Biological activities of the shrub Salsola tuberculatiformis Botsch.: Contraceptive or stress alleviator?

Abstract

Plants belonging to the genus Salsola (Family: Chenopodiaceae) are common in the arid and semiarid regions of our planet with no less than 69 different Salsola species found in Namibia and the Republic of South Africa. This genus is used as a traditional medicine and aqueous extracts of Salsola have been used by Bushmen women as an oral contraceptive. Ingestion of the Namibian shrub Salsola tuberculatiformis Botsch. by pregnant Karakul sheep leads to prolonged gestation and fetal post-maturity and, as a result, the pelts of the new-born karakul lambs are worthless. This initiated an investigation into the active agents in the plant, using the terminal enzyme in adrenal corticosteroidogenesis, cytochrome P450-dependent 11beta-hydroxylase (P450c11), as a bioassay. Although the active fraction, S2, was extremely labile, partial structure determination suggested the presence of synephrine and a highly reactive aziridine. Therefore a more stable analogue, 2-(4-acetoxyphenyl)2-chloro-N-methylethylammonium-chloride (compound A), was synthesised, which, like the active plant extracts, inhibited adrenal steroidogenesis and acted as a contraceptive. In addition, compound A was stabilised by interaction with steroid-binding globulins in plasma thus enhancing biological activity in vivo. These findings provided explanations for the complex biological effects of the shrub as well as a new insight into the mode of action of chemically labile plant products in vivo.

Novel Steroid Receptor Phyto-Modulator Compound A Inhibits Growth and Survival of Prostate Cancer Cells

“…The chemical structure of CpdA significantly differs from most known AR/GR antagonists and GR-dissociated ligands (11,19,27,41,42): CpdA is small molecule with only one benzene ring (Fig. 1C).…”

“…It was discovered recently that CpdA directly interacts with steroid receptors AR and GR in model cells (19,23). Remarkably, CpdA inhibited AR activity via mechanisms similar to ones used by clinically used antiandrogens flutamide and cyproterone acetate (19,(24)(25)(26)(27). CpdA was also reported to act as a GR ligand with ''dissociated'' properties: CpdA did not affect GR transactivation but induced GR-mediated transrepression evaluated by inhibition of NF-nB and NF-nB-dependent genes (23).…”

“…It was shown that CpdA, like the active plant extracts, interacts with steroidogenic enzymes and steroid-binding globulins in plasma displacing the endogenous steroids and affects the bioavailability of these hormones in different target tissues (19,20,22). It was discovered recently that CpdA directly interacts with steroid receptors AR and GR in model cells (19,23). Remarkably, CpdA inhibited AR activity via mechanisms similar to ones used by clinically used antiandrogens flutamide and cyproterone acetate (19,(24)(25)(26)(27).…”

“…Our work presented here is centered on a novel AR/GR ligand, 2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium chloride, also called compound A (CpdA). CpdA is a synthetic analogue of a hydroxyphenyl aziridine precursor found in the African shrub Salsola tuberculatiformis Botschantzev (19)(20)(21)(22). It was shown that CpdA, like the active plant extracts, interacts with steroidogenic enzymes and steroid-binding globulins in plasma displacing the endogenous steroids and affects the bioavailability of these hormones in different target tissues (19,20,22).…”

Selective Glucocorticoid Receptor Agonists for the Treatment of Inflammatory Bowel Disease: Studies in Mice with Acute Trinitrobenzene Sulfonic Acid Colitis

“…CpdA is a nonsteroidal synthetic analog of a natural substance isolated from the African shrub Salsola tuberculatiformis Botschantzev (Swart et al, 2003). Both CpdA and its natural counterpart are relatively unstable and give rise to reactive phenyl aziridines, although this decay seems to be reduced by binding to serum proteins, including corticosteroid binding globulin (Swart et al, 2003).…”