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. 2024 Jun 24;14(28):20120-20129.
doi: 10.1039/d4ra03157a. eCollection 2024 Jun 18.

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

Dalal Nasser Binjawhar  1 , Hanadi A Katouah  2 , Najla A Alshaye  1 , Jawaher Alharthi  3 , Ghadi Alsharif  4   5 , Fahmy G Elsaid  6 , Eman Fayad  3 , Ali H Abu Almaaty  7
Affiliations

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

Dalal Nasser Binjawhar et al. RSC Adv. .

Abstract

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 IC50 result of 1.05 μM, which was better than Dox (IC50 = 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.

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Conflict of interest statement

The authors report no conflicts of interest.

Figures

Fig. 1
Fig. 1. Examples of some reported imidazolone, sulphonamide and clinically approved pyrimidine scaffold as anti-EGFR candidates.
Scheme 1
Scheme 1. Synthesis of imidazolone-sulphonamide-pyrimidine compounds 5a–l and 6a,b. Reagents: (i) glycine, aqueous sodium hydroxide, rt, 2 h; (ii) Ac2O, 80 °C, 2 h; (iii) respective aryl aldehyde, NaOAc, 80 °C, 2 h; (iv) sulfadiazine, NaOAc, glacial acetic acid, reflux 16–18 h.
Fig. 2
Fig. 2. Graphical illustration of IC50 (μM) for imidazolone-sulphonamide-pyrimidine hybrids 5h, 5j, 6b and Lapatinib on EGFR enzyme. Values indicate the mean ± SE for three replicates.
Fig. 3
Fig. 3. Cell cycle investigation of phosphatidylserine externalized Annexin-V interaction and cell membrane integrity (PI labelling). MCF-7 cells underwent treatment with 4-(furan-2-ylmethylene)imidazolone-sulphonamide-pyrimidine 6b at (A) 0, (B) 1.05 μM, respectively.
Fig. 4
Fig. 4. Flow cytometric method by Annexin V/PI method of the tested MCF-7 cells treated with 4-(furan-2-ylmethylene)imidazolone-sulphonamide-pyrimidine hybrid 6b at the IC50 compared with having no treatment control for 48 h.
Fig. 5
Fig. 5. Roles of Bcl-2 family protein in apoptosis induced by 4-(furan-2-ylmethylene)imidazolone-sulphonamide-pyrimidine hybrid 6b. (A) Pro-survival Bcl-2 protein; (B) pro-apoptotic Bax protein. Cells underwent treatment with an IC50 concentration of imidazolone hybrids 6b for 48 h and the expression of apoptosis-related proteins was examined by qRT-PCR assay.
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