Alkanoyl and aroyl derivatives of a lathyrane-type macrocyclic diterpene
Multidrug-resistance phenomenon (MDR) to anti-cancer drugs is one of the most serious obstacles in the success of a chemotherapeutic treatment. P-glycoprotein (P-gp) is often implied in the efflux of drugs as anthracyclins, vinca alkaloids, taxanes and other non-related drug, lowering the effective concentration of such drugs in the cytoplasmatic compartment . One of the most promising approaches to overcome MDR is the development of molecules that can effectively modulate the activity of P-gp, thus inhibiting the drug efflux. In the past decades, several natural and synthetic compounds have been reported as MDR modulators, but none is currently available for the clinical practice.
In previous works, we have isolated, from Euphorbia species (Euphorbiaceae), several macrocyclic jatrophane [2,3] and lathyrane-type [3,4,5] diterpenes with strong P-gp modulation activity. In order to obtain a library of bioactive lathyrane and jatrophane diterpenes, required for QSAR studies and further refinement of an in-house P-gp modulators pharmacophore model, the phytochemical study of Euphorbia piscatoria Ait., an endemic species from Madeira island traditionally used in fishing activities, has been carried out. Fractionation by chromatographic methods of the crude methanolic extract of the aerial parts of Euphorbia piscatoria yielded a large amount of a lathyrane-type diterpenoid that was acylated, using different alkanoyl and aroyl chlorides/anhydrides. Several new esters were obtained whose structures were assigned based on spectroscopic methods namely 1D NMR (1H, 13C, DEPT) and 2D NMR (COSY, HMBC, HMQC) data.
Acknowledgement: This work was supported by Fundação para a Ciência e Tecnologia (FCT) (Project PTDC/QUI-QUI/099815/2008 and grant SFRH/BD/72915/2010).
References: 1. Teodori E et al. (2002) Il Farmaco 57: 385–415
2. Valente C et al. (2004) Planta Med 70: 81–84
3. Duarte N et al. (2006) Planta Med 72: 162–168
4. Duarte N et al. (2007) Bioorg Med Chem 15: 546–554
5. Duarte N et al. (2008) Bioorg Med Chem 16: 9323–9330