Design, synthesis and cytotoxic evaluation of nitric oxide-releasing derivatives of isosteviol.

Twenty-six novel isosteviol derivatives coupled with two types of nitric oxide (NO) donors (furoxans and NONOates) were synthesized and screened for cytotoxic activities against four human cancer cell lines with sunitinib as the positive control. The results showed that seven furoxan-based derivatives (8a, 8b, 8c, 8d, 8e, 9e, and 9f) exhibited desirable cytotoxic activities, while NONOate-based derivatives displayed poor potency because of unstability. Compared with sunitinib, compounds 8a and 8e were more active on all tested cell lines, especially in HCT116 (8a, IC50  = 0.48 ± 0.02 μm; 8e, IC50  = 0.94 ± 0.01 μm); compounds 8b and 8d were more potent on HCT116 (IC50  = 3.39 ± 0.06 and 3.29 ± 0.03 μm), HepG2 (IC50  = 1.05 ± 0.03 and 5.37 ± 0.08 μm), and SW620 (IC50  = 1.33 ± 0.02 and 4.11 ± 0.05 μm) cell lines, and 8c exhibited higher activities on HepG2 cells with an IC50  = 4.76 ± 0.14 μm. NO-releasing experiment of compounds 8a-e, 17a, 18a, 19a, and 21a reminded us that NO-releasing amount of this series of isosteviol derivatives positively correlates with their cytotoxic activities.