Synthesis and antiproliferative activity of culicinin D analogues containing simplified AHMOD-based residues

Louise A Stubbing; Iman Kavianinia; Maria R Abbattista; Paul W R Harris; Jeff B Smaill; Adam V Patterson; Margaret A Brimble

doi:10.1016/j.ejmech.2019.05.052

Synthesis and antiproliferative activity of culicinin D analogues containing simplified AHMOD-based residues

Eur J Med Chem. 2019 Sep 1:177:235-246. doi: 10.1016/j.ejmech.2019.05.052. Epub 2019 May 23.

Authors

Louise A Stubbing¹, Iman Kavianinia¹, Maria R Abbattista², Paul W R Harris³, Jeff B Smaill², Adam V Patterson², Margaret A Brimble⁴

Affiliations

¹ School of Chemical Sciences, The University of Auckland, 23 Symonds St, Auckland, 1010, New Zealand; The Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland, 1010, New Zealand.
² The Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland, 1010, New Zealand; Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland, 1010, New Zealand.
³ School of Chemical Sciences, The University of Auckland, 23 Symonds St, Auckland, 1010, New Zealand; The Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland, 1010, New Zealand; School of Biological Sciences, The University of Auckland, 3A Symonds St, Auckland, 1010, New Zealand.
⁴ School of Chemical Sciences, The University of Auckland, 23 Symonds St, Auckland, 1010, New Zealand; The Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland, 1010, New Zealand; School of Biological Sciences, The University of Auckland, 3A Symonds St, Auckland, 1010, New Zealand. Electronic address: m.brimble@auckland.ac.nz.

PMID: 31152989
DOI: 10.1016/j.ejmech.2019.05.052

Abstract

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 cells. An SAR study focusing on replacement of the AHMOD residue was undertaken, culminating in the revelation that a 6-hydroxy or 6-keto substituent was essential to retain potent low nanomolar antiproliferative activity.

Keywords: AHMOD; Cancer; Culicinin D; Peptaibol; Toxin.

MeSH terms

Amino Acid Substitution
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Decanoic Acids / chemistry
Drug Screening Assays, Antitumor
Humans
Oligopeptides / chemical synthesis
Oligopeptides / chemistry
Oligopeptides / pharmacology*
Peptaibols / chemical synthesis
Peptaibols / chemistry
Peptaibols / pharmacology*
Stereoisomerism
Structure-Activity Relationship

Substances

2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid
Antineoplastic Agents
Decanoic Acids
Oligopeptides
Peptaibols
culicinin D