Chemoreactive 2,5-Diketopiperazines from a Penicillium sp., Structure Revision of Reported Analogues and Proposed Facile Transformation Pathways

• Published in: Journal of natural products (Washington, D.C.) Vol. 87; no. 7; pp. 1826 - 1837
• Main Authors: Khong, Quan T., Smith, Emily A., Wendt, Karen L., Dalilian, Masoumeh, Goncharova, Ekaterina I., Brownell, Isaac, Cichewicz, Robert H., Henrich, Curtis J., Beutler, John A., O’Keefe, Barry R., Du, Lin
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society and American Society of Pharmacognosy 26.07.2024
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; Diketopiperazines - chemistry; Diketopiperazines - pharmacology; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Penicillium - chemistry
• ISSN: 0163-3864; 1520-6025; 1520-6025
• DOI: 10.1021/acs.jnatprod.4c00478

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous cancer. Two new prenylated indole 2,5-diketopiperazine alkaloids, brevianamides E1 (1) and E2 (2), were isolated from a Penicillium fungus. Both compounds showed moderate cytotoxic activity against select MCC cell lines (i.e., MCC13, MKL-1, UISO, and WaGa) in the low micromolar range. The relative and absolute configurations of 1 and 2 were determined by combined approaches, including NOESY spectroscopy, DFT ECD and DP4 plus calculations, and Marfey’s reaction. Literature research and the comparison of NMR and ECD data led to the structure revision of three previously reported natural analogues, notoamides K and P and asperversiamide L. The structurally unstable 1 and 2 underwent steady interconversion under neutral aqueous conditions. Investigation of the degradation of 2 in acidic methanol solutions led to the identification of a new methoxylated derivative (6) and two new ring-opened products (7 and 8) with the rearranged, elongated, 4-methylpent-3-ene side chain. The facile transformation of 2 to 7 and 8 was promoted by the intrinsic impurity (i.e., formaldehyde) of HPLC-grade methanol through the aza-Cope rearrangement.