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

Abstract

Six series of novel isosteviol derivatives; modified in the C-19 position; were synthesized; and their antiproliferative activity was evaluated against three human cancer cell lines (HCT-116; BEL-7402; HepG2) and the human L02 normal cell line in vitro. Most of the derivatives tested here exhibited improved antiproliferative activity with high selectivity when compared with the parent compound isosteviol and the positive control drug 5-fluorouracil. Among these derivatives; compound 5d exhibited the most potent antiproliferative activity and commendable selectivity between cancer and normal cells. In addition; compound 5d inhibited the colony formation of HCT-116 cells in a concentration-dependent manner. Further studies revealed that compound 5d arrested the HCT-116 cell cycle in the S phase; and western blot analysis demonstrated the mechanism may be correlated with a change in the expression of cyclin A; cyclin B1; and cyclin E1. Furthermore; the results of a docking study that involved placing compound 5d into the CDK2/cyclin A binding site revealed that its mode of action was possibly as a CDK2/cyclin A inhibitor.

Application of triazoles in the structural modification of natural products

“…Derivatives of isosteviol-triazole not only possess anti-colon cancer activity 73 , but also they exhibit anti-multiple cancer cell activity 98 . Compounds with different phenyl 1,2,3-triazole chloroacetamide showed considerably higher antiproliferative activity against the HCT-116 and HepG2 cell lines.…”

Synthesis and biological evaluation of ursolic acid derivatives bearing triazole moieties as potential anti-Toxoplasma gondii agents

“…The compound UA-1 was synthesised as per the protocol described in a previous study 6 . Ia-Ij (different 1-phenyl-1 H -1,2,3-triazole-4-carbaldehyde) and IIa-IIe (different 2-chloro- N -((1-phenyl-1 H -1,2,3-triazol-4-yl)methyl)acetamide) were prepared as previously described 17 , 20 . IIIa-IIIe were prepared as per Scheme 1: different substitutions of benzoyl hydrazide (10 mmol) and N,N-Dimethylformamide dimethyl acetal (DMFDMA; 1.31 g, 11 mmol) were added to CH 3 CN (20 ml); the resulting mixture was stirred at 60 °C for 1 h. Then, 2-aminoethanol (1.22 g, 20 mmol) and CH 3 COOH (2.40 g, 40 mmol) were added, and the resulting mixture was stirred at 90 °C for 8–12 h. After confirming the reaction progress by TLC, the solvent was evaporated in vacuo .…”

Click Chemistry in Natural Product Modification

“…Tao et al reported that C15 isosteviol-triazole D7 (IC 50 = 2.987 μ M) could exert slightly better inhibitory activity than cisplatin (IC 50 = 3.906 μ M) against HCT-116 cells ( Liu et al, 2016 ). Quan et al reported that C19 isosteviol-triazole D8 could inhibit the growth of several cancer cell lines (HCT-116, BEL-7402, and HepG2) with IC 50 values in the range of 5.38–15.91 μ M, and that was 1.3- to 4.6-fold more potent than the reference drug 5-fluorouracil, and 6.3- to 16.8-fold more potent than the parental isosteviol ( Luan et al, 2019 ). Mechanism studies indicated that D8 could inhibit colony formation and arrest cell cycle (S phase) in HCT-116 cells.…”