Poster Presentation 6th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2017

Naturally occurring AHMOD-containing peptaibiotics, a promising source for the development of a new class of drugs (#48)

Iman Kavianinia 1 2 , Louise A Stubbing 1 2 , Margaret A Brimble 1 2
  1. Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand
  2. School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand

 

Peptides are rapidly changing the pharmaceutical landscape due to their virtually non-toxic profile, high specificity and affinity for receptor targets, less immunogenicity than recombinant proteins and antibodies and ease of manufacture by solid phase synthesis. Peptaibiotics belong to a constantly growing family of biologically active peptides, and are characterised by a high proportion of 2-aminoisobutyric acid residues (Aib). A small subset of these peptides also have the unusual non-natural amino acid, 2-amino-6- hydroxy-4-methyl-8-oxodecanoic acid (AHMOD) in common, such as culicinin D and trichoderin A. Culicinin D is a 10mer linear peptide isolated from the fungus Culicinomyces clavisporus. This natural product was shown to exhibit strong growth inhibition against PTEN-deficient MDA468 breast tumour cells. An Fmoc-based solid phase peptide synthesis strategy was utilised for the synthesis of the peptaibol framework of culicinin D due to the presence of the highly acid-sensitive AHMOD residue.1 The low loading of the C-terminal aminoalcohol to the solid support was overcome by using an O–N acyl transfer reaction, and the high potency of the synthetic peptide was found to be comparable to the isolated product.2 Trichoderin A is a 10-residue member of the trichoderin family isolated from a marine sponge-derived fungus of Trichoderma sp and was reported to exhibit significant activity against several strains of mycobacteria including Mycobacterium tuberculosis H37Rv. A late-stage solution phase C-terminal coupling was employed to effectively introduce the C-terminal aminoalcohol moiety, and this proved to be the significant factor to enable an efficient synthesis.3 The AHMOD-containing subfamily of peptaibiotics exhibit an array of interesting biological activities, whilst having a high degree of structural similarity.4 Flexible synthetic access to both (2S,4S,6S)-AHMOD,5 and its (2S,4S,6R)-epimer enabled the synthesis and structures of this intriguing subfamily to be confirmed, and also structure–activity relationship studies of these natural products to be conducted.

  1. Hung, K.y.; Harris, P. W.; Brimble, M. A., Synthesis of the peptaibol framework of the anticancer agent culicinin D: stereochemical assignment of the AHMOD moiety. Organic letters 2012, 14 (22), 5784-5787.
  2. Stach, M.; Weidkamp, A. J.; Yang, S. H.; Hung, K. y.; Furkert, D. P.; Harris, P. W.; Smaill, J. B.; Patterson, A. V.; Brimble, M. A., Improved Strategy for the Synthesis of the Anticancer Agent Culicinin D. European Journal of Organic Chemistry 2015, 2015 (28), 6341-6350.
  3. Kavianinia, I.; Kunalingam, L.; Harris, P. W.; Cook, G. M.; Brimble, M. A., Total Synthesis and Stereochemical Revision of the Anti-Tuberculosis Peptaibol Trichoderin A. Organic Letters 2016, 18, 3878−3881.
  4. Stubbing, L. A.; Kavianinia, I.; Brimble, M. A., Synthesis of AHMOD-containing aminolipopeptides, unique bioactive peptaibiotics. Organic & Biomolecular Chemistry 2017, 15, 3542-3549
  5. Ko, K.Y.; Wagner, S.; Yang, S.-H.; Furkert, D. P.; Brimble, M. A., Improved Synthesis of the Unnatural Amino Acids AHMOD and AMD, Components of the Anticancer Peptaibol Culicinin D. The Journal of organic chemistry 2015, 80 (17), 8631-8636.