Planta Med 2014; 80 - P1L78
DOI: 10.1055/s-0034-1394735

Facing a still unsolved problem: Dihydro-β-agarofuran sesquiterpenes from Celastrus vulcanicola as multidrug resistance reversal agents

IL Bazzocchi 1, O Callies 1, MP Sánchez-Cañete 2, IA Jiménez 1, F Gamarro 2, S Castanys 2
  • 1Instituto Universitario de Bio-Orgánica Antonio González, Departamento de Química Orgánica and Instituto Canario de Investigación del Cáncer, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain
  • 2Instituto de Parasitología y Biomedicina “López-Neyra”, IPBLN-CSIC, Parque Tecnológico de Ciencias de la Salud, Armilla, Granada, Spain

Despite the advance in clinical cancer treatment today, one of the primary causes of its failure is the appearance of multidrug resistance (MDR) during chemotherapy. One mayor form of MDR is correlated with overexpression of the ATP binding cassette (ABC) transporter P-glycoprotein (Pgp) decreasing the intracellular anticancer drug concentration [1]. As there is still no drug available in clinical oncology to reverse this phenomenon, Pgp presents a promising target in the search for new MDR reversal agents. Natural products (NPs), with their wide range of structural diversity and biological activities, present an excellent starting point for the development of new chemotherapeutical agents [2]. In fact, over 60% of the current anticancer drugs have their origin in nature. In order to get new insights into the potential of NPs to inhibit Pgp, we carried out a phytochemical study focusing on the dihydro-β-agarofuran sesquiterpene polyesters [3] from Celastrus vulcanicola J. Donnell Smith (Celastraceae) from El Salvador known to be rich in this kind of metabolites. Thus, we isolated 15 compounds, nine of them reported for the first time, with (1R,2S,4S,5R,6R,7R,8R,9R,10S)-1,8-diacetyloxy-6,9-dibenzoyloxy-2,4-dihydroxy-dihydro-β-agarofuran as the new major metabolite. Their structures were determined by means of spectroscopic and spectrometric techniques. Six compounds of this series exhibited reversal potency up to 2-fold higher than the reversal agent verapamil, a classical first-generation chemosensitizer, when reversing resistance to daunomycin (DNM) and vinblastine (VNB). Their reversal indices values were in the range of 3.9 – 7.2 (DNM) and 12.1 – 28.5 (VBN) at 10µM sesquiterpene. A preliminary structure-activity relationship study was performed.

Keywords: Celastrus vulcanicola, Celastraceae, dihydro-β-agarofuran sesquiterpenes, human MDR1/P-glycoprotein inhibitors

References:

[1] Breier A et al. (2013) Anticancer Agents Med Chem 13: 159 – 170.

[2] Wink M et al. (2012) Frontiers in Microbiology 3: 1 – 15.

[3] Perestelo NR et al. (2011) Eur J Med Chem 46: 4915 – 4923.