Insight on antitumoral properties of plant diterpenes

Plant diterpenes constitute a large group of natural products that play diverse functional roles in plants as hormones, photosynthetic pigments, attractants for pollinators, herbivore repellents and phytotoxins. Diterpenes are biosynthesized especially in plastids and an increasing number of diterpenoids are being found with skeletons that may arise by rearrangements of well known bi- and tri-cyclic systems [1]. Different plant extracts containing diterpenes as main secondary metabolites showed several biological actions such as antitumor, antimicrobial, anti-inflammatory, antioxidant, and larvicidal activities [2]. Although diterpenes are present in a wide number of plant families, some genera are characterized by the presence of peculiar skeletons. In the last few years our research group was involved in the building-up of diterpenes and diterpenes-like library to screen against biological targets, selecting plants belonging to different genera through a chemotaxonomic approach; among them some species of Euphorbia and Podocarpus were investigated. Diterpenes occurring in Euphorbia species have provided many lead compounds for drug development due to their broad structural diversity including polycyclic and macrocyclic skeletons and various aliphatic and aromatic ester groups. These species are well known to contain skin-irritant diterpenes, such as ingenane, tigliane, and daphnane derivatives, together with non-irritant polyoxygenated macrocyclic constituents, lathyrane, jatrophane and their polycyclic derivatives [3 – 4]. Aiming at the characterization of lathyrane diterpene target in a cellular system [5], a chemical proteomics approach, DARTS, was employed for a new lathyrane diterpene, (2R,9S,10R,11R,13S)-18-hydroxy-9αH,11αH-lathyra-4(15),5(6)-dien-1,14-dione-18-β-d-glucopyranoside (1), named as laurifolioside, showing that clathrin heavy chain is the main partner. Compound 1 ability to modulate clathrin heavy chain activity has been assessed through Western-Blot, microscopy and molecular docking analyses, suggesting a new activity of lathyrane diterpenes in the modulation of trafficking pathways.

Keywords: Diterpenes, Euphorbia, antitumoral.

References:

[1] McGarvey DJ, Croteau R. Terpenoid metabolism. Plant Cell 1995; 7: 1015 – 1026

[2] Hanson JR. Diterpenoids. Nat Prod Rep 2005; 22: 594 – 602

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[4] Ferreira MJU, Duarte N, Reis M Madureira AM, Molnar J. Euphorbia and Momordica metabolites for overcoming multidrug resistance Phytochem Rev 2014; 13; 915 – 935

[5] Dal Piaz F, Cotugno R, Lepore L, Vassallo A, Malafronte N, Lauro G, Bifulco G, Belisario MA, De Tommasi N. Chemical proteomics reveals HSP70 1A as a target for the anticancer diterpene oridonin in Jurkat cells. J Proteomics 2013; 82: 14 – 26