Boholamide A, an APD-Class, Hypoxia-Selective Cyclodepsipeptide

• Published in: Journal of natural products (Washington, D.C.) D.C.), 2020-04, Vol.83 (4), p.1249-1257
• Main Authors: Torres, Joshua P, Lin, Zhenjian, Fenton, David S, Leavitt, Lee U, Niu, Changshan, Lam, Pui-Ying, Robes, Jose Miguel, Peterson, Randall T, Concepcion, Gisela P, Haygood, Margo G, Olivera, Baldomero M, Schmidt, Eric W
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; Biological Products - chemistry; Biological Products - isolation & purification; Biological Products - pharmacology; Calcium - chemistry; Calcium - metabolism; Cytotoxins - chemistry; Cytotoxins - pharmacology; Depsipeptides - chemistry; Depsipeptides - isolation & purification; Depsipeptides - pharmacology; Hypoxia - physiopathology; Molecular Structure; Neoplasms
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.0c00038

Calcium homeostasis is implicated in some cancers, leading to the possibility that selective control of calcium might lead to new cancer drugs. On the basis of this idea, we designed an assay using a glioblastoma cell line and screened a collection of 1000 unique bacterial extracts. Isolation of the active compound from a hit extract led to the identification of boholamide A (1), a 4-amido-2,4-pentadieneoate (APD)-class peptide. Boholamide A (1) applied in the nanomolar range induces an immediate influx of Ca2+ in glioblastoma and neuronal cells. APD-class natural products are hypoxia-selective cytotoxins that primarily target mitochondria. Like other APD-containing compounds, 1 is hypoxia selective. Since APD natural products have received significant interest as potential chemotherapeutic agents, 1 provides a novel APD scaffold for the development of new anticancer compounds.