Discovery of nitroaryl urea derivatives with antiproliferative properties

Figures & data

Scheme 1. Structures of sunitinib, imatinib, gefitinib and dasatinib.

Scheme 2. Urea compounds active in CDK assay with their IC₅₀ values21.

Scheme 3. Synthesis of 1-substituted-3-{2-[(4-nitrophenyl)amino]ethyl}urea (5a–d), 1-substituted-3-{2-[(5-nitropyridin-2-yl)amino]ethyl}urea (6a–g), 2-imino-3-(4-nitrophenyl)-N-phenylimidazolidine-1-carboxamide (8) and 1-[1-(4-nitrophenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-phenylurea (9). (i) NH₂CH₂CH₂NH₂, reflux. (ii) RNCO or RNHCOIm, room temperature. (iii) BrCN, MeOH, reflux. (iv) 1. NaOH 2.PhNCO, DCM.

Figure 1. A view of the X-ray molecular structure of 9 with the atomic labelling scheme. Non H-atoms are represented by displacement ellipsoids of 30% probability.

Table 1. Effects of the synthesized compounds on cancer and normal cells in vitro.

	HSF	RK33		TE671
	GI50 ± SD	GI50 ± SD	SI	GI50 ± SD	SI
5a	14.73 ± 2.86	16.08 ± 1.10	0.92	12.22 ± 1.07	1.21
5b	41.40 ± 2.73	62.70 ± 1.07	0.66	20.74 ± 1.09	2.00
5c	77.75 ± 2.57	42.33 ± 1.06	1.84	23.01 ± 1.08	3.38
5d	21.52 ± 1.90	6.67 ± 1.05	3.23	11.79 ± 1.07	1.83
6a	56.80 ± 2.63	42.89 ± 1.05	1.32	24.25 ± 1.08	2.34
6b	58.05 ± 1.57	168.20 ± 1.16	0.35	35.47 ± 1.12	1.64
6c	129.08 ± 1.57	105.90 ± 1.18	1.22	37.75 ± 1.10	3.44
6d	24.37 ± 2.09	21.25 ± 1.05	1.15	15.76 ± 1.05	1.55
6e	54.79 ± 3.64	13.71 ± 1.10	4.00	6.46 ± 1.09	8.48
6f	23.24 ± 1.27	20.89 ± 1.09	1.11	30.16 ± 1.10	0.77
6g	>100	>100		>100
8	53.08 ± 1.78	122.90 ± 1.15	0.43	31.22 ± 1.06	1.70
9	38.01 ± 1.91	117.10 ± 1.13	0.32	26.44 ± 1.09	1.44
CDDP	146.66 ± 1.1	83.33 ± 1.1	1.8	56.66 ± 1.2	2.6

Shown GI₅₀ values are the concentrations [µM] for half-maximal inhibition of cell viability and were calculated from data obtained during three independent experiments. The selectivity index (SI) represents GI₅₀ for normal cell line/GI₅₀ for cancer cell line after 72 h treatment with NUD.

Table 2. Effect of the synthesized compounds on inhibition of protein kinases CDK2/cyclin E and c-Abl.

	IC50 (µM)
Compound	CDK2/cyclin E	Abl
5a	>50	>50
5b	>12.5	>12.5
5c	>25	>25
5d	>12.5	>12.5
6a	>50	>50
6b	>50	>50
6c	>50	>50
6d	>25	>25
6e	>12.5	>12.5
6f	>12.5	>12.5
6g	>100	>100
8	>50	>50
9	14.3	>100

Figure 2. HOMO (A) and LUMO (B) orbitals for 9. (C) The map of the electrostatic potential onto a surface of the electron density for 9.

Table 3. Molecular descriptors of the investigated compounds.

Compound	Surface area, Å^2	Polar surface area, Å^2	Volume, Å^3	Ovality	HOMO, eV	LUMO, eV	Polarizability	clogP	Molecular weight	Number of H bond donors	Number of H bond acceptors
5a	620.2	145.7	304.2	1.6601	−8.83	−0.72	38.11	3.206	350.371	3	7
5b	605.9	187.3	297.3	1.6655	−8.92	−0.79	35.22	2.037	342.349	3	8
5c	600.1	152.6	293.7	1.6786	−8.82	−0.71	35.05	2.969	348.784	3	7
5d	620.9	166.4	300.8	1.7046	−8.74	−0.66	35.66	2.288	344.365	3	8
6a	594.2	190.1	301.1	1.6603	−9.25	−0.93	36.96	2.594	351.359	3	8
6b	595.5	227.3	295.4	1.6755	−9.39	−1.07	35.03	1.426	343.337	3	9
6c	598.2	194.3	291.2	1.6762	−9.32	−0.97	34.60	2.357	349.772	3	8
6d	620.4	207.8	301.8	1.7104	−9.20	−0.93	35.22	1.676	345.353	3	9
6e	585.1	196.7	285.5	1.6652	−9.34	−0.10	34.78	3.015	370.191	3	8
6f	585.1	204.7	284.0	1.6556	−8.76	−0.99	33.83	1.670	331.327	3	9
6g	455.5	212.1	205.5	1.5843	−9.61	−1.21	23.45	0.109	239.231	3	8
8	567.3	178.5	277.9	1.6392	−9.10	−1.30	34.05	2.482	325.322	2	8
9	548.2	151.8	265.6	1.5764	−9.03	−1.35	33.34	2.482	325.322	2	8

Figure 3. Compound 9 in stick representation with magenta carbon atoms in the binding pocket of CDK2 (protein colored with green carbon atoms) (A), 2D interaction map (B) and 9 superimposed to the reference ligand (stick representation, cyan carbon atoms, hydrogen atoms not shown in ligands for clarity; protein shown as green cartoon) (C). Hydrogen bonds shown as red dashed lines (color version available online).

Honma T, Hayashi K, Aoyama T, et al. Structure-based generation of a new class of potent Cdk4 inhibitors: new de novo design strategy and library design. J Med Chem 2001;44:4615–27

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