Exploring New Structural Features of the 18β-Glycyrrhetinic Acid Scaffold for the Inhibition of Anaplastic Lymphoma Kinase

Abstract

Novel 18β-glycyrrhetinic acid derivatives possessing a carbamate moiety and structurally similar ester derivatives were developed and evaluated for their efficacy as antitumor inhibitors. In the cellular assays, most of the N-substituted carbamate derivatives at the C3-position exhibited potent activities. The results of SAR investigation revealed that the introduction of the morpholine group at the C30-COOH led to a significant loss of the inhibitory potency. Among the ester derivatives, the ester group at C3-position also determined a noticeable reduction in the efficacy. Compound 3j exhibited the most prominent antiproliferative activity against six human cancer cells (A549, HT29, HepG2, MCF-7, PC-3, and Karpas299). Furthermore, compound 3j exerted a moderate inhibiting effect on the ALK. The results of molecular docking analyses suggested that it could bind well to the active site of the receptor ALK, which was consistent with the biological data. These results might inspire further structural optimization of 18β-glycyrrhetinic acid aiming at the development of potent antitumor agents. The structures 4d, 4g, 4h, 4j, and 4n were studied by X-ray crystallographic analyses.

Design, synthesis and biological evaluation of novel amide-linked 18β-glycyrrhetinic acid derivatives as novel ALK inhibitors

“…in the presence of EDCl, HOBt, and triethylamine in CH 3 CN at room temperature for 24 h. However, an intermediate (6) was largely isolated from the reaction mixture. 7 The intermediate (6) did not react with piperazine at low reaction temperatures even aer the extended reaction time (up to 48 h). Nevertheless, the above reaction was performed in reuxing CH 3 CN, and intermediate (6) could be fully converted into bisamide (5) and trace amount of the desired monoamide (3).…”

“…The C3-OH of 18b-GA did not interfere with these amidation reactions. However, the amidation of monoamide (3) with 2-(4-chlorophenyl)acetyl chloride was carried out in the solution of triethylamine and CH 2 Cl 2 at 40 C, and competitive esterication to form the corresponding compound (7) in 38.4% isolated yield contributed to a lower yield of the target compound (4w). Moreover, if the acid chloride is excessively large and the reaction time is too long at room temperature, it will also lead to competitive esterication (Scheme 3).…”

“…[4][5][6] The 18b-GA nucleus, a feasible structure for in-depth pharmaceutical exploration and for development of new potential antiproliferative drug candidates, has aroused extensive attention from medicinal chemists over the last decade. [7][8][9][10][11] The presence of polar functional groups (C3-OH and C30-COOH) in its structure could impact the biological activities of the mentioned analogues. 12 Inspired by the mentioned developments and facts, our previous work was continued in structural modication of 18b-GA. 7 In the present study, substituted piperazine amide fragments were introduced into the C30-COOH of 18b-GA, and a novel series of amide-linked derivatives was designed as potential antitumor inhibitors.…”

“…[7][8][9][10][11] The presence of polar functional groups (C3-OH and C30-COOH) in its structure could impact the biological activities of the mentioned analogues. 12 Inspired by the mentioned developments and facts, our previous work was continued in structural modication of 18b-GA. 7 In the present study, substituted piperazine amide fragments were introduced into the C30-COOH of 18b-GA, and a novel series of amide-linked derivatives was designed as potential antitumor inhibitors. To assess the effect of different substituents on the piperazine amide fragment, the substitution of phenyl or benzyl group was modied, and the aromatic ring was altered (Fig.…”

Research progress on antiviral constituents in traditional Chinese medicines and their mechanisms of action

“…They are reported to have antitumor, antioxidant, anti-inflammatory and antiviral properties (Cai et al. 2019 ; Shafik et al. 2019 ; Bailly and Vergoten 2020 ; Shiba et al.…”