Poster Presentation 7th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2019

Synthesis and antiproliferative activity of culicinin D analogues containing simplified AHMOD-based residues (#131)

Louise A Stubbing 1 2 , Iman Kavianinia 1 2 , Maria R Abbattista 2 3 , Paul WR Harris 1 2 , Jeffrey B Smaill 2 3 , Adam V Patterson 2 3 , Margaret A Brimble 1 2
  1. University of Auckland, Auckland, New Zealand
  2. The Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
  3. Auckland Cancer Society Research Centre, Auckland, New Zealand

Culicinin D is a 10 amino acid peptaibol containing a rare and synthetically challenging (2S,4S,6R)-AHMOD residue, that exhibits potent antiproliferative activity against MDA-MB-468 cancer cells. The AHMOD residue, in particular, has presented a significant obstacle to synthesis of culicinin D and other AHMOD-containing peptaibols due to the difficulty of synthesis in addition to the chemical sensitivity of the β-hydroxyketone motif.

Here we report the third-generation total synthesis of culicinin D using a strategy that employs a combination of both solid- and solution-phase synthesis. We have taken advantage of the versatility of this synthetic method to design and prepare a series of peptides based on the culicinin D framework, with structurally simpler building blocks in place of (2S,4S,6R)-AHMOD. A structure-activity relationship based on the AHMOD residue in these peptaibols is also established. Importantly, the simplified AHMOD building blocks are far more synthetically tractable than (2S,4S,6R)-AHMOD, and further, enable more efficient assembly of the peptaibol skeleton due to the lack of a sensitive β-hydroxyketone that affords undesired elimination byproducts.