Design, Synthesis, and Apoptosis-Promoting Effect Evaluation of Rhopaladins’ Analog 4-Arylidene-5-Oxopyrrolidine Derivatives

Abstract

Marine alkaloids have novel structures and antitumor activities. Therefore, we synthesized rhopaladins’ analogs from marine alkaloids rhopaladins A-D and modified their structures to synthesize 4-benzylidene-5-pyrrolidone derivatives. Among the compounds, (2E, 4E)-4-(4-chlorobenzylidene)-2-(4-chlorostyryl)-N-cyclohexyl-1-(4-fluorophenyl)-5-oxopyrrolidine-2-carboxamide (RPDPRH) has high efficiency and less hepatotoxicity, with IC50 values of 4.66, 6.42, 17.66, 15.2, 12.36, 22.4, and 243.2 μM in vitro anti-proliferative activity testing against cervical cancer C-33A, CaSki, SiHa, and HeLa cells, human hepatocarcinoma HepG2 and 7402 cells, and human normal liver LO2 cells, respectively. In particular, RPDPRH has similar activity to cisplatin on human hepatocarcinoma cells, and cisplatin served as a positive control in our study. Next, the apoptosis of HepG2 and 7402 cells induced by RPDPRH at different concentrations was detected by Annexin V/PI flow cytometry. Moreover, the expression of apoptotic proteins was detected by Western blot analysis. Finally, the results showed that RPDPRH could induce apoptosis of hepatocarcinoma cells by regulating Bax and Bcl-2 expressions. In summary, our results indicate that RPDPRH has the potential to serve as an antitumor agent and plays a significant role in future studies.

Green synthesis, structure optimization and biological evalution of Rhopaladins’ analog 2–styryl–5-oxopyrrolidine-2- carboxamide RPDPRH on CaSki cells

“…The synthesis procedure was based on our previous research ( Zhu et al, 2022 ). First, a mixture of 4-fluoroaniline 2 (1 mmol) and substituted ( E )-3-(4-chlorophenyl) acrylaldehyde 3 (1 mmol) was stirred in ethanol-water (3:1, vol/vol, 8 ml) at room temperature for 30 min.…”

“…Following previous studies ( Zhu et al, 2022 ), cell activity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, MultiSciences) assay. The logarithmic growth phase cells were digested and inoculated into 96 well cell culture plates with 5 × 10 3 cells per well.…”

“…Further, in order to obtain compounds with better apoptosis inducing activity of tumor cells, analogs of Rhopaladins (2 E ,4 E )-4-arylidene-2-styryl-5-oxopyrrolidine (RPDPR serial chemicals) were synthesized after structural optimization ( Kong et al, 2021 ). Among them (2 E ,4 E )-4-chlorobenzylidene-2-(4-chlorostyryl)- N -cyclohexyl-1-(4-fluorophenyl)-5-oxopyrrolidine-2-carboxamide (RPDPRH for short, see Scheme 1 ) has better anti-hepatoma activity and low hepatotoxicity ( Zeng et al, 2020 ; Zhu et al, 2022 ). Thus, we further explored the effect of RPDPRH on CaSki cell apoptosis.…”

Synthesis and Anticancer Activity of Rhopaladins’ Analog RPDPD Against the HeLa Human Cervical Cancer Cell Line

“…The studies have shown that marine alkaloids rhopaladins A–D have significant cytotoxicity to human tumor cell lines. Rhopaladin B has inhibitory activity against CDK4 and c-erbB-2 kinases (IC 50 of 12.5 and 7.4 μg/ml, respectively) ( Hiroyasu et al, 1998 ; Zhu et al, 2019 .). We have previously synthesized rhopaladins’ analogs 2-aroyl-4-arylidene-5-oxopyrrolidine derivatives (see Scheme 1 ) via a tandem Ugi 4CC/S N cyclization and studied their cytotoxicity to HeLa cells ( Wang et al, 2020 ).…”

Green synthesis, crystal structure, and antifungal activities of (E)-4-arylidene-5-oxotetrahydrofuran

“…Studies have shown that rhopaladins A-D alkaloids (Janosik et al, 2002;Méndez et al, 2018) (Scheme 1) present in marine cysts have significantly biological activities. We have previously synthesized several different series of rhopaladins' analogs, such as (E)-2-aroyl-4-arylidene-5-oxopyrrolidines (Scheme 1), and (2E, 4E)-2-styryl-4-arylidene-5-oxopyrrolidines, via multi-component one-pot method starting from Baylis-Hillman acid, and found that these compounds showed good anti-proliferation and apoptosis-inducing effects on cervical cancer cells and liver cancer cells, respectively (Zeng et al, 2013;Zhu et al, 2020;Wang et al, 2021;Wang et al, 2021;Kong et al, 2021;Zhu et al, 2022). Baylis Hillman (B-H) reaction is a coupling reaction between active alkenes and electrophiles under catalyst, which can be used to synthesize compounds with polyfunctional groups under mild reaction conditions (Huang and Cui, 2018).…”