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DOI: 10.1055/s-0035-1565486
Exploring epoxylathyrane derivatives to overcome ABCB1-mediated multidrug resistance in human colon adenocarcinoma cells
Multidrug resistance (MDR) in cancer is nowadays regarded as the leading problem in chemotherapy. The different mechanisms of MDR have been intensively studied. One of the most important is related with the overexpression of the energy-dependent membrane efflux proteins known as ATP-binding cassette (ABC) transporters, which include, among others, the ABCB1 transporter (P-glycoprotein, P-gp). ABCB1 confers significant resistance to a wide range of drugs, including taxanes, Vinca alkaloids and anthracyclines. For this reason, the development of molecules that are able to modulate the ABCB1 mediated efflux has been one of the most promising strategies to overcome MDR. In the last decade, macrocyclic diterpenes with the lathyrane and jatrophane scaffold isolated from Euphorbia species have been shown to be potent inhibitors of ABCB1-related efflux activity. However, despite of the already existing work, there is still a long way ahead to be followed for optimizing macrocyclic diterpenes as ABCB1 modulators.
Aiming to obtain a set of homologous bioactive compounds in order to develop further structure-activity relationship studies, an epoxylathyrane diterpene, isolated from Euphorbia sp., was submitted to several chemical transformations, including hydrolysis, reduction and acylation reactions. Overall, twenty three novel derivatives were prepared, and fully characterized using spectroscopic methods. Their anti-MDR potential was evaluated by flow cytometry in MDR human colon adenocarcinoma (Colo 320) cells. Most epoxylathyrane derivatives, in particular those with aromatic moities showed a remarkable upgrade in their MDR-modifying activity enabling the establishment of structure activity relationships. Moreover, ATPase inhibition by three representative MDR-modifying compounds was investigated and revealed that they all act as ABCB1 slowly transported substrates.
Acknowledgements: This study was financially supported by FCT, Portugal (PTDC/QEQ-MED/0905/2012).