Regioselective Synthesis and Cytotoxic Effects of New Juglone Derivatives with an Aliphatic Substituent at C(2) or C(3)

The naphthoquinone juglone (5-hydroxynaphthalene-1,4-dione) (1) occurs abundantly in nature, especially in species belonging to the Juglandaceae family. Due to its multifaceted biological activities, this compound is considered a privileged structure in Medicinal Chemistry for the development of new prototypes with several biological and pharmacological actions. However, the regioselective synthesis of 2-substituted juglones is challenging due to the non-symmetric naphthoquinone nucleus. Starting from non-symmetric 2,3-unsubstituted naphthalenes, in this paper we describe two general synthetic routes to juglone derivatives bearing an unsaturated or an oxygenated aliphatic side chain at C(2) or C(3). In an MTT test, a few products were more active than the parent unsubstituted juglone as inhibitors of the viability of human lung cancer H460 and breast cancer MCF-7 cells. The most potent compound featured a 1′-acetoxyhomoprenyl sidechain at the carbon C(2) of juglone.