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

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

Publication History

Received: 11 March 2021

Accepted after revision: 26 April 2021

Article published online:
10 June 2021

• 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