Synthesis and Biological Evaluation of Steviol Derivatives with Improved Cytotoxic Activity and Selectivity

Abstract

Steviol is an ent-kaurene diterpenoid with interesting pharmacological activity. Several steviol derivatives with an exo-methylene cyclopentanone unit were discovered as potent antitumor agents. However, their poor selectivity for tumor cells relative to normal cells reduces their prospects as potential anticancer drugs. In this study, based on previous work, 32 steviol derivatives, including 28 new analogues, were synthesized. Their cytotoxicity against tumor cells and normal cells was evaluated. Several new derivatives, such as 7a, 7h, and 8f, with improved cytotoxic selectivity and antiproliferative activity were obtained, and the structure–activity relationship correlations were investigated. The new compound 8f displayed potent antiproliferative activity against Huh7 cells (IC50 = 2.6 μM) and very weak cytotoxicity against the corresponding normal cells HHL5 (IC50 = 97.0 μM). Further investigation showed that 8f arrested the cell cycle at the G0/G1 phase and caused reactive oxygen species overproduction, decreased mitochondrial membrane potential, and induced apoptosis of Huh7 cells through inhibition of the PI3K/Akt/mTOR and NF-κB pathway as well as upregulation of Bax/Bcl-2 ratio. The present study suggested that 8f is a promising lead compound for new cancer therapies, and the results presented herein may encourage the further modification of steviol for additional derivatives with enhanced efficacy and selectivity.

Stereoselective Synthesis and Antiproliferative Activities of Tetrafunctional Diterpene Steviol Derivatives

“…In derivatives, the molecular weight (MW) of 10, 11, while the lipophilic slightly exceeded the drugability limits defined by Ro5. A higher level of be identified in the case of the three naphthyl derivatives (13)(14)(15), calculated logP values exceeded the specified rule of thumb thresh character of steviol derivatives was also evaluated based on the predic steviol (2) starting compound has an acidic character (pKa = 4.6) due to acid group, while the steviol methyl ester derivative 3 and the spiro-epo that can be derived from it have a neutral character. The other steviol-(5-18) have a basic character of almost the same strength (pKa = characteristic differences.…”

“…Sci. 2023, 24, x FOR PEER REVIEW 2 of 1 bioactive diterpenoid derivatives since it can be isolated at an industrial scale from Stevi rebaudiana and it can be easily transformed to its aglycons, steviol and isosteviol [15][16][17][18]. Stereoselective transformations of both steviol and isosteviol, affording reactive inter mediates (II, III) and aminoalcohols (IV), as well as aminodiols (V) with antiproliferative activity, were studied previously (Figure 1) [15,17,19,20].…”

“…2023, 24, x FOR PEER REVIEW 2 of 1 bioactive diterpenoid derivatives since it can be isolated at an industrial scale from Stevi rebaudiana and it can be easily transformed to its aglycons, steviol and isosteviol [15][16][17][18]. Stereoselective transformations of both steviol and isosteviol, affording reactive inter mediates (II, III) and aminoalcohols (IV), as well as aminodiols (V) with antiproliferative activity, were studied previously (Figure 1) [15,17,19,20]. The outstanding pharmacologica effects of the N-substituted derivatives raised our curiosity about this class of compounds Therefore, our aim was to expand the aforementioned topic by introducing a third hydroxy function to study its effect on the antiproliferative activity of a library of novel aminotriol obtained from stevioside (I).…”

“…A large majority of these compounds are derived from commercially available monoterpenes, such as (–)-isopulegol, α- or β-pinene [ 6 , 11 ], while only a handful of chiral sources of diterpenes are commercially available in a large scale [ 12 , 13 , 14 ]. Among them, stevioside ( I ) is a frequently used source of bioactive diterpenoid derivatives since it can be isolated at an industrial scale from Stevia rebaudiana and it can be easily transformed to its aglycons, steviol and isosteviol [ 15 , 16 , 17 , 18 ].…”

“…Stereoselective transformations of both steviol and isosteviol, affording reactive intermediates ( II , III ) and aminoalcohols ( IV ), as well as aminodiols ( V ) with antiproliferative activity, were studied previously ( Figure 1 ) [ 15 , 17 , 19 , 20 ]. The outstanding pharmacological effects of the N -substituted derivatives raised our curiosity about this class of compounds.…”