Synthetic studies on the mycolactone core

Ko, Kwang-Seuk; Alexander, Matthew D.; Fontaine, Shaun D.; Biggs‐Houck, James E.; Clair, James J. La; Burkart, Michael D.

doi:10.1039/c0ob00540a

Cited by 19 publications

(6 citation statements)

References 62 publications

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“…This observation is in line with results from the Burkart [ 173 , 240 ] and the Blanchard [ 182 ] groups, showing that the successful closure of the 12-membered ring is sensitive to subtle changes of the substituent at the C13 position. As an alternative to the RCM-based cyclization of 219 , lactone 220 could eventually be obtained in good yields by reduction of tosylate 90 with an excess of NaBH 4 in DMSO at 100 °C followed by the removal of the TES protecting group under slightly acidic conditions.…”

Section: Reviewsupporting

confidence: 90%

“…With known intermediate 55 in hand, the endgame was realized according to Negishi’s approach [ 37 ] and gave the unprotected extended mycolactone core in 45% yield over 5 more steps. The Aggarwal synthesis outcompetes the other published syntheses in terms of longest linear sequence (11 or 13 steps, respectively, vs 14 steps [ 123 ]) and total step count (15 or 19 steps, respectively, vs 26 steps [ 173 ]), but not in terms of overall yield (17% and 13%, respectively, vs 23% [ 123 ]). The optional implementation of “one pot” reaction sequences suggest that this synthesis may be performed in a very time-efficient manner.…”

Section: Reviewmentioning

confidence: 99%

“…While Burkart’s 2006 paper did not discuss the elaboration of 64 into a protected version of the extended macrolactone core, such attempts were described in a follow-up paper published in 2010 [ 173 ]. Due to problems with the originally envisaged extension of 64 at C14 by means of Wittig or Julia-type olefinations, a number of alternative strategies were explored for the elaboration of the C-linked upper side chain ( Scheme 6 ).…”

Section: Reviewmentioning

confidence: 99%

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The chemistry and biology of mycolactones

Gehringer¹,

Altmann²

2017

Beilstein J. Org. Chem.

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Mycolactones are a group of macrolides excreted by the human pathogen Mycobacterium ulcerans, which exhibit cytotoxic, immunosuppressive and analgesic properties. As the virulence factor of M. ulcerans, mycolactones are central to the pathogenesis of the neglected disease Buruli ulcer, a chronic and debilitating medical condition characterized by necrotic skin ulcers. Due to their complex structure and fascinating biology, mycolactones have inspired various total synthesis endeavors and structure–activity relationship studies. Although this review intends to cover all synthesis efforts in the field, special emphasis is given to the comparison of conceptually different approaches and to the discussion of more recent contributions. Furthermore, a detailed discussion of molecular targets and structure–activity relationships is provided.

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Section: Reviewsupporting

confidence: 90%

Section: Reviewmentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

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The chemistry and biology of mycolactones

Gehringer¹,

Altmann²

2017

Beilstein J. Org. Chem.

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“…Therefore, biological studies with highly defined synthetic mycolactones represent an attractive alternative. Based on the established synthesis of the mycolactone core [27]–[30], different synthesis strategies have been pursued for the stereoselective partial and total synthesis of mycolactones [31]–[33]. In addition, simplified C8-desmethyl-mycolactone analogues have been synthesized, which were analyzed for their cytopathic potency by using cell rounding as a parameter to compare cytotoxic activities [34].…”

Section: Introductionmentioning

confidence: 99%

Structure-Activity Relationship Studies on the Macrolide Exotoxin Mycolactone of Mycobacterium ulcerans

et al. 2013

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BackgroundMycolactones are a family of polyketide-derived macrolide exotoxins produced by Mycobacterium ulcerans, the causative agent of the chronic necrotizing skin disease Buruli ulcer. The toxin is synthesized by polyketide synthases encoded by the virulence plasmid pMUM. The apoptotic, necrotic and immunosuppressive properties of mycolactones play a central role in the pathogenesis of M. ulcerans.Methodology/Principal FindingsWe have synthesized and tested a series of mycolactone derivatives to conduct structure-activity relationship studies. Flow cytometry, fluorescence microscopy and Alamar Blue-based metabolic assays were used to assess activities of mycolactones on the murine L929 fibroblast cell line. Modifications of the C-linked upper side chain (comprising C12–C20) caused less pronounced changes in cytotoxicity than modifications in the lower C5-O-linked polyunsaturated acyl side chain. A derivative with a truncated lower side chain was unique in having strong inhibitory effects on fibroblast metabolism and cell proliferation at non-cytotoxic concentrations. We also tested whether mycolactones have antimicrobial activity and found no activity against representatives of Gram-positive (Streptococcus pneumoniae) or Gram-negative bacteria (Neisseria meningitis and Escherichia coli), the fungus Saccharomyces cerevisae or the amoeba Dictyostelium discoideum.ConclusionHighly defined synthetic compounds allowed to unambiguously compare biological activities of mycolactones expressed by different M. ulcerans lineages and may help identifying target structures and triggering pathways.

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“…We next applied an esterification and RCM protocol derived from our prior synthetic endeavors. 19,8 Acid 17 was coupled to alcohol 18 to afford ester 19 . The conversion from 14 to 19 was ideally conducted in a single direct sequence without long term storage or purification.…”

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confidence: 99%

Structure of FD-895 Revealed through Total Synthesis

Villa¹,

Mandel²,

Jones³

et al. 2012

Org. Lett.

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The total synthesis of FD–895 was completed through a strategy that featured the use of a tandem esterification ring–closing metathesis (RCM) process to construct the 12–membered macrolide and a modified Stille coupling to append the side chain. These studies combined with detailed analysis of all four possible C16–C17 stereoisomers, was used to confirm the structure of FD–895 and identify an analog with an enhanced sub-nanomolar bioactivity.

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Synthetic studies on the mycolactone core

Cited by 19 publications

References 62 publications

The chemistry and biology of mycolactones

The chemistry and biology of mycolactones

Structure-Activity Relationship Studies on the Macrolide Exotoxin Mycolactone of Mycobacterium ulcerans

Structure of FD-895 Revealed through Total Synthesis

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