Design, synthesis and biological evaluation of naphthostyril derivatives as novel protein kinase FGFR1 inhibitors

Figures & data

Figure 1. Chemical structures of kinase inhibitors from oxindole and naphthostyril classes.

Table 1. Chemical characteristics of synthesized compound.

Compound No.	1H NMR data	Yield (%)
12	^1H NMR (DMSO-d6), δ: 7.15 (d, 2H), 7.22 (d, 2H), 7.85 (d, 1H), 8.13 (t, 1H), 8.36 (d, 1H), 8.56 (d, 1H), 8.61 (d, 1H), 10.50 (s, 1H), 10.66 (s, 1H)	84
13	^1H NMR (DMSO-d6), δ: 7.13 (d, 1H), 7.26 (d, 1H), 7.43 (s, 1H), 7.83 (d, 1H), 8.14 (t, 1H), 8.38 (d, 1H), 8.54 (d, 1H), 8.59 (d, 1H), 10.47 (s, 1H), 10.63 (s, 1H)	81
14	^1H NMR (DMSO-d6), δ: 7.05 (t, 1H), 7.17 (d, 1H), 7.23 (d, 1H), 7.83 (d, 1H), 8.12 (t, 1H), 8.36 (d, 1H), 8.56 (d, 1H), 8.61 (d, 1H), 10.46 (s, 1H), 10.65 (s, 1H)	80
15	^1H NMR (DMSO-d6), δ: 7.09 (d, 2H), 7.37 (d, 2H), 7.85 (d, 1H), 8.15 (t, 1H), 8.38 (d, 1H), 8.57 (d, 1H), 8.62 (d, 1H), 10.53 (s, 1H), 10.68 (s, 1H)	86
16	^1H NMR (DMSO-d6), δ: 6.94 (d, 2H), 7.09 (d, 2H), 7.80 (d, 1H), 8.11 (t, 1H), 8.35 (d, 1H), 8.54 (d, 1H), 8.59 (d, 1H), 10.47 (s, 1H), 10.60 (s, 1H)	79
17	^1H NMR (DMSO-d6), δ: 6.96 (m, 3H), 7.08 (d, 1H), 7.81 (d, 1H), 8.12 (t, 1H), 8.35 (d, 1H), 8.54 (d, 1H), 8.59 (d, 1H), 10.47 (s, 1H), 10.60 (s, 1H)	77
18	^1H NMR (DMSO-d6), δ: 7.22 (d, 1H), 7.33 (m, 2H), 7.53 (s, 1H), 7.81 (d, 1H), 8.13 (t, 1H), 8.37 (d, 1H), 8.55 (d, 1H), 8.60 (d, 1H), 10.50 (s, 1H), 10.63 (s, 1H)	74
19	^1H NMR (DMSO-d6), δ: 7.01 (t, 1H), 7.12 (d, 2H), 7.18 (d, 2H), 7.80 (d, 1H), 8.14 (t, 1H), 8.34 (d, 1H), 8.55 (d, 1H), 8.57 (d, 1H), 10.48 (s, 1H), 10.60 (s, 1H)	88
20	^1H NMR (DMSO-d6), δ: 6.67 (d, 2H), 7.05 (d, 2H), 7.80 (d, 1H), 8.10 (t, 1H), 8.32 (d, 1H), 8.53 (d, 1H), 8.60 (d, 1H), 10.46 (s, 1H), 10.61 (s, 1H)	82
21	^1H NMR (DMSO-d6), δ: 6.78 (d, 1H), 7.17 (d, 1H), 7.23 (s, 1H), 7.81 (d, 1H), 8.13 (t, 1H), 8.35 (d, 1H), 8.57 (d, 1H), 8.61 (d, 1H), 10.47 (s, 1H), 10.62 (s, 1H)	78
22	^1H NMR (DMSO-d6), δ: 2.00 (s, 3H), 6.54 (d, 1H), 6.62 (s, 1H), 7.03 (d, 1H), 7.80 (d, 1H), 8.12 (t, 1H), 8.35 (d, 1H), 8.55 (d, 1H), 8.60 (d, 1H), 10.45 (s, 1H), 10.60 (s, 1H)	73
23	^1H NMR (DMSO-d6), δ: 3.60 (s, 3H), 6.73 (d, 2H), 7.02 (d, 2H), 7.82 (d, 1H), 8.14 (t, 1H), 8.36 (d, 1H), 8.57 (d, 1H), 8.62 (d, 1H), 10.47 (s, 1H), 10.62 (s, 1H)	86
24	^1H NMR (DMSO-d6), δ: 3.71 (s, 6H), 5.80 (s, 1H), 6.71 (s, 2H), 7.81 (d, 1H), 8.12 (t, 1H), 8.30 (d, 1H), 8.52 (d, 1H), 8.58 (d, 1H), 10.43 (s, 1H), 10.57 (s, 1H)	84
25	^1H NMR (DMSO-d6), δ: 3.72 (s, 3H), 3.80 (s, 3H), 6.55 (d, 1H), 6.59 (s, 1H), 7.24 (d, 1H), 7.82 (d, 1H), 8.13 (t, 1H), 8.32 (d, 1H), 8.54 (d, 1H), 8.59 (d, 1H), 10.47 (s, 1H), 10.61 (s, 1H)	82
26	^1H NMR (DMSO-d6), δ: 3.66 (s, 3H), 3.75 (s, 3H), 6.67 (d, 1H), 6.93 (d, 1H), 6.98 (s, 1H), 7.85 (d, 1H), 8.15 (t, 1H), 8.34 (d, 1H), 8.56 (d, 1H), 8.61 (d, 1H), 10.48 (s, 1H), 10.63 (s, 1H)	83
27	^1H NMR (DMSO-d6), δ: 3.72 (s, 6H), 6.52 (d, 2H), 6.84 (t, 1H), 7.84 (d, 1H), 8.13 (t, 1H), 8.32 (d, 1H), 8.55 (d, 1H), 8.59 (d, 1H), 10.45 (s, 1H), 10.61 (s, 1H)	73
28	^1H NMR (DMSO-d6), δ: 7.18 (t, 1H), 7.27 (d, 1H), 7.42 (t, 1H), 7.73 (d, 1H), 7.85 (d, 1H), 8.16 (t, 1H), 8.40 (d, 1H), 8.59 (d, 1H), 8.65 (d, 1H), 10.64 (s, 1H), 11.36 (s, 1H), 11.50 (s, 1H)	68

Table 2. Chemical structure and in vitro activities of the naphthostyril derivatives.

Compounds	Structure	Kinase activity (% at 33 μM*)	Log S†	IC50 (μM)
1		15	−4.64	4.2
2		6	−5.46	48.9
3		11	−5.32	34
4		42	−3.5	22
5		35	−2.72	12.1
6		17	−2.79	4.4

*Residual kinase activity is percent of kinase activity at inhibitor concentration 33 µM related to control with DMSO. †Calculated logarithm of solubility.

Figure 2. Docking model of compound 1 bound to the ATP-binding site of the FGFR1. Hydrogen bonds marked as dashed lines.

Scheme 1. Synthesis of N-phenylnaphthostyril-1-sulfonamides.

Table 3. Chemical structure and in vitro activities of the N-phenylnaphthostyril-1-sulfonamide derivatives. 

Compounds	R1	Kinase residual activity (%)*	IC^50 (µM)†
1	3′-Cl	15	4.22
12	4′-Cl	21.5	6.3
13	3′,4′-diCl	5.5	2.3
14	2′,3′-diCl	8.3	9.5
15	4′-Br	17.5	7.4
16	4′-F	18.7	5.9
17	2′-F	15.3	8.2
18	3′-CF3	11.6	3.4
19	H	32.7	ND
20	4′-OH	7.2	2
21	3′-Cl, 4′-OH	8.8	3.55
22	4′-OH, 2′-CH3	3.5	2.25
23	4′-OCH3	41.5	ND
24	3′,5′-diOCH3	68	ND
25	2′,4′-diOCH3	33.1	ND
26	3′,4′-diOCH3	76.3	ND
27	2′,5′-diOCH3	31.7	ND
28	2′-COOH	47.5	ND

*Kinase residual activity is percent of kinase activity at inhibitor concentration 33 µM related to control with DMSO. †ND, not determined.

Table 4. Kinase selectivity of 20 and 22.

Kinase	Inhibitor 20	Inhibitor 22
FGFR1	11 ± 4.1	15 ± 3.9
Tie-2	117.7 ± 11.6	67 ± 9.0
c-MET	99.7 ± 4.0	75 ± 7.9
Aurora А	92 ± 8.4	63.4 ± 3.5
JNK3	115.3 ± 13.2	108.6 ± 11.3
CK2	83.4 ± 3.0	69 ± 4.7
ASK1	89.6 ± 6.1	103.8 ± 7.4

Kinase residual activity is percent of kinase activity at inhibitor concentration 33 µM related to control with DMSO, ATP concentration was 100 µM for all kinases.

Table 5. Antiproliferative activity of compounds 13, 20 and 22 at KG1 cancer cell line.

Compounds	13	20	22
Cell viability, % at 100 µM	58.5 ± 2.0	69.8 ± 2.4	103.8 ± 2.4
Cell viability, % at 10 µM	98.9 ± 3.5	90.8 ± 3.8	108.6 ± 6.4

The percentage of cell viability was presented as mean of three replicates with standard deviation.