The Veratrum alkaloids jervine, veratramine, and their analogues as prostate cancer migration and proliferation inhibitors: biological evaluation and pharmacophore modeling

Veratrum alkaloids are a group of steroidal alkaloids with penta-, hexa-, or heptacyclic C-nor-D-homosteroidal or regular hexacycliccholestane skeleton. Activation of the Hedgehog (Hh) pathway aberrantly associated with numerous malignancies. Cyclopamine blocked Hh pathway by directly binding Smo and slows down the growth of these tumors in various animal models. To less extent, jervine and the veratrane Veratrum alkaloid veratramine were also reported as possible Hh signaling inhibitors. This encouraged the study of our small library of natural, biocatalytic, and semisynthetic jervane and veratrane alkaloids' ability to inhibit the growth, proliferation, and migration of the prostate metastatic cancer cell line PC-3 to establish a preliminary structure-activity relationship. Alkaloids possessing C-3-keto functionality with a dagger(4,5) or a dagger(1,2) and a dagger(4,5) exhibited significant enhancement of antiproliferative and antimigratory activities. A common feature pharmacophore model of active Veratrum alkaloids was built and validated using receiver-operating characteristic curve analyses.