Synthesis of C-aryl glycosides related to the chrysomycins

Hart, David J.; Merriman, Gregory; Young, David W.

doi:10.1016/0040-4020(96)00876-9

Cited by 23 publications

(9 citation statements)

References 38 publications

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“…Secondly, one can assume from the close structural relationship between the gilvocarcins, ravidomycins, chrysomycins, and Mer compounds[7,8,16,34–37] that all these compounds evolved from a common ancestral origin and share a common set of biosynthetic genes. While the Mer sugar moiety[7,8,38] is still in the unreduced state (4-keto group) the ravidomycin[7,39–41] and chrysomycin[42–45] sugars are both pyranoses with an axial 4-OH group. It is therefore likely that all of these pathways inherited the same set of three basic deoxysugar enzymes, namely an NDP- d -glucose synthase and a NDP- d -glucose-4,6-dehydratase (GilD and GilE in the gil pathway), plus an unusual GilU-like 4-ketoreductase, which generates the axial 4-OH group of the NDP-fucopyranose intermediate of the gil pathway as well as the axial 4-OH residues in the pyranose moieties of chrysomycin and ravidomycin, whose pathways are currently under investigation in our lab.…”

Section: Resultsmentioning

confidence: 99%

Inactivation of the Ketoreductase gilU Gene of the Gilvocarcin Biosynthetic Gene Cluster Yields New Analogues with Partly Improved Biological Activity

et al. 2009

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Four new analogues of the gilvocarcin-type aryl-C-glycoside anti-tumor compounds, namely 4′-hydroxy gilvocarcin V (4′-OH-GV), 4′-hydroxy gilvocarcin M, 4′-hydroxy gilvocarcin E and 12-demethyl-defucogilvocarcin V, were produced through inactivation of the gilU gene. The 4′-OHanalogues showed improved activity against lung cancer cell lines as compared to their parent compounds without 4′-OH group (gilvocarcins V and E). The structures of the sugar-containing new mutant products indicate that the enzyme GilU acts as an unusual ketoreductase involved in the biosynthesis of the C-glycosidically linked deoxysugar moiety of the gilvocarcins. The structures of the new gilvocarcins indicate substrate flexibility of the post-polyketide synthase modifying enzymes, particularly the C-glycosyltransferase and the enzyme responsible for the sugar ring contraction. The results also shed light into biosynthetic sequence of events in the late steps of biosynthetic pathway of gilvocarcin V.

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Section: Resultsmentioning

confidence: 99%

Inactivation of the Ketoreductase gilU Gene of the Gilvocarcin Biosynthetic Gene Cluster Yields New Analogues with Partly Improved Biological Activity

et al. 2009

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“…Upon treatment with H 2 SO 4 /MeOH, 31a was converted to polycarcin V ( 10 ) in 62% yield. Considering that the acidic conditions would cause anomerization and/or ring expansion of d -fucofuranose, the basic condition using NaOMe in MeOH was applied for the synthesis of gilvocarcin V ( 8 ). As a result, polycarcin V and gilvocarcin V were also synthesized in 10 steps (LLS).…”

Section: Resultsmentioning

confidence: 99%

“…To our knowledge, no successful total synthesis of chrysomycins has been reported since the original discovery of these natural products 60 years ago. The Hart group attempted to synthesize chrysomycin B with a strategy to form the lactone in the presence of carbohydrate moiety at the C4 position but without success . Attracted by the fascinating structure and potent anti-TB activity of chrysomycin A, we set out to accomplish its total synthesis that would serve as a sustainable source and platform for a structure–activity relationship study, which may facilitate the discovery of potential lead compounds for the treatment of TB.…”

Section: Introductionmentioning

confidence: 99%

Chrysomycin A Derivatives for the Treatment of Multi-Drug-Resistant Tuberculosis

Zhang

Song

et al. 2020

ACS Cent. Sci.

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Tuberculosis (TB) is a life-threatening disease resulting in an estimated 10 million new infections and 1.8 million deaths annually, primarily in underdeveloped countries. The economic burden of TB has been estimated as approximately 12 billion USD annually in direct and indirect costs. Additionally, multi-drug-resistant (MDR) and extreme-drug-resistant (XTR) TB strains resulting in about 250 000 deaths annually are now widespread, increasing pressure on the identification of new anti-TB agents that operate by a novel mechanism of action. Chrysomycin A is a rare C-aryl glycoside first discovered over 60 years ago. In a recent highthroughput screen, we found that chrysomycin A has potent anti-TB activity, with minimum inhibitory concentration (MIC) = 0.4 μg/mL against MDR-TB strains. However, chrysomycin A is obtained in low yields from fermentation of Streptomyces, and the mechanism of action of this compound is unknown. To facilitate the mechanism of action and preclinical studies of chrysomycin A, we developed a 10-step, scalable synthesis of the isolate and its two natural congeners polycarcin V and gilvocarcin V. The synthetic sequence was enabled by the implementation of two sequential C−H functionalization steps as well as a late-stage C-glycosylation. In addition, >10 g of the advanced synthetic intermediate has been prepared, which greatly facilitated the synthesis of 33 new analogues to date. The structure−activity relationship was subsequently delineated, leading to the identification of derivatives with superior potency against MDR-TB (MIC = 0.08 μg/mL). The more potent derivatives contained a modified carbohydrate residue which suggests that further optimization is additionally possible. The chemistry we report here establishes a platform for the development of a novel class of anti-TB agents active against drug-resistant pathogens.

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“…An approach involving modification of glycosyl donors prior to C ‐glycosylation has also been reported in the literature, but failed in some critical cases 7. De novo approaches involving the construction of the glycosyl ring have seldom been reported 8,9…”

Section: Introductionmentioning

confidence: 99%

[4+2]/HyBRedOx Approach to C‐Naphthyl Glycosides: Failure in the Projuglone Series and Reinvestigation of the HyBRedOx Sequence

Maingot

Collet

et al. 2009

Eur J Org Chem

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C‐Naphthyl glycosides displaying a 1,5‐difunctionality on the naphthalene ring that can undergo oxidation to bromonaphthoquinone are key intermediates in the synthesis of natural C‐aryl glycoside analogues. In this area, sugar‐modified derivatives are of specific interest, but their synthesis is challenging. The de novo access to such compounds has been investigated through a [4+2] heterocycloaddition route, previously validated in a model series. For this purpose, two new dienophiles, conveniently protected at the phenolic positions, were synthesized. From an extensive study of their reactivity towards a range of 4‐hetero‐substituted (“prosugar”) heterodienes, the expected heteroadducts were stereoselectively obtained in acceptable yields. Application of the hydroboration/reduction/oxidation sequence did not afford the target C‐glycosides from the reduced adducts. The negative effect of the conformational bias of the substrate on this tandem reaction is discussed.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

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Synthesis of C-aryl glycosides related to the chrysomycins

Cited by 23 publications

References 38 publications

Inactivation of the Ketoreductase gilU Gene of the Gilvocarcin Biosynthetic Gene Cluster Yields New Analogues with Partly Improved Biological Activity

Inactivation of the Ketoreductase gilU Gene of the Gilvocarcin Biosynthetic Gene Cluster Yields New Analogues with Partly Improved Biological Activity

Chrysomycin A Derivatives for the Treatment of Multi-Drug-Resistant Tuberculosis

[4+2]/HyBRedOx Approach to C‐Naphthyl Glycosides: Failure in the Projuglone Series and Reinvestigation of the HyBRedOx Sequence

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