Late-stage modification of the alkaloid toxin veratridine to photocontrol excitable tissues.

Abstract

Natural products and their structural derivatives have long played a crucial role in the discovery of new medical treatments and pharmacotherapies. However, certain natural compounds, such as toxins, are classified as hazardous substances that pose risk to human health. It is desirable to modulate the activity of toxins to minimize their harmful effects and unleash their potential as selective and bioavailable drugs. Yet, the functionalization of natural products remains a challenge due to their structural complexity. Here, we present two methods for late-stage C-H nitration and subsequent derivatization of the alkaloid steroidal neurotoxin veratridine, a sodium channel opener, by introducing an azobenzene photoswitch in its structure. The resulting compound, Azoveratridine, displays aqueous solubility, reversible photoisomerization, and light-dependent activity in neurons and myocardial slices.