Synthesis, Anticancer Assessment, and Molecular Docking of Novel Chalcone‐Thienopyrimidine Derivatives in HepG2 and MCF‐7 Cell Lines

Abstract

Heterocycles containing thienopyrimidine moieties have attracted attention due to their interesting biological and pharmacological activities. In this research article, we reported the synthesis of a series of new hybrid molecules through merging the structural features of chalcones and pyridothienopyrimidinones. Our results indicated that the synthesis of chalcone-thienopyrimidine derivatives from the corresponding thienopyrimidine and chalcones proceeded in a relatively short reaction time with good yields and high purity. Most of these novel compounds exhibited moderate to robust cytotoxicity against HepG2 and MCF-7 cancer cells similar to that of 5-fluorouracil (5-FU). The results indicated that IC50 of the two compounds (3b and 3g) showed more potent anticancer activities against HepG2 and MCF-7 than 5-FU. An MTT assay and flow cytometry showed that only 3b and 3g had anticancer activity and antiproliferative activities at the G1 phase against MCF-7 cells, while six compounds (3a-e and 3g) had cytotoxicity and cell cycle arrest at different phases against HepG2 cells. Their cytotoxicity was achieved through downregulation of Bcl-2 and upregulation of Bax, caspase-3, and caspase-9. Although all tested compounds increased oxidative stress via increment of MDA levels and decrement of glutathione reductase (GR) activities compared to control, the 3a, 3b, and 3g in HepG2 and 3b and 3g in MCF-7 achieved the target results. Moreover, there was a positive correlation between cytotoxic efficacy of the compound and apoptosis in both HepG2 ( R 2 = 0.531 ; P = 0.001 ) and MCF-7 ( R 2 = 0.219 ; P = 0.349 ) cell lines. The results of molecular docking analysis of 3a-g into the binding groove of Bcl-2 revealed relatively moderate binding free energies compared to the selective Bcl-2 inhibitor, DRO. Like venetoclax, compounds 3a-g showed 2 violations from Lipinski’s rule. However, the results of the ADME study also revealed higher drug-likeness scores for compounds 3a-g than for venetoclax. In conclusion, the tested newly synthesized chalcone-pyridothienopyrimidinone derivatives showed promising antiproliferative and apoptotic effects. Mechanistically, the compounds increased ROS production with concomitant cell cycle arrest and apoptosis. Therefore, regulation of the cell cycle and apoptosis are possible targets for anticancer therapy. The tested compounds could be potent anticancer agents to be tested in future clinical trials after extensive pharmacodynamic, pharmacokinetic, and toxicity profile investigations.

Antimicrobial, Antiproliferative Effects and Docking Studies of Methoxy Group Enriched Coumarin‐Chalcone Hybrids

“…In literature, it has been shown in various studies that coumarin or chalcone structures hybridized with thiophene group inhibit proliferation of gastric cancer (MKN‐45), [39] prostate cancer (PC‐3), [40] breast cancer (MCF‐7) and liver cancer (HepG2) [41] cell lines. In our study, coumarin‐chalcone hybrids bearing thiophene moiety ( 4f and 4g ) showed weaker antiproliferative potential against all mentioned cell lines compared to other prepared compounds.…”

Chalcones: Effective Agents for Fighting Cancer Across Multiple Cell Lines

“…These novel compounds possessed moderate to robust cytotoxicity against HepG2 and MCF-7 cancer cells, in comparison to 5-fluorouracil (5-FU). [28] Importantly, compounds 59 b and 59 c exhibited more potent anticancer activity than 5-FU, as evident by lower IC 50 values (Scheme 19). In MCF-7 cells, 59 b and 59 c displayed anticancer and antiproliferative effects in the G1 phase, while in HepG2 cells, six compounds induced cytotoxicity and cell cycle arrest at various phases.…”

“…The aldol condensation of 4‐acetyl thiazole derivative with various aromatic aldehydes led to the synthesis of thiazolyl chalcone derivatives. These novel compounds possessed moderate to robust cytotoxicity against HepG2 and MCF‐7 cancer cells, in comparison to 5‐fluorouracil (5‐FU) [28] . Importantly, compounds 59 b and 59 c exhibited more potent anticancer activity than 5‐FU, as evident by lower IC 50 values (Scheme 19).…”

Design and synthesis of novel quinazolinone–chalcone hybrids as potential apoptotic candidates targeting caspase-3 and PARP-1:in vitro, molecular docking, and SAR studies

“…It is considered the second cause of death worldwide after heart disease. 1–3 The American Cancer Society reported that in 2020 there were 18.1 million new cancer cases and 9.9 million cancer deaths in the world. It is expected to reach about 28.0 million cases and the death cases will be about 16.2 million by 2040.…”