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

Johanes K. Kasim; Iman Kavianinia; Matthew Bull; Paul W. R. Harris; Jeff B. Smaill; Adam V. Patterson; Margaret A. Brimble

doi:10.1055/s-0040-1706264

Synthesis, Inhaltsverzeichnis

Synthesis 2021; 53(22): 4239-4245
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

Authors

Johanes K. Kasim

^aSchool of Biological Sciences, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand

^bMaurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand
Iman Kavianinia∗

^aSchool of Biological Sciences, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand

^cSchool of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand
Matthew Bull

^bMaurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand

^dAuckland 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

^aSchool of Biological Sciences, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand

^cSchool of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand
Jeff B. Smaill

^bMaurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand

^dAuckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand
Adam V. Patterson

^bMaurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand

^dAuckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand
Margaret A. Brimble ∗

^aSchool of Biological Sciences, The University of Auckland, 3A Symonds Street, Auckland 1010, New Zealand

^cSchool of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand

Abstract

Alle Artikel dieser Rubrik

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.

Key words

anticancer compounds - peptides - peptaibols - culicinin D - hydrophobicity - halogenation - cytotoxicity

Volltext

Referenzen

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