Synthesis and biological research of new imidazolone-sulphonamide-pyrimidine hybrids as potential EGFR-TK inhibitors and apoptosis-inducing agents

• Published in: RSC advances Vol. 14; no. 28; pp. 212 - 2129
• Main Authors: Binjawhar, Dalal Nasser, Katouah, Hanadi A, Alshaye, Najla A, Alharthi, Jawaher, Alsharif, Ghadi, Elsaid, Fahmy G, Fayad, Eman, Abu Almaaty, Ali H
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 18-06-2024; The Royal Society of Chemistry
• Subjects: Cell cycle; Chemistry; Doxorubicin; Heterocyclic compounds; Kinases; Pyrimidines; Sulfonamides; Synthesis
• ISSN: 2046-2069; 2046-2069
• DOI: 10.1039/d4ra03157a

Development of new effective EGFR-targeted antitumor agents is needed because of their clinical significance. A new series of imidazolone-sulphonamide-pyrimidine hybrids was designed and synthesized as modified analogs of some reported EGFR inhibitors. The cytotoxic activity of all the synthesized hybrids was investigated against the breast MCF-7 cancerous cell line using doxorubicin (Dox) as a positive control. 4-(Furan-2-ylmethylene)imidazolone-sulphonamide-pyrimidine
6b
had the best potent activity against MCF-7 cells with IC
50
result of 1.05 μM, which was better than Dox (IC
50
= 1.91 μM). In addition, mechanistic studies revealed the ability of compounds
5g
,
5h
and
6b
to inhibit EGFR kinase. Cell cycle analysis revealed that compound
6b
can halt MCF-7 cells at the G1 phase with a concomitant decrease in cellular percentage at the S and G2/M phases. This compound produced a noticeable rise in the proportion of apoptotic cells with regard to the untreated control. Furthermore, the effects of hybrid
6b
on the expression levels of pro-apoptotic Bax and pro-survival Bcl2 were assessed. The results showed that this compound upregulated the level of Bax expression as well as declined the expression value of Bcl-2 with regard to the untreated control.
A sequence of novel imidazolone-sulphonamide-pyrimidine hybrids was synthesized and evaluated for
in vitro
cytotoxicity against MCF-7 breast cancer cell line.