Antiproliferative withanolides from several solanaceous species

Abstract

To date, our work on solanaceous species (Datura wrightii, Jaborosa caulescens, Physalis hispida, Physalis longifolia, Vassobia breviflora and Withania somnifera) has resulted in the isolation of 65 withanolides, 31 of which were new, as well as the semi-synthesis of a further 30 withanolides. Structure identification and MTS assay-based antiproliferative evaluation of these 95 compounds revealed that a Δ(2)-1-oxo functionality in ring A, in conjunction with either a 5β,6β-epoxy or 5α-chloro-6β-hydroxy moiety in ring B, is the minimum structural requirement for withanolides to produce potent cytotoxic activity. Such structure-activity relationship analysis also revealed that oxygenation (the -OH or -OR groups) at C-4, 7, 11 and 12, as well as C-14 to C-28, did not contribute towards the observed antiproliferative activity. Herein, we present a complete overview of our work as it relates to the withanolides reported from 1965 to 2013.

Keywords: Solanaceae; antiproliferative; cytotoxicity; structure–activity relationship; withanolide.

Figure 1

The withanolide types (I–XXIV) isolated between 1965 and 2013.

Figure 2

New* (6, 19–34, 66–68) and known (1–5, 7–18, 35–38) withanolides from Physalis longifolia (1, 15, 16, 19–38), Vassobia breviflora (1), Withania somnifera (1–18) and withanolide artifacts (66–68).

Figure 3

New* (39–47) and known (48–56) withanolides from Physalis hispida.

Figure 4

New* (57, 62–63) and known (58–61, 64–65) withanolides from Datura wrightii (57–61) and Jaborosa caulescens (62–65).

Figure 5

Derivatives 69–95 prepared from the natural products withaferin A (1), withalongolides A (19), B (20) and O (33)

Figure 6

Structural variations in rings A (left) and B (right) of the withanolides are closely related to the observed antiproliferative activity.