Semisynthetic derivatives of the fungal metabolite eupenifeldin via targeting the tropolone hydroxy groups
- Bioorg Med Chem Lett. 2024 Sep 15:110:129875. doi: 10.1016/j.bmcl.2024.129875.
- 1. Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan; Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, P.O. Box 26170, Greensboro, NC 27402, United States.
- 2. Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, P.O. Box 26170, Greensboro, NC 27402, United States.
- 3. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, 500 W. 12(th) Ave., Columbus, OH 43210, United States.
- 4. Department of Pharmaceutical Sciences, University of Illinois at Chicago, 900 S. Ashland Ave (M/C 870), Chicago, IL 60607, United States.
- 5. Mycosynthetix, Inc., Hillsborough, NC 27278, United States.
- 6. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, 500 W. 12(th) Ave., Columbus, OH 43210, United States. Electronic address: [email protected].
- 7. Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, P.O. Box 26170, Greensboro, NC 27402, United States. Electronic address: [email protected].
Eupenifeldin (1) is a Fungal secondary metabolite possessing bis-tropolone moieties that demonstrates nanomolar cytotoxic activity against a number of Cancer cell types. As a potential Anticancer lead, this meroterpenoid was used to access 29 semisynthetic analogues via functionalization of the reactive hydroxy groups of the bis-tropolones. A series of ester (2-6), carbonate (7-8), sulfonate (9-16), carbamate (17-20), and ether (21-30) analogues of 1 were generated via 22 reactions. Most of these compounds were disubstituted, produced via functionalization of both of the tropolonic hydroxy moieties, although three mono-functionalized analogues (6, 8, and 24) and one tri-functionalized analogue (3) were also obtained. The cytotoxic activities of 1-30 were evaluated against human melanoma and ovarian Cancer cell lines (i.e., MDA-MB-435 and OVCAR3, respectively). Ester and carbonate analogues of 1 (i.e., 2-8) maintained cytotoxicity at the nanomolar level, and the greatest improvement in aqueous solubility came from the monosuccinate analogue (6), which was acylated on the secondary hydroxy at the 11 position.