Synthesis of the Peptaibol Framework of the Anticancer Agent Culicinin D: Stereochemical Assignment of the AHMOD Moiety

Hung, Kuo-yuan; Harris, Paul W. R.; Brimble, Margaret A.

doi:10.1021/ol302852q

Cited by 29 publications

(61 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This allowed the stereospecific assignment of CβH2 protons of AHMOD, and ROESY contacts between the Cδ2 methyl group and CβH2 protons reveal the S-configuration of the stereo center. The 4-S configuration of AHMOD was previously confirmed for the other peptaibol [ 10 ]. The further analysis of AHMOD configuration is impossible, because the χ3 and following side chain angles are not fixed in the certain conformation and Cδ1H2 protons are not resolved, which leaves the configuration of stereo center 6 (Cε1) undefined.…”

Section: Resultssupporting

confidence: 62%

“…The further analysis of AHMOD configuration is impossible, because the χ3 and following side chain angles are not fixed in the certain conformation and Cδ1H2 protons are not resolved, which leaves the configuration of stereo center 6 (Cε1) undefined. However, 6-R configuration may be expected based on the structures of other AHMOD-containing peptaibols [ 10 ]. Similarly, we failed to determine the configuration of C1 center in the C-terminal N -(2-Hydroxyethyl)-1,2-propanediamine.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

A Novel Lipopeptaibol Emericellipsin A with Antimicrobial and Antitumor Activity Produced by the Extremophilic Fungus Emericellopsis alkalina

et al. 2018

View full text Add to dashboard Cite

Soil fungi are known to contain a rich variety of defense metabolites that allow them to compete with other organisms (fungi, bacteria, nematodes, and insects) and help them occupy more preferential areas at the expense of effective antagonism. These compounds possess antibiotic activity towards a wide range of other microbes, particularly fungi that belong to different taxonomical units. These compounds include peptaibols, which are non-ribosomal synthesized polypeptides containing non-standard amino acid residues (alpha-aminoisobutyric acid mandatory) and some posttranslational modifications. We isolated a novel antibiotic peptide from the culture medium of Emericellopsis alkalina, an alkalophilic strain. This peptide, called emericellipsin A, exhibited a strong antifungal effect against the yeast Candida albicans, the mold fungus Aspergillus niger, and human pathogen clinical isolates. It also exhibited antimicrobial activity against some Gram-positive and Gram-negative bacteria. Additionally, emericellipsin A showed a significant cytotoxic effect and was highly active against Hep G2 and HeLa tumor cell lines. We used NMR spectroscopy to reveal that this peptaibol is nine amino acid residues long and contains non-standard amino acids. The mode of molecular action of emericellipsin A is most likely associated with its effects on the membranes of cells. Emericellipsin A is rather short peptaibol and could be useful for the development of antifungal, antibacterial, or anti-tumor remedies.

show abstract

Section: Resultssupporting

confidence: 62%

Section: Resultsmentioning

confidence: 99%

A Novel Lipopeptaibol Emericellipsin A with Antimicrobial and Antitumor Activity Produced by the Extremophilic Fungus Emericellopsis alkalina

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The combined organic extracts were dried over anhydrous Na 2 SO 4 and concentrated in vacuo.3H, J = 6.5 Hz). Spectroscopic data were in agreement with that reported in the literature 3. To a solution of 18b (50 mg, 0.11 mmol) in THF (5 mL) was added 2 M HCl (5 mL).…”

supporting

confidence: 86%

“…Our group recently reported the total synthesis of culicinin D and confirmed the stereochemistry of the hydroxyl group in the AHMOD unit. 3 The key unnatural amino acids, Fmoc-AMD-OH (2) and Fmoc-AHMOD-OH (3), were prepared in 15% (13 steps) and 3% (12 steps) yields, respectively (Schemes 1 and 2), starting from propionyl (1S,2S)- 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 pseudoephedrine (4). In this study we established that installation of the sidechain methyl group could be achieved by stereoselective Myers alkylation of propionate 4, 4 followed by reductive removal of the auxiliary and conversion to the iodide (5).…”

Section: Introductionmentioning

confidence: 99%

Improved Synthesis of the Unnatural Amino Acids AHMOD and AMD, Components of the Anticancer Peptaibol Culicinin D

Wagner

Yang

et al. 2015

J. Org. Chem.

Self Cite

View full text Add to dashboard Cite

An improved second-generation synthesis of the unnatural amino acid components of the anticancer peptaibol culicinin D has been developed. With a protected glutamic acid derivate as the starting material, the process readily delivered the Fmoc-protected free acid derivatives of AHMOD ((2S)-amino-(6R)-hydroxy-(4S)-methyl-8-oxodecanoic acid) and AMD ((2S)-amino-(4S)-methyldecanoic acid) required to support solid phase peptide synthesis (SPPS) for structure-activity studies of the natural product. The same approach also provides improved access to pipecolic acid derivatives. A novel Wittig reagent for one-carbon homologation of aldehydes, developed during this work, is also reported.

show abstract

“…The amino-terminal acyl group (M8a) has a 2R configuration at the methylated C atom. The second residue Ahmod has a (2S,4S,6S) configuration, which contradicts the (2S,4S,6R) configuration of the C " atom in the respective residues of the lipoaminopeptaibols trichoderin A (Kavianinia et al, 2016) and culicinin D (Hung et al, 2012). The last residue, Apae/ Amae, has the S configuration at the chiral C atom C1.…”

Section: Figurementioning

confidence: 94%

The crystal structure of the lipoaminopeptaibol helioferin, an antibiotic peptide fromMycogone rosea

Geßmann

Brückner²,

Berg

et al. 2018

Acta Cryst Sect D Struct Biol

View full text Add to dashboard Cite

The crystal structure of the natural nonapeptide antibiotic helioferin has been determined and refined to 0.9 Å resolution. Helioferin consists of helioferin A and B, which contain 2-(2'-aminopropyl)aminoethanol (Apae) and 2-[(2'-aminopropyl)methylamino]ethanol (Amae) at their respective alkanolamine termini. In addition, helioferin contains the unusual amino-acid residues α-aminoisobutyric acid (Aib) and (2S,4S,6S)-2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid (Ahmod). The amino-terminus is capped with 2-methyl-n-1-octanoic acid (M8a). The peptide crystallizes with a 1:1 molar ratio of helioferin A and B in the monoclinic space group C2, with unit-cell parameters a = 34.711, b = 10.886, c = 17.150 Å, β = 93.05°. The peptide backbone folds in a regular right-handed α-helical conformation, with eight intramolecular hydrogen bonds, all but one forming 5→1 interactions. The two aliphatic chains of the fatty-acyl (M8a) and the second residue (Ahmod) extend out of the α-helical structure in opposite directions and lead to a corkscrew-like shape of the peptide molecule. Halogen anions (Cl and F) have been co-crystallized with the peptide molecules, implying a positive charge at the aminoalcohol end of the peptide. In the tightly packed crystal the helices are linked head to tail via the anions by electrostatic, hydrogen-bond and van der Waals interactions, forming continuous helical rods. Two nonparallel rods (forming an angle of 118°) interact directly via hydrogen bonds and via the anions, forming a double layer. Successive double layers are held together only via van der Waals contacts. The helical axes of successive double layers are also related by an angle of 118°. The structure of helioferin reported here and the previously determined structure of the homologous leucinostatin A have a total straight length of about 21 Å, indicating a different membrane-modifying bioactivity from that of long-chain, amphiphilic peptaibols.

show abstract

Synthesis of the Peptaibol Framework of the Anticancer Agent Culicinin D: Stereochemical Assignment of the AHMOD Moiety

Cited by 29 publications

References 29 publications

A Novel Lipopeptaibol Emericellipsin A with Antimicrobial and Antitumor Activity Produced by the Extremophilic Fungus Emericellopsis alkalina

A Novel Lipopeptaibol Emericellipsin A with Antimicrobial and Antitumor Activity Produced by the Extremophilic Fungus Emericellopsis alkalina

Improved Synthesis of the Unnatural Amino Acids AHMOD and AMD, Components of the Anticancer Peptaibol Culicinin D

The crystal structure of the lipoaminopeptaibol helioferin, an antibiotic peptide fromMycogone rosea

Contact Info

Product

Resources

About