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Semisynthesis of Hypothemycin Analogues Targeting the C8-C9 Diol.

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.

SUBMITTER: Al Subeh ZY

PROVIDER: S-EPMC9677340 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Semisynthesis of Hypothemycin Analogues Targeting the C8-C9 Diol.

Al Subeh Zeinab Y ZY Li Tian T Ustoyev Abraham A Obike Jennifer C JC West Philip M PM Khin Manead M Burdette Joanna E JE Pearce Cedric J CJ Oberlies Nicholas H NH Croatt Mitchell P MP

Journal of natural products 20220714 8

Hypothemycin, an epoxide derivative of (5<i>Z</i>)-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 inhibi ...[more]

PMID: 35834411

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