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, Table of Contents

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

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

› Author Affiliations

Abstract

All articles of this category

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

Full Text

References

References
1 He H, Janso JE, Yang HY, Bernan VS, Lin SL, Yu K. J. Nat. Prod. 2006; 69: 736
2 Porta C, Paglino C, Mosca A. Front. Oncol. 2014; 4: 64
3 Hanahan D, Weinberg RA. Cell 2011; 144: 646
4 Zhang W, Sun T.-T, Li Y.-X. J. Pept. Sci. 2009; 15: 366
5 Hung K, Harris PW. R, Brimble MA. Org. Lett. 2012; 14: 5784
6 Stach M, Weidkamp AJ, Yang S.-H, Hung K, Furkert DP, Harris PW. R, Smaill JB, Patterson AV, Brimble MA. Eur. J. Org. Chem. 2015; 6341
7 Stubbing LA, Kavianinia I, Abbattista MR, Harris PW. R, Smaill JB, Patterson AV, Brimble MA. Eur. J. Med. Chem. 2019; 177: 235
8 Kavianinia I, Stubbing LA, Abbattista MR, Harris PW. R, Smaill JB, Patterson AV, Brimble MA. Bioorg. Med. Chem. Lett. 2020; 30: 127135
9 Li FF, Stubbing LA, Kavianinia I, Abbattista MR, Harris PW. R, Smaill JB, Patterson AV, Brimble MA. Bioorg. Med. Chem. Lett. 2020; 30: 127331
10 Kavianinia I, Kunalingam L, Harris PW. R, Cook GM, Brimble MA. Org. Lett. 2016; 18: 3878
11 Vichai V, Kirtikara K. Nat. Protoc. 2006; 1: 1112
12 Mant CT, Zhou NE, Hodges RS. J. Chromatogr. A 1989; 476: 363
13 Bartalis J, Halaweish FT. J. Chromatogr. B 2005; 818: 159
14 Bolt HL, Williams CE. J, Brooks RV, Zuckermann RN, Cobb SL, Bromley EH. C. Pept. Sci. 2017; 108: e23014
15 Chemical Terms (accessed Feb 8, 2021): https://disco.chemaxon.com/calculators/demo/plugins/chemicalterms/
16 Jiménez JC, López-Macià A, Gracia C, Varón S, Carrascal M, Caba JM, Royo M, Francesch AM, Cuevas C, Giralt E, Albericio F. J. Med. Chem. 2008; 51: 4920

Supplementary Material

Supporting Information