New Antimetastatic Pregnane Alkaloids

Epidermal growth factor receptor (EGFR)-mediated chemotaxis is now recognized as an important mechanistic component in the process of metastasis in breast cancer. Hence, an investigation was initiated by Hong-Quan Duan and co-workers to identify experimental therapeutic candidates (natural products) that inhibit the migration of breast cancer cells induced by the chemokine EGF. Bioassay-guided phytochemical investigation of the ethanol extract of Pachysandra terminalis, a small shrub found in China and Japan, has resulted in the isolation and structural elucidation of the terminamines (e.g. terminamine C, structure shown below), pregnane alkaloids with unique antimetastatic therapeutic potential.

For example, terminamine C inhibited EGF-induced invasion of breast cancer cells with an IC50 of 80 nM. In addition, a close structural derivative of terminamine C was reported to dose-dependently inhibit the phosphorylation of integrin beta-1. Integrin beta-1 is a known component of a protein complex which binds to extracellular matrix molecules such as collagen and fibronectin in a process that mediates the attachment between a cell and the tissues that surround it. This biochemical phenomenon is associated with cancer cell adhesion and metastasis. Therefore, the inhibition of phosphorylation of integrin beta-1 by a terminamine natural product, along with generally potent in vitro antimetastatic activity, suggests a potential mechanism of action for this structurally interesting steroidal alkaloid natural product family.