Alanine scan-guided synthesis and biological evaluation of analogues of culicinin D, a potent anticancer peptaibol

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

doi:10.1016/j.bmcl.2020.127135

Alanine scan-guided synthesis and biological evaluation of analogues of culicinin D, a potent anticancer peptaibol

Bioorg Med Chem Lett. 2020 Jun 1;30(11):127135. doi: 10.1016/j.bmcl.2020.127135. Epub 2020 Mar 23.

Authors

Iman Kavianinia¹, Louise A Stubbing¹, 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: 32229061
DOI: 10.1016/j.bmcl.2020.127135

Abstract

Culicinin D (1), a 10 amino acid peptaibol originally isolated from Culicinomyces clavisporus, exhibits potent activity against a range of cancer cell lines. Building on our previous work exploring the structure-activity relationship (SAR) of the unusual (2S,4S,6R)-AHMOD residue, a series of analogues of culicinin D were prepared to further investigate the SAR of these peptaibols. Alanine scanning of a potent and readily accessible analogue 23 revealed the effect of each residue on antiproliferative activity, and a small panel of analogues were prepared to explore the SAR of the non-natural amino acid residue (2S,4R)-AMD. Results from the alanine scan were used to design an expanded library of culicinin D analogues, leading to the discovery of cyclohexylalanine analogue 52, which exhibited better antiproliferative activity than the natural product 1.

Keywords: Cancer; Culicinin D; Peptaibol.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alanine / chemistry*
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor
Humans
Hypocreales / chemistry
Hypocreales / metabolism
Oligopeptides / chemical synthesis
Oligopeptides / chemistry*
Oligopeptides / pharmacology
Peptaibols / chemical synthesis
Peptaibols / chemistry*
Peptaibols / pharmacology
Structure-Activity Relationship

Substances

Antineoplastic Agents
Oligopeptides
Peptaibols
culicinin D
Alanine