Alan J Cameron1,2,3, Emma K Davison1,2,3, Chalice An1,2, Louise A Stubbing1,3, P Rod Dunbar2,3, Paul W R Harris1,2,3, Margaret A Brimble1,2,3. 1. School of Chemical Sciences , University of Auckland , 23 Symonds Street , Auckland , 1010 , New Zealand. 2. School of Biological Sciences , University of Auckland , 3 Symonds Street , Auckland , 1010 , New Zealand. 3. The Maurice Wilkins Centre for Molecular Biodiscovery , The University of Auckland , Private Bag 92019, Auckland , 1142 , New Zealand.
Abstract
The first syntheses of the cytotoxic peptides lipovelutibols B and D are described. While lipovelutibol D was prepared using solid-phase peptide synthesis followed by an O-N acyl migration to install the C-terminal amino alcohol, a different strategy was required to access lipovelutibol B and a series of N-terminal lipid analogues of the natural products. A cytotoxicity structure-activity relationship study revealed that the lipovelutibol D framework, whereby serine is substituted for alanine in the fifth position, provided the most potent analogues. Modification of the lipid tail was generally well tolerated, with longer alkyl chains enhancing analogue cytotoxicity.
The first syntheses of the cytotoxic peptides lipovelutibols B and D are described. While lipovelutibol D was prepared using solid-phase peptide synthesis followed by an O-N acyl migration to install the C-terminal n class="Chemical">amino alcohol, a different strategy was required to access lipovelutibol B and a series of N-terminal lipid analogues of the natural products. A cytotoxicity structure-activity relationship study revealed that the lipovelutibol D framework, whereby serine is substituted for alanine in the fifth position, provided the most potent analogues. Modification of the lipid tail was generally well tolerated, with longer alkyl chains enhancing analogue cytotoxicity.