Synthetic Approaches to l-Iduronic Acid and l-Idose

Mohamed, Shifaza; Ferro, Vito

doi:10.1016/bs.accb.2015.07.001

Cited by 16 publications

(15 citation statements)

References 139 publications

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“…Significant efforts have been devoted to the synthesis of l ‐iduronic acids ( l ‐ ido As) and derivatives thereof as conformationally flexible l ‐ ido A is a key monosaccharide component of glycosaminoglycans (GAGs) of biological relevance such as well‐known heparin, heparin sulfate, and dermatan . The facile preparation of 8 a – c offers prospects for the synthesis of novel ido A analogues because of the rich chemical reactivity of C=C bonds and the carbonyl group, thus facilitating the synthesis of diverse GAGs.…”

Section: Resultsmentioning

confidence: 99%

“…Significant efforts have been devoted to the synthesis of liduronic acids (l-idoAs) and derivatives thereof as conformationally flexible l-idoAi sakey monosaccharide component of glycosaminoglycans (GAGs) of biological relevance such as well-known heparin, heparin sulfate,and dermatan. [33] The facile preparation of 8a-c offers prospects for the synthesis of novel idoAanalogues because of the rich chemical reactivity of C = Cb onds and the carbonyl group,t hus facilitating the synthesis of diverse GAGs.F riedel-Crafts reaction of 6 with furan 7dprovided reverse aryl C-glycoside 8din 84 %yield as am ixture of stereoisomers (Table 2). Heteroatomic nucleophiles were also viable coupling partners,y ielding novel reverse glycosides with the stereoselectivity depending on the nature of the nucleophile.T hiolysis of 6 with octanethiol 7e provided 8e in 80 %with the C-5 axially substituted isomer as the major product while alcoholysis with sugar 1b showed reverse stereoselectivity,furnishing 8fin 86 %yield favoring the isomer with the C-5 equatorially oriented substituent.…”

Section: Divergent Derivatizations Of the Rgfsmentioning

confidence: 99%

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Radical Dehydroxymethylative Fluorination of Carbohydrates and Divergent Transformations of the Resulting Reverse Glycosyl Fluorides

et al. 2020

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A mild and convenient method for the synthesis of reverse glycosyl fluorides (RGFs) has been developed that is based on the silver‐promoted radical dehydroxymethylative fluorination of carbohydrates. A salient feature of the reaction is that furanoid and pyranoid carbohydrates furnish structurally diverse RGFs bearing a wide variety of functional groups in good to excellent yields. Intramolecular hydrogen atom transfer experiments revealed that the reaction involves an underexploited radical fluorination that proceeds via β‐fragmentation of sugar‐derived primary alkoxyl radicals. Structurally divergent RGFs were obtained by catalytic C−F bond activation, and our method thus offers a concise and efficient strategy for the synthesis of reverse glycosides by late‐stage diversification of RGFs. The potential of this method is showcased by the preparation and diversification of sotagliflozin, leading to the discovery of a promising SGLT2 inhibitor candidate.

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Section: Resultsmentioning

confidence: 99%

Section: Divergent Derivatizations Of the Rgfsmentioning

confidence: 99%

Radical Dehydroxymethylative Fluorination of Carbohydrates and Divergent Transformations of the Resulting Reverse Glycosyl Fluorides

et al. 2020

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“…Major advances in the field of carbohydrate synthesis such as building block preparation (one-pot multi-step procedures), coupling reactions, and the development of convergent strategies for coupling key building blocks, has led to an increase in the synthesis of complex oligosaccharides which can act as heparin mimetics [ 16 , 17 , 18 , 19 , 20 ]. Such synthetic methods allow the preparation of tailor-made saccharides, with customized sizes and functional groups.…”

Section: Introductionmentioning

confidence: 99%

Heparin Mimetics: Their Therapeutic Potential

Mohamed

Coombe

2017

Pharmaceuticals

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Heparin mimetics are synthetic and semi-synthetic compounds that are highly sulfated, structurally distinct analogues of glycosaminoglycans. These mimetics are often rationally designed to increase potency and binding selectivity towards specific proteins involved in disease manifestations. Some of the major therapeutic arenas towards which heparin mimetics are targeted include: coagulation and thrombosis, cancers, and inflammatory diseases. Although Fondaparinux, a rationally designed heparin mimetic, is now approved for prophylaxis and treatment of venous thromboembolism, the search for novel anticoagulant heparin mimetics with increased affinity and fewer side effects remains a subject of research. However, increasingly, research is focusing on the non-anticoagulant activities of these molecules. Heparin mimetics have potential as anti-cancer agents due to their ability to: (1) inhibit heparanase, an endoglycosidase which facilitates the spread of tumor cells; and (2) inhibit angiogenesis by binding to growth factors. The heparin mimetic, PI-88 is in clinical trials for post-surgical hepatocellular carcinoma and advanced melanoma. The anti-inflammatory properties of heparin mimetics have primarily been attributed to their ability to interact with: complement system proteins, selectins and chemokines; each of which function differently to facilitate inflammation. The efficacy of low/non-anticoagulant heparin mimetics in animal models of different inflammatory diseases has been demonstrated. These findings, plus clinical data that indicates heparin has anti-inflammatory activity, will raise the momentum for developing heparin mimetics as a new class of therapeutic agent for inflammatory diseases.

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“…However, each strategy toward chemical synthesis of heparin oligosaccharides faces the same difficulty: the lengthy, laborious and low-yielding synthesis of the L-iduronic acid building block, which is a critically important structural component for the anticoagulant activity. Despite recent progress 33 – 35 , the short and efficient synthesis of an orthogonally protected L-idose or iduronic acid glycosyl donor useful for heparinoid synthesis remained unmet. We envisioned that replacing the IdoA with a more easily available sugar unit would solve the problem and L-talopyranuronic acid could be a good candidate as a potential structural substituent.…”

Section: Introductionmentioning

confidence: 99%

Replacement of the L-iduronic acid unit of the anticoagulant pentasaccharide idraparinux by a 6-deoxy-L-talopyranose – Synthesis and conformational analysis

Demeter

Gyöngyösi

Bereczky

et al. 2018

Sci Rep

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One critical part of the synthesis of heparinoid anticoagulants is the creation of the L-iduronic acid building block featured with unique conformational plasticity which is crucial for the anticoagulant activity. Herein, we studied whether a much more easily synthesizable sugar, the 6-deoxy-L-talose, built in a heparinoid oligosaccharide, could show a similar conformational plasticity, thereby can be a potential substituent of the L-idose. Three pentasaccharides related to the synthetic anticoagulant pentasaccharide idraparinux were prepared, in which the L-iduronate was replaced by a 6-deoxy-L-talopyranoside unit. The talo-configured building block was formed by C4 epimerisation of the commercially available L-rhamnose with high efficacy at both the monosaccharide and the disaccharide level. The detailed conformational analysis of these new derivatives, differing only in their methylation pattern, was performed and the conformationally relevant NMR parameters, such as proton-proton coupling constants and interproton distances were compared to the corresponding ones measured in idraparinux. The lack of anticoagulant activity of these novel heparin analogues could be explained by the biologically not favorable 1C4 chair conformation of their 6-deoxy-L-talopyranoside residues.

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Synthetic Approaches to l-Iduronic Acid and l-Idose

Cited by 16 publications

References 139 publications

Radical Dehydroxymethylative Fluorination of Carbohydrates and Divergent Transformations of the Resulting Reverse Glycosyl Fluorides

Radical Dehydroxymethylative Fluorination of Carbohydrates and Divergent Transformations of the Resulting Reverse Glycosyl Fluorides

Heparin Mimetics: Their Therapeutic Potential

Replacement of the L-iduronic acid unit of the anticoagulant pentasaccharide idraparinux by a 6-deoxy-L-talopyranose – Synthesis and conformational analysis

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