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.

Figure 1.

Structures of hypothemycin and (5Z)-7-oxozeaenol (A) and mechanism of TAK1 inhibition (B).

Figure 2.

Comparison of three approaches to diol analogues. Approach III was pursued in this study.

Scheme 1.

Routes to functionalize C8-C9 diol of hypothemycin. (See Supporting Information for yields of individual structures and yields).

Scheme 2.

Synthesis of heterocyclic analogues.