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.

Synthesis and Bioactivity Evaluation of Nepetaefolin F and Its Analogues

“…Furthermore, triptobenzene L (7) was Esterification has been considered as a useful method to expand the diversity of candidate compounds and enhance the biological activity. 24,25 With sufficient amount of triptobenzene L (7) in hand, we next set out to streamline the synthesis of derivatives 18−42 at the diol at C3 and C19 positions in a nonselective manner with different carboxylic acids (Scheme 4). In addition, derivatives 43 and 44 were prepared by the treatment of triptobenzene L (7) with triethylamine (TEA) and methanesulfonyl chloride (MsCl) (Scheme 5).…”