2. Academic Validation
  3. Semisynthesis of Hypothemycin Analogues Targeting the C8-C9 Diol

Semisynthesis of Hypothemycin Analogues Targeting the C8-C9 Diol

  • J Nat Prod. 2022 Aug 26;85(8):2018-2025. doi: 10.1021/acs.jnatprod.2c00434.
Zeinab Y Al Subeh 1 2,  Tian Li 1,  Abraham Ustoyev 1,  Jennifer C Obike 1,  Philip M West 1,  Manead Khin 3,  Joanna E Burdette 3,  Cedric J Pearce 4,  Nicholas H Oberlies 1,  Mitchell P Croatt 1
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States.
  • 2 Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, 22110, Jordan.
  • 3 Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois 60612, United States.
  • 4 Mycosynthetix, Inc., Hillsborough, North Carolina 27278, United States.
PMID: 35834411 DOI: 10.1021/acs.jnatprod.2c00434
Abstract

Hypothemycin, an epoxide derivative of (5Z)-7-oxozeaenol, was used in the semisynthesis of a series of C8-C9 diol derivatives, with many inhibiting TAK1 at submicromolar concentrations. A step-economical approach was chosen, whereby nonselective reactions functionalized the diol to generate multiple analogues in a single reaction. Using this approach, 35 analogues were synthesized using 12 reactions, providing a wealth of information about the role that the C8-C9 diol plays in TAK1 inhibition and cytotoxicity in ovarian and breast Cancer cell lines. Monofunctionalized analogues exhibited strong inhibition of TAK1, showing potential for modification of this section of the molecule to assist with solubility, formulation, and Other desirable properties. Most analogues were cytotoxic, and three compounds had similar or slightly increased potency with >100-fold improvement in solubility profiles.

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