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

Abstract

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, IC = 0.48 ± 0.02 μm; 8e, IC = 0.94 ± 0.01 μm); compounds 8b and 8d were more potent on HCT116 (IC = 3.39 ± 0.06 and 3.29 ± 0.03 μm), HepG2 (IC = 1.05 ± 0.03 and 5.37 ± 0.08 μm), and SW620 (IC = 1.33 ± 0.02 and 4.11 ± 0.05 μm) cell lines, and 8c exhibited higher activities on HepG2 cells with an IC = 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.

Bioactivity Profile of the Diterpene Isosteviol and its Derivatives

“…Different observations showed that these derivatives encouraged apoptosis in HepG2 cells, blocked angiogenic signaling and it didn’t cause toxicity in the treated hosts [85]. Another researcher used the same approach, synthesizing twenty-six novel isosteviol derivatives coupled with two types of nitric oxide (NO) donors (furoxans and NONOates) [86]. Seven of the furoxan based derivatives were tested for their in vitro cytotoxic activity against four cancer cell lines HCT116, Huh7, HepG2, and SW620, while the NONOates displayed negative result [86].…”

“…Another researcher used the same approach, synthesizing twenty-six novel isosteviol derivatives coupled with two types of nitric oxide (NO) donors (furoxans and NONOates) [86]. Seven of the furoxan based derivatives were tested for their in vitro cytotoxic activity against four cancer cell lines HCT116, Huh7, HepG2, and SW620, while the NONOates displayed negative result [86]. These derivatives can be lead compounds for further research.…”

“…These derivatives can be lead compounds for further research. Greater than the amount of NO released by compounds enhances its activity [85,86]. Some of the derivatives of isosteviol with nitric oxide releasing properties have a higher potency than the comptothecin [85].…”

Synthesis and anti-cancer activities of glycosides and glycoconjugates of diterpenoid isosteviol

“…Isosteviol 1 has moderate antihypertensive, 12 antihyperglycemic, 13 cardioprotective, 14 anti-tumor, 10 anti-tuberculosis, 15 and antimicrobial 16 effects. Chemical modification of isosteviol 1 did not only increase its antituberculosis, 15,[17][18][19] anti-cancer, 20,21 and anti-bacterial 22 activities but also provided it with antiviral, 23 antimitotic, 24 and mitochondriotropic 25 effects. It is interesting to note that although glycosylation of biologically active natural compounds that are not glycosides has long been considered as one of the ways to "tune their activity", 26 among more than 200 derivatives of isosteviol 1 (ref.…”

Design and Synthesis of C-19 Isosteviol Derivatives as Potent and Highly Selective Antiproliferative Agents

“…Furthermore, the cytotoxic activities of isosteviol derivatives have attracted much attention in recent years. In the previous study, the C-15 and C-16 functionalized isosteviol derivatives, obtained by means of group-conversion or structural modification exhibited good cytotoxic activities [17,18,19,20,21,22,23,24]. In view of the low cytotoxicity of isosteviol, it is suitable for the development of highly selective anticancer drugs by chemical modification [14,15,16].…”