Semisynthetic Derivatives of the Verticillin Class of Natural Products through Acylation of the C11 Hydroxy Group

Abstract

The verticillins, a class of epipolythiodioxopiperazine alkaloids (ETPs) first described 50 years ago with the discovery of verticillin A (1), have gained attention due to their potent activity against cancer cells, noted both in vitro and in vivo. In this study, the complex scaffold afforded through optimized fermentation was used as a feedstock for semisynthetic efforts designed to explore the reactivity of the C11 and C11' hydroxy substituents. Functionality introduced at these positions would be expected to impact not only the potency but also the pharmacokinetic properties of the resulting compound. With this in mind, verticillin H (2) was used as a starting material to generate nine semisynthetic analogues (4-12) containing a variety of ester, carbonate, carbamate, and sulfonate moieties. Likewise, verticillin A succinate (13) was synthesized from 1 to demonstrate the successful application of this strategy to other ETPs. The synthesized compounds and their corresponding starting materials (i.e., 1 and 2) were screened for activity against a panel of melanoma, breast, and ovarian cancer cell lines: MDA-MB-435, MDA-MB-231, and OVCAR3. All analogues retained IC₅₀ values in the nanomolar range, comparable to, and in some cases more potent than, the parent compounds.

Figure 1

Structures of symmetric (verticillin A (1) and verticillin H (2)) and asymmetric (Sch 52901 (3)) analogues biosynthesized by Clonostachys rogersoniana (strain MSX59553).

Figure 2

Comparison of the ¹H NMR spectra in CDCl₃ (500 MHz) of verticillin H (2, top) and the acetylated analogue 4. The reaction was monitored via ¹H NMR by tracking the asymmetry that appeared mainly in the aromatic region (δ_H 6.5–8.0) through acylation of the alcohol at the C11 position.