Synthesis, antitumor activity, and molecular docking study of 2-cyclopentyloxyanisole derivatives: mechanistic study of enzyme inhibition

Figures & data

Figure 1. The structures of the reported antitumor agents (A–F) with COX-2 or PDE4 and the designed compounds 3–14.

Scheme 1. Synthesis of the designed compounds 3–6.

Scheme 2. Synthesis of the designed compounds 7–11.

Scheme 3. Synthesis of the designed compounds 12–14.

Table 1. In vitro antitumor activity of the designed compounds, celecoxib, afatinib, and doxorubicin against human tumour cells.

Compound no.	IC50 (µM)^a
	HePG2	HCT-116	MCF-7	PC3	HeLa
3a	95.96 ± 5.2	>100	56.14 ± 2.6	51.43 ± 3.0	59.12 ± 3.8
3b	53.87 ± 3.7	80.56 ± 3.9	23.81 ± 1.5	19.34 ± 1.8	26.11 ± 1.9
3c	86.90 ± 4.5	93.46 ± 5.1	>100	>100	81.65 ± 4.7
4a	6.04 ± 0.5	4.38 ± 0.4	5.13 ± 0.3	9.18 ± 0.8	7.24 ± 0.7
4b	10.96 ± 1.1	9.48 ± 0.8	7.18 ± 0.8	14.32 ± 1.2	8.56 ± 0.9
5a	73.41 ± 3.7	66.48 ± 3.8	92.37 ± 5.2	78.95 ± 4.1	84.26 ± 4.6
5b	59.08 ± 3.5	61.13 ± 3.6	81.20 ± 4.3	55.17 ± 3.1	46.29 ± 3.0
6a	18.53 ± 1.7	30.49 ± 1.8	28.62 ± 1.6	27.44 ± 2.1	19.12 ± 1.7
6b	16.05 ± 1.4	25.41 ± 1.7	10.27 ± 1.1	17.95 ± 1.6	13.49 ± 1.4
7a	78.21 ± 4.4	90.34 ± 4.9	89.79 ± 4.3	>100	77.64 ± 4.6
7b	13.68 ± 1.2	19.67 ± 1.4	11.85 ± 1.3	22.89 ± 1.9	17.18 ± 1.5
7c	57.08 ± 3.9	81.19 ± 4.2	65.32 ± 3.4	68.06 ± 3.5	53.18 ± 3.7
7e	29.89 ± 2.1	44.82 ± 2.3	42.41 ± 2.2	46.97 ± 2.7	38.05 ± 2.5
8	41.82 ± 3.0	70.52 ± 3.5	60.48 ± 2.8	55.82 ± 3.2	43.47 ± 2.9
9a	32.87 ± 2.3	48.13 ± 2.4	35.17 ± 1.9	29.23 ± 2.3	37.50 ± 2.5
9b	24.85 ± 1.9	39.07 ± 2.2	37.09 ± 2.0	31.50 ± 2.4	28.37 ± 2.3
19c	36.27 ± 2.5	52.87 ± 2.7	48.93 ± 2.3	33.39 ± 2.6	40.61 ± 2.8
10	49.86 ± 3.5	79.12 ± 3.8	64.10 ± 3.1	47.32 ± 2.9	52.50 ± 3.7
11	91.23 ± 4.8	96.79 ± 5.5	94.27 ± 4.7	88.63 ± 5.0	90.89 ± 4.9
12a	45.24 ± 3.4	76.05 ± 3.6	71.63 ± 3.9	79.83 ± 4.0	65.72 ± 4.1
12b	38.14 ± 2.8	67.74 ± 3.5	58.28 ± 2.7	61.45 ± 3.3	45.69 ± 3.2
12c	59.63 ± 4.0	83.42 ± 4.3	66.07 ± 3.7	73.48 ± 3.8	62.76 ± 3.9
13	8.71 ± 0.7	7.66 ± 0.6	6.93 ± 0.5	11.45 ± 1.1	5.86 ± 0.6
14	20.11 ± 1.8	34.93 ± 1.9	9.62 ± 0.9	15.31 ± 1.3	12.48 ± 1.2
Celecoxib	25.6 ± 2.3	29.54 ± 2.1	31.28 ± 2.5	30.69 ± 2.7	36.08 ± 2.8
Afatinib	5.4 ± 0.25	11.4 ± 1.26	7.1 ± 0.49	7.7 ± 0.57	6.2 ± 0.67
DOX	4.50 ± 0.2	5.23 ± 0.3	4.17 ± 0.2	8.87 ± 0.6	5.57 ± 0.4

DOX: doxorubicin.

^a IC₅₀, compound concentration required to inhibit tumour cell proliferation by 50% (mean ± SD, n = 3). IC₅₀, (μM): 1–10 (very strong), 11–25 (strong), 26–50 (moderate), 51–100 (weak), and above 100 (non-cytotoxic). Compound 7d had an IC₅₀ of >100 µM.

Table 2. In vitro inhibitory effects of COX-2, PDE-4B, and TNF-α of the antitumor compounds 4a, 4b, 7b, and 13.^a

Compound no.	IC50 (µM)^a
	COX-2 inhibition	PDE-4B inhibition	TNFα inhibition
4a	3.34	5.62	2.012
4b	1.08	11.62	17.67
7b	24.02	5.65	13.94
13	1.88	3.98	6.72
Roflumilast	–	1.55	–
Celecoxib	0.68	–	6.44

^a IC₅₀ value is the compound concentration required to produce 50% inhibition.

Figure 2. Three-dimensional (3D) orientation of the docked ligand SC-558 (upper left panel); docked compounds 4b (lower left panel), and 13 (lower right panel) in the active pocket of the COX-2 enzyme (H bond interactions are shown as green lines). Upper right panel showed the alignment of SC-558, 4b, and 13 in the active pocket of the COX-2 enzyme.

Figure 3. Three-dimensional (3D) orientation of the docked roflumilast (upper left panel); docked compound 13 (upper right panel), in the active pocket of the PDE4B enzyme (H bond interactions are shown as green lines). Lower left panel showed near picture of compound 13 in the active pocket of the PDE4B enzyme. Lower right panel showed the hydrophobic interactions of compound 13 in the active pocket of the PDE4B enzyme.