Synthesis
DOI: 10.1055/s-0040-1706264
special topic
Special Issue dedicated to Prof. Sarah Reisman, recipient of the 2019 Dr. Margaret Faul Women in Chemistry Award

Fourth-Generation Analogues of the Anticancer Peptaibol Culicinin D: Probing the Effects of Hydrophobicity and Halogenation on Cytotoxicity

a  School of Biological Sciences, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand
b  Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand
,
Iman Kavianinia
a  School of Biological Sciences, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand
c  School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand
,
Matthew Bull
b  Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand
d  Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand
,
Paul W. R. Harris
a  School of Biological Sciences, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand
c  School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand
,
Jeff B. Smaill
b  Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand
d  Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand
,
Adam V. Patterson
b  Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand
d  Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand
,
a  School of Biological Sciences, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand
c  School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand
› Author Affiliations
This work was supported by the Health Research Council of New Zealand (#18/219), the Maurice Wilkins Centre for Molecular Biodiscovery, and Uniservices Return on Science.


Abstract

Preliminary results of the effect of hydrophobicity and halogenation on the cytotoxicity of the anticancer peptaibol culicinin D are reported. Building on previous work, the synthetically challenging (2S,4S,6R)-2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid and (2S,4R)-2-amino-4-methyldecanoic acid building blocks were replaced with derivatives of l-phenylalanine and 2-aminodecanoic acid, respectively. Substitution of (2S,4S,6R)-2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid with l-4,4′-biphenylalanine yielded an analogue that was tenfold more potent than the natural product and was also the most hydrophobic analogue, as judged by an antiproliferative IC50 assay and logD calculations; these results suggest that the potency of culicinin D may be governed by its hydrophobicity. However, the introduction of halogenated moieties into the peptide sequence generated analogues that were similarly potent, although not necessarily hydrophobic. Thus, the parameters regulating the cytotoxicity of culicinin D, and by extension other peptaibols, are multimodal and include both halogenation and hydrophobicity.

Supporting Information



Publication History

Received: 11 March 2021

Accepted after revision: 26 April 2021

Publication Date:
10 June 2021 (online)

© 2021. Thieme. All rights reserved

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