar methodology. The synthesised compounds were also tested for anti-tubercular activity using a BCG alamar blue assay.</p>

scholarly journals Multidisciplinary Studies of Folk Medicine “Five Thieves’ Oil” (Olejek Pięciu Złodziei) Components

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 2931
Author(s):  
Przemysław Siejak ◽  
Wojciech Smułek ◽  
Farahnaz Fathordobady ◽  
Anna Grygier ◽  
Hanna Maria Baranowska ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Membrane Permeability ◽  
Significant Contribution ◽  
Spectroscopic Analysis ◽  
Folk Medicine ◽  
Cell Activity ◽  
Biological Properties ◽  
Cell Membrane Permeability ◽  
Comparable Activity ◽  
Terpene Derivatives

To meet the growing interest in natural antibacterial agents, we evaluated the physicochemical and biological properties of the folk medicine known as “five thieves’ oil” (Polish name: olejek pięciu złodziei). Five thieves’ oil consists of a mixture of five oils: rosemary, lemon, clove, eucalyptus, and cinnamon. In this study, we performed gas chromatography, FTIR, and UV–vis spectroscopic analysis, as well as L-a-b color tests, contact angle determination, and surface tension determination. To verify its antibacterial activity, the metabolic activity and changes in cell membrane permeability of bacteria of the genus Pseudomonas were studied. As a result, it was found that among the constituent oils, the oils of clove and cinnamon were the least volatile and, at the same time, had the strongest antibacterial activity. However, a mix of all the oils also showed comparable activity, which was even more pronounced for the oils after 4 weeks of aging. This effect can be linked to the high content of terpene derivatives such as eugenol and cinnamaldehyde, which can cause changes in bacterial membrane permeability, affecting cell activity and survival. This study is the first to characterize the constituents of the popular folk medicine five thieves’ oil, confirming and explaining its strong antibacterial activity, thus constituting a significant contribution to contemporary health education.

The synthesis of a carbohydrate-like dihydrooxazine and tetrahydrooxazine as putative inhibitors of glycoside hydrolases: A direct synthesis of isofagomine

2002 ◽  
Vol 80 (8) ◽  
pp. 857-865 ◽  
Author(s):  
Wayne M Best ◽  
James M Macdonald ◽  
Brian W Skelton ◽  
Robert V Stick ◽  
D Matthew G Tilbrook ◽  
...  
Keyword(s):  
Direct Synthesis ◽  
Glycoside Hydrolases ◽  
Crystalline Solid ◽  
Glycosidase Inhibitors ◽  
Protecting Group ◽  
Mild Acid Hydrolysis ◽  
Catalytic Hydrogenolysis ◽  
Palladium On Carbon ◽  
Mild Acid

The treatment of benzyl 2,3-O-isopropylidene-β-L-xylopyranoside with N-hydroxyphthalimide under Mitsunobu conditions, followed by protecting-group interchange, gave benzyl 4-O-[(tert-butoxycarbonyl)amino]-2,3- O-isopropylidene-α-D-arabinoside. Mild acid hydrolysis and catalytic hydrogenolysis afforded 4-O-[(tert-butoxycarbonyl)amino]-D-arabinose that, upon heating in water, gave the dihydrooxazine [(4R,5S,6R)-5,6-dihydro-4,5-dihydroxy-6-hydroxymethyl-4H-1,2-oxazine] as a crystalline solid. A single-crystal structure determination of this solid showed it to exist in the 5H6 conformation. Reduction of the dihydrooxazine gave the tetrahydrooxazine [(4R,5S,6R)-4,5-dihydroxy-6-hydroxymethyl-3,4,5,6-tetrahydro-2H-1,2-oxazine]. The dihydrooxazine was an effective inhibitor of two β-glucosidases (Ki = 27 and 35 µM). Benzyl 2,3-O-isopropylidene-β-L-xylopyranoside, via the derived imidazylate, was converted into a nitrile that, upon reduction and protecting-group manipulations, gave benzyl 4-C-aminomethyl-4-deoxy-α-D-arabinoside. Treatment of this amine with hydrogen and palladium-on-carbon gave isofagomine.Key words: dihydrooxazine, tetrahydrooxazine, isofagomine, iminosugars, glycosidase inhibitors.

ChemInform Abstract: The “Benzostabase” Protecting Group for Primary Amines. Application to Aliphatic Amines.

ChemInform ◽  
2010 ◽  
Vol 23 (15) ◽  
pp. no-no
Author(s):  
R. P. BONAR-LAW ◽  
A. P. DAVIS ◽  
B. J. DORGAN ◽  
M. T. REETZ ◽  
A. WEHRSIG
Keyword(s):  
Aliphatic Amines ◽  
Primary Amines ◽  
Protecting Group

Protecting Groups

2008 ◽  
Author(s):  
Jie Jack Li ◽  
Chris Limberakis ◽  
Derek A. Pflum
Keyword(s):  
Low Temperature ◽  
Organic Synthesis ◽  
Secondary Alcohol ◽  
Primary Alcohol ◽  
Protecting Groups ◽  
Silyl Ether ◽  
Benzyl Ether ◽  
Protecting Group ◽  
Selective Protection ◽  
Death Taxes

In his book, Protecting Groups, Philip J. Kocieński stated that there are three things that cannot be avoided: death, taxes, and protecting groups. Indeed, protecting groups mask functionality that would otherwise be compromised or interfere with a given reaction, making them a necessity in organic synthesis. In this chapter, for each protecting group showcased, only the most widely used methods for protection and cleavage are shown. Also, this section is not comprehensive and only addresses some of the most common blocking groups in organic synthesis. For a thorough review of protecting groups, the reader should consult the following references: (a) Wuts, P. G. M.; Greene, T. W.; Protective Groups in Organic Synthesis, 4th ed.; Wiley: Hoboken, NJ, 2007; (b) Kocienski, P. J. Protecting Groups, 3rd edition.; Thieme: Stuggart, 2004. In this section, the formation and cleavage of eight protecting groups for alcohols and phenols are presented: acetate; acetonides for diols; benzyl ether; para-methoxybenzyl (PMB) ether; methyl ether; methoxymethylene (MOM) ether; tert-butyldiphenylsilyl (TBDPS) silyl ether; and tetrahydropyran (THP). Acetate is a convenient protecting group for alcohols—easy on and easy off. Selective protection of a primary alcohol in the presence of a secondary alcohol can be achieved at low temperature. The drawback of this protecting group is its incompatibility with hydrolysis and reductive conditions.

scholarly journals 2,3-Diaminopropanols Obtained from d-Serine as Intermediates in the Synthesis of Protected 2,3-l-Diaminopropanoic Acid (l-Dap) Methyl Esters

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1313
Author(s):  
Andrea Temperini ◽  
Donatella Aiello ◽  
Fabio Mazzotti ◽  
Constantinos M. Athanassopoulos ◽  
Pierantonio De Luca ◽  
...  
Keyword(s):  
Amino Acid ◽  
Reductive Amination ◽  
Methyl Esters ◽  
Primary Amines ◽  
Synthetic Approach ◽  
Protecting Group ◽  
Synthetic Strategy ◽  
Crude Product ◽  
Diaminopropanoic Acid ◽  
Acid Labile

A synthetic strategy for the preparation of two orthogonally protected methyl esters of the non-proteinogenic amino acid 2,3-l-diaminopropanoic acid (l-Dap) was developed. In these structures, the base-labile protecting group 9-fluorenylmethyloxycarbonyl (Fmoc) was paired to the p-toluensulfonyl (tosyl, Ts) or acid-labile tert-butyloxycarbonyl (Boc) moieties. The synthetic approach to protected l-Dap methyl esters uses appropriately masked 2,3-diaminopropanols, which are obtained via reductive amination of an aldehyde prepared from the commercial amino acid Nα-Fmoc-O-tert-butyl-d-serine, used as the starting material. Reductive amination is carried out with primary amines and sulfonamides, and the process is assisted by the Lewis acid Ti(OiPr)4. The required carboxyl group is installed by oxidizing the alcoholic function of 2,3-diaminopropanols bearing the tosyl or benzyl protecting group on the 3-NH2 site. The procedure can easily be applied using the crude product obtained after each step, minimizing the need for chromatographic purifications. Chirality of the carbon atom of the starting d-serine template is preserved throughout all synthetic steps.

How the sperm triggers development of the egg: what have we learned and what can we expect in the next millennium?

Zygote ◽  
1999 ◽  
Vol 8 (S1) ◽  
pp. S7-S8
Author(s):  
David Epel
Keyword(s):  
Sea Urchin ◽  
Cell Biology ◽  
Control Cell ◽  
Rapid Evolution ◽  
Cell Activity ◽  
Turn Of The Century ◽  
Direct Demonstration ◽  
Creative Research ◽  
Contemporary Work ◽  
Species Specific

The problem of how the sperm activates the egg has captivated the attention of cell and developmental biologists since the turn of the century. An early focus concerned species-specific fertilisation and the pioneering work of Lilly and Tyler (Tyler & Tyler, 1966) used immunological analogies to provide explanations of species-specific fertilisation. Contemporary work has focused on the identity of unique receptors on the sperm and the egg as exemplified in the work of Lennarz (Ohlendieck & Lennarz, 1996), Vacquier (Vacquier, et al., 1995) and Wasserman (1999). Lately, this approach has provided unexpected insights on how speciation might occur. Speciation requires reproductive isolation and creative research from the Vacquier laboratory has demonstrated how reproductive barriers might occur through rapid evolution of sperm/egg recognition systems (Lee et al., 1995).Studies on the cell biology of activation received a major impetus in the 1930s with Mazia's observation of a calcium increase in eggs of the sea urchin following fertilisation (Mazia, 1937). His discovery, however, was a premature one in that there was no satisfactory model at that time for explaining how a calcium increase could affect cell activity. It took almost 40 years to develop a paradigm, and this came from studies on muscle and nerve which revealed how calcium increases could somehow control cell activity. Work in the 1970s rapidly established a similar role for calcium in activation of the egg at fertilisation. The first break-through was the direct demonstration by Steinhardt & Epel (1974) that calcium was involved in egg activation, through manipulation of calcium levels in sea urchin oocytes by use of calcium ionophores.

Protecting-group-free synthesis of haterumadienone- and puupehenone-type marine natural products

2017 ◽  
Vol 19 (9) ◽  
pp. 2140-2144 ◽  
Author(s):  
Hong-Shuang Wang ◽  
Hui-Jing Li ◽  
Jun-Li Wang ◽  
Yan-Chao Wu
Keyword(s):  
Natural Products ◽  
Transition Metals ◽  
Marine Natural Products ◽  
Protecting Groups ◽  
Protecting Group

The atom- and step-economical synthesis of seven puupehenone- and haterumadienone-type marine natural products without the use of protecting groups and transition metals has been achieved from the abundant feedstock chemical sclareolide in only 6 to 9 steps.

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