Novel sulfonamide benzoquinazolinones as dual EGFR/HER2 inhibitors, apoptosis inducers and radiosensitizers

Figures & data

Figure 1. Examples of dual EGFR/HER2 inhibitors.

Scheme 1. Synthesis of the benzo[g]quinazolinone derivatives 4–18.

Table 1. The cytotoxic activity and percentage inhibition of compounds 5–18 on EGFR against MDA-MB-231 breast cancer cell line.

Compound no.	IC50 against MDA-MB-231 (µM)*	% Inhibition of EGFR
5	2.47 ± 0.08	42.00
6	23.24 ± 1.88	18.13
7	26.47 ± 2.14	25.98
8	2.91 ± 0.03	54.61
9	2.19 ± 0.05	52.49
10	0.31 ± 0.01	69.04
11	0.28 ± 0.01	70.34
12	2.19 ± 0.09	41.86
13	0.40 ± 0.01	67.36
14	0.37 ± 0.01	72.90
15	21.80 ± 1.63	21.45
16	0.32 ± 0.01	59.66
17	161.49 ± 4.69	8.71
18	0.26 ± 0.01	67.26
Erlotinib	0.48 ± 0.01	68.30

*The values represent the mean ± SE of three independent experiments.

Table 2. IC₅₀ of compounds 10, 11, 13, 14, and 18 against EGFR and HER2 enzymes.

Compound no.	EGFR IC50 (µM)*	HER2 IC50 (µM)*
10	3.90 ± 0.03	5.40 ± 0.12
11	2.55 ± 0.17	31.31 ± 0.31
13	10.20 ± 0.10	13.01 ± 0.09
14	4.11 ± 0.02	26.03 ± 0.22
18	9.66 ± 0.08	3.20 ± 0.04
Erlotinib	6.21 ± 0.31	9.42 ± 0.21

*The values represent the mean ± SE of three independent experiments.

Table 3. The effect of compound 10 on the level of caspase-3.

Compound no.	Caspase 3 (Pg/mL)	Folds
10	545.7	10.25
Erlotinib	480.1	9.02
Control	53.2	–

Table 4. The effect of compound 10 on Bax/Bcl2 expression levels.

Compound no.	Bax (Folds)	Bcl2 (Folds)
10	9.37193	0.13794
Erlotinib	11.0418	0.07182

Figure 2. The effect of inhibitors on the phases of the cell cycle (A) compound 10, (B) erlotinib, and (C) control MDA-MB-231 cells.

Table 5. The effect of compound 10 and erlotinib on the phases of cell cycle.

Compound no.	%G0-G1	%S	%G2-M	%Apoptosis
10	49.36	18.28	17.52	14.84
Erlotinib	41.55	16.31	24.81	17.33
Control	69.55	23.04	6.44	0.97

Table 6. The cytotoxicity of compound 10 and erlotinib on 184A1 normal breast cells

Compound no.	IC50 (µM)
10	84.50 ± 0.72
Erlotinib	101.9 ± 3.55

Table 7. IC₅₀ of compound 10 on MDA-MB-231 cells before and after being subjected to a single dose of 8 Gy γ-radiation.

Compound no.	IC50 before Irradiation (µM)	IC50 after Irradiation (µM)
10	0.31 ± 0.01	0.22 ± 0.03

Figure 3. 2 D and 3 D ligand interactions of erlotinib inside the active site of 1M17.

Figure 4. 2 D and 3 D interaction maps of compound 10 inside the active site of 1M17.

Table 8. Docking results of compound 10 inside 1M17 and 3RCD active sites.

Receptor	Compound	Energy score (S) (Kcal/mol)	Amino acids	Interacting groups	Length (Å)
1M17	Erlotinib	−9.82	Met 769	N-1 of quinazolinone	2.70
	10	−9.88	Met 769	NH2 of sulfonamide	0.85
			Cys 773	CO of quinazolinone	1.91
			Phe 699	Ph of acetamide	4.23
3RCD	TAK-285	−9.70	Met 801	N-1 of pyrrolopyrimidine	2.18
	10	−9.71	Met 801	SO2 of sulfonamide	3.15
			Thr 862	CO of acetamide	1.97
			Asp 863	CO of acetamide	2.73
			Lys 753	N-1 of quinazolinone	1.87

Figure 5. 2 D and 3 D interaction maps of TAK-285 inside the active site of 3RCD.

Figure 6. 2 D and 3 D interaction maps of 10 inside the active site of 3RCD.