CATIVIC ACID HYBRIDS: SEMI-SYNTHESIS AND THEIR EFFECT ON VIABILITY OF HUMAN NEUROBLASTOMA CELLS

ALZA, N.P.; MURRAY, A.P.; SALVADOR, G.

Rosario

Congreso; Reunion Internacional de Ciencias Farmacéuticas; 2016

Universidad Nacional de Rosario

Design and development of hybrids, particularly from natural products, has emerged as a new field in drug discovery due to their inherent biological activities that could be significant different, enhanced or combined with respect to the original monomers.1,2 In the present study, we synthetized hybrids of a labdane isolated from Grindelia ventanensis (Asteraceae), 17-hydroxycativic acid (1).3 Through Mitsunobu protocol,4 hybrids 3-5 of 1 and natural phenols (coniferyl alcohol, ferulic acid and caffeic acid, respectively) were prepared. Our first aim was to evaluate cell viability of human neuroblastoma IMR-32 cell line in the presence of the above mentioned compounds. Compound 5 inhibited cell growth in a dose- and time-dependent manner, with an IC50 value of 18.0 μM. However, 3 did not affect cell viability at the tested concentrations (0.5-50 μM), whereas 4 reduced cell growth at 25 and 50 μM. Neither diterpenoid 1 nor natural phenols displayed any effect on cell viability.Treatment with 5 (10-25 μM), the most active hybrid, increased the number of dead cells in a dose-dependent manner. In line with this, IMR-32 cells exposed to 5 (25 μM) displayed an increase in LDH leakage. Furthermore, caspase-3 activity increased 1.5-fold in 5-treated conditions. These results suggest that cell growth inhibition displayed by 5 is, at least in part, a consequence of its cytotoxic effect and apoptosis induction.Our results show that 17-hydroxicativic acid and its hybrids constitute a promising platform for additional studies aimed at understanding their biological implication in pathologies with cell growth out of control.