Diseño, síntesis y evaluación biológica de nuevos selenoésteres con actividad antiproliferativa, citotóxica y quimiopreventiva

Zusammenfassung

DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL SELENOESTERS WITH ANTIPROLIFERATIVE, CYTOTOXIC AND CHEMOPREVENTIVE ACTIVITY Enrique Domínguez Álvarez Department of Organic and Medicinal Chemistry. School of Pharmacy. University of Navarra. Pamplona, Spain. According to the antecedents found in bibliography regarding the antitumor and chemopreventive properties of certain organoselenium derivatives, it is proposed that selenocompounds which contain the selenoester functional group, following the general structure R¿CO-SeR, may possess a dual antitumor and chemopreventive activity; because these compounds could suffer an heterolytic breakdown of the selenoester bound, releasing selenium anions with capacity to take part in reductive-oxidative reactions, as well as with antiproliferative and cytotoxic properties. Thus, 51 selenoesters which contain a methyl group or a carbonyl or carboxylic functional group as R, bounded to the selenium atom directly or through and aliphatic linker have been synthesized. Meanwhile, R¿ includes an aromatic or heteroaromatic ring, monocyclic or bicyclic, substituted or no, and bounded to the selenoester carbonyl directly or through an aliphatic linker. To synthesize the compounds, the acyl chloride with the R¿ required in each case has been selenated with sodium hydrogenselenide generated in situ. Afterwards, a Sn2 reaction has been carried out, in which the selenium salt displaces the halogen of the alkyl halide which provides the desired R. In accordance with the results obtained through the biological techniques applied to evaluate the cytotoxicity and voltammetric ones used to determine the redox properties, selenoesters show the dual antitumor and in vitro chemopreventive activity against cancer predicted in the hypothesis. Regarding the chemopreventive activity of the selenoesters, all the derivatives possess redox activity for developing peaks in cyclic voltammetry when the mercury-drop electrode is used as working electrode. Alternatively, it is found that three selenoesters with aromatic or heteroaromatic difunctionalized rings with the methylselenocarbonyl moiety have nanomolar GI50 values in prostatic, colorectal, lung and breast tumour cell lines; whereas the oxopropyl 4-chlorobenzoselenoate possesses cytotoxic properties for having a LC50 in PC-3 and A549 cells at concentrations of 4.71 and 9.09 μM, respectively; four and seven fold lower than doxorubicin, the most potent reference drug considered. Abovementioned selenoesters have a certain selectivity between the PC-3 (tumour) and RWPE-1 (non-tumour) cell lines, being the dimethyl benzene-1,4-dicarboselenolate the most selective selenoester for showing a GI50 value six-fold higher in the non-cancer cells than in the tumour ones.