2. Academic Validation
  3. Semisynthetic derivatives of the fungal metabolite eupenifeldin via targeting the tropolone hydroxy groups

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.
Zeinab Y Al Subeh 1,  Herma C Pierre 2,  Ross H Bockbrader 3,  Robert J Tokarski 2nd 3,  Amanda C Maldonado 4,  Monica A Haughan 4,  Manuel E Rangel-Grimaldo 2,  Cedric J Pearce 5,  Joanna E Burdette 4,  James R Fuchs 6,  Nicholas H Oberlies 7
Affiliations

Affiliations

  • 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].
PMID: 38964520 DOI: 10.1016/j.bmcl.2024.129875
Abstract

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.

Keywords

Bis-tropolone; Eupenifeldin; Fungal metabolites; Meroterpenoids; Semisynthetic analogues.

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