Total Synthesis of the Macrolide Antitumor Antibiotic Lankacidin C

Kende, Andrew S.; Liu, Kun; Káldor, István; Dorey, Gilbert; Koch, Kevin

doi:10.1021/ja00136a025

Cited by 98 publications

(37 citation statements)

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“…Cleavage of the acetonide moiety in 36 with CuCl 2 ⋅2H 2 O51 followed by regioselective PMB protection of the primary hydroxyl group in the resulting diol via a cyclic Sn‐acetal52 then concluded the alternative synthesis of secondary alcohol 20 . In comparison to the D ‐aspartic acid‐based route depicted in Scheme , the malic acid‐based approach to 20 involved more steps (22 steps for the longest linear sequence vs 14 from D ‐aspartic acid) and provided the target alcohol in lower overall yield (2.1 vs 17 %).…”

Section: Resultsmentioning

confidence: 99%

Total Synthesis of (−)‐Zampanolide and Structure–Activity Relationship Studies on (−)‐Dactylolide Derivatives

Zurwerra¹,

Glaus²,

Betschart³

et al. 2012

Chemistry A European J

116

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A new total synthesis of the marine macrolide (-)-zampanolide (1) and the structurally and stereochemically related non-natural levorotatory enantiomer of (+)-dactylolide (2), that is, ent-2, has been developed. The synthesis features a high-yielding, selective intramolecular Horner-Wadsworth-Emmons (HWE) reaction to close the 20-membered macrolactone ring of 1 and ent-2. The β-keto phosphonate/aldehyde precursor for the ring-closure reaction was obtained by esterification of a ω-diethylphosphono carboxylic acid fragment and a secondary alcohol fragment incorporating the THP ring that is embedded in the macrocyclic core structure of 1 and ent-2. THP ring formation was accomplished through a segment coupling Prins-type cyclization. Employing the same overall strategy, 13-desmethylene-ent-2 as well as the monocyclic desTHP derivatives of 1 and ent-2 were prepared. Synthetic 1 inhibited human cancer cell growth in vitro with nM IC(50) values, while ent-2, which lacks the diene-containing hemiaminal-linked side chain of 1, is 25- to 260-fold less active. 13-Desmethylene-ent-2 as well as the reduced versions of ent-2 and 13-desmethylene-ent-2 all showed similar cellular activity as ent-2 itself. The same activity level was attained by the monocyclic desTHP derivative of 1. Oxidation of the aldehyde functionality of ent-2 gave a carboxylic acid that was converted into the corresponding N-hexyl amide. The latter showed only μM antiproliferative activity, thus being several hundred-fold less potent than 1.

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Section: Resultsmentioning

confidence: 99%

Total Synthesis of (−)‐Zampanolide and Structure–Activity Relationship Studies on (−)‐Dactylolide Derivatives

Zurwerra¹,

Glaus²,

Betschart³

et al. 2012

Chemistry A European J

116

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show abstract

“…Taking into account the presence of the sensitive oxirane in 43 , silyl ether deprotection was first attempted by using TAS‐F as source of fluoride anion, but slow degradation of the starting product was observed. Successful deprotection to 29 (74 % yield) was achieved upon treating the silyl ether 43 with a solution of formic acid in THF/H 2 O at 0 °C for 6 h 49…”

Section: Resultsmentioning

confidence: 99%

Total Synthesis of Enantiopure Pyrrhoxanthin: Alternative Methods for the Stereoselective Preparation of 4‐Alkylidenebutenolides

Vaz

Otero

Álvarez

et al. 2013

Chemistry A European J

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A new stereocontrolled total synthesis of the configurationally labile C37 -norcarotenoid pyrrhoxanthin in enantiopure form has been completed. A highly stereoselective Horner-Wadsworth-Emmons (HWE) condensation of a C17-allylphosphonate and a C20-aldehyde was used as the last conjunctive step. Both a Sonogashira reaction to form the C17-phosphonate and the final HWE condensation proved to be compatible with the sensitive C7-C10 enyne E configuration. Regioselective (5-exo-dig) silver-promoted lactonization reactions of three alternative pent-2-en-4-ynoic acid precursors with increased complexity, including a fully functionalized C20-fragment, were explored for the preparation of the γ-alkylidenebutenolide fragment. This survey extends the existing methodologies for the preparation of oxygen-containing carotenoids (xanthophylls) and streamlines the synthesis of additional members of the C37-norcarotenoid butenolide family of natural products.

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“…Particularly intriguing is the presence of a hybrid trans -AT PK-NRPS gene cluster only in the type strain P. axinellae AD2. trans -AT PKS systems are involved in the biosynthesis of many pharmacologically important polyketides, such as the antibiotic mupirocin ( El-Sayed et al, 2003 ) and lankacidin, which possesses antitumor activities ( Kende et al, 1995 ). This type of PKS differs from the canonical PKS (also called “ cis AT-PKS”) because it has free-standing AT domains, as opposed to the integrated AT domains found within the modules of cis AT-PK multienzyme systems ( Piel, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of Secondary Metabolite Gene Clusters in the Pseudovibrio Genus Reveals Encouraging Biosynthetic Potential toward the Production of Novel Bioactive Compounds

et al. 2017

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Increased incidences of antimicrobial resistance and the emergence of pan-resistant ‘superbugs’ have provoked an extreme sense of urgency amongst researchers focusing on the discovery of potentially novel antimicrobial compounds. A strategic shift in focus from the terrestrial to the marine environment has resulted in the discovery of a wide variety of structurally and functionally diverse bioactive compounds from numerous marine sources, including sponges. Bacteria found in close association with sponges and other marine invertebrates have recently gained much attention as potential sources of many of these novel bioactive compounds. Members of the genus Pseudovibrio are one such group of organisms. In this study, we interrogate the genomes of 21 Pseudovibrio strains isolated from a variety of marine sources, for the presence, diversity and distribution of biosynthetic gene clusters (BGCs). We expand on results obtained from antiSMASH analysis to demonstrate the similarity between the Pseudovibrio-related BGCs and those characterized in other bacteria and corroborate our findings with phylogenetic analysis. We assess how domain organization of the most abundant type of BGCs present among the isolates (Non-ribosomal peptide synthetases and Polyketide synthases) may influence the diversity of compounds produced by these organisms and highlight for the first time the potential for novel compound production from this genus of bacteria, using a genome guided approach.

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Total Synthesis of the Macrolide Antitumor Antibiotic Lankacidin C

Cited by 98 publications

References 0 publications

Total Synthesis of (−)‐Zampanolide and Structure–Activity Relationship Studies on (−)‐Dactylolide Derivatives

Total Synthesis of (−)‐Zampanolide and Structure–Activity Relationship Studies on (−)‐Dactylolide Derivatives

Total Synthesis of Enantiopure Pyrrhoxanthin: Alternative Methods for the Stereoselective Preparation of 4‐Alkylidenebutenolides

Identification of Secondary Metabolite Gene Clusters in the Pseudovibrio Genus Reveals Encouraging Biosynthetic Potential toward the Production of Novel Bioactive Compounds

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