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.
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.
Bioorg Med Chem Lett. 2020 Jun 1;30(11):127135. doi: 10.1016/j.bmcl.2020.127135. Epub 2020 Mar 23.
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.
Culicinin D (1)，一种最初从 Culicinomyces clavisporus 中分离出来的 10 个氨基酸的肽类抗生素，对多种癌细胞系表现出很强的活性。在我们之前研究不寻常的 (2S,4S,6R)-AHMOD 残基的结构-活性关系 (SAR) 的工作基础上，我们制备了一系列 culicinin D 的类似物，以进一步研究这些肽类抗生素的 SAR。对一种有效且易于获得的类似物 23 进行丙氨酸扫描，揭示了每个残基对增殖活性的影响，并用一组小类似物来探索非天然氨基酸残基 (2S,4R)-AMD 的 SAR。丙氨酸扫描的结果被用来设计一个扩展的 culicinin D 类似物文库，导致发现了环己基丙氨酸类似物 52，其具有比天然产物 1 更好的增殖抑制活性。
