Cyclopeptides from the Mushroom Pathogen Fungus Cladobotryum varium

• Published in: Journal of natural products (Washington, D.C.) D.C.), 2021-02, Vol.84 (2), p.327-338
• Main Authors: Zhou, Tao, Katsuragawa, Misaki, Xing, Tian, Fukaya, Keisuke, Okuda, Toru, Tokiwa, Toshiyuki, Tashiro, Etsu, Imoto, Masaya, Oku, Naoya, Urabe, Daisuke, Igarashi, Yasuhiro
• Format: Article
• Language: English
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.0c00980

Three new cyclopeptides with serial Phe residues were identified with the aid of HPLC-DAD analysis, from the culture broth of Cladobotryum varium, a fungal pathogen causing mushroom cobweb disease. Cladoamides A (1) and B (2) have two consecutive N-methylphenylalanine units in the destruxin class cyclic depsipentapeptide framework, while cladoamide C (3) has a three consecutive Phe motif in a cyclopentapeptide structure. Of these three cyclopeptides, 1 showed potent autophagy-inducing activity at 10 μg/mL, comparable to a positive control, rapamycin. For the determination of the absolute configurations of the Ile residues in 1 and 3, new conditions for separating Ile and allo-Ile, using a pentafluorophenyl-bonded solid phase and methanolic solvent, were established within the analytical scheme of the advanced Marfey’s method, thus offering a convenient alternative to the C3 Marfey’s method, which requires elution with a three-solvent mixture. The sequence of two d-Phe and one l-Phe in 3 was determined through NMR chemical shift prediction by DFT-based calculations and chemical synthesis, which demonstrated the significance of noncovalent interactions in the accurate calculation of stable conformers for peptides with multiple aromatic rings.