Discovery of novel conjugates of quinoline and thiazolidinone urea as potential anti-colorectal cancer agent

Figures & data

Figure 1. The structures of Regorafenib, Fruquintinib, Foretinib, BMS-777607, MK-8033, Crizotinib, Cabozantinib and BC2021-104511-15i.

Figure 2. The binding mode of BC2021-104511-15i with HGFR (PBD ID: 3LQ8), the SARs of lead compound BC2021-104511-15i and the modification of fragments I, II and III. Lead compound was shown by blue sticks, and the H-bonds were represented by green dotted lines, and the H-arene interaction was shown by red dotted lines.

Scheme 1. Synthesis of target compounds 10a–i. Reagents and conditions: (i) 1a: 2-fluoro-4-nitrophenol, PhCl, reflux, 14 h; 1b: 2-fluoro-4-nitroaniline, i-PrOH, conc. HCl, reflux, 3 h; (ii) 33% HBr in HOAc, rt, 3 h; (iii) 1-Boc-4-methanesulfonyloxypiperidine, Cs₂CO₃, DMF, 110 °C, 6 h; (iv) Fe, 90% EtOH-H₂O, conc. HCl (cat.), reflux, 4–6 h; (v) phenyl chloroformate, pyridine, CH₂Cl₂, rt, 2 h; (vi) 50% hydrazine hydrate, xylene, 70 °C, 2 h; (vii) 2, 6-difluorobenzaldehyde, i-PrOH, HOAc (cat.), reflux, 2–3 h; (viii) CF₃COOH, CH₂Cl₂, rt, 2 h; (ix) RCOCl, Et₃N, CH₂Cl₂, rt, 4–5 h; R-Cl, Cs₂CO₃, DMF, 90 °C, 6–8 h; (x) mercaptoacetic acid, SiCl₄, CH₂Cl₂, reflux, 6–8 h; (xi) MeOH, NaOH, 50 °C, 1 h.

Scheme 2. Synthesis of target compound 19. Reagents and conditions: (i) 2-fluoro-4-nitrophenol, PhCl, reflux, 14 h; (ii) 33% HBr in HOAc, rt, 3 h; (iii) 1-Boc-4-methanesulfonyloxypiperidine, Cs₂CO₃, DMF, 110 °C, 6 h; (iv) Fe, 90% EtOH-H₂O, conc. HCl (cat.), reflux, 4 h; (v) (1) phenyl chloroformate, pyridine, CH₂Cl₂, rt, 2 h; (2) 50% hydrazine hydrate, xylene, 70 °C, 2 h; (vi) 2, 6-difluorobenzaldehyde, i-PrOH, HOAc (cat.), reflux, 3 h; (vii) CF₃COOH, CH₂Cl₂, rt, 2 h; (viii) 2-chloroacetamide, Cs₂CO₃, DMF, 90 °C, 8 h; (ix) mercaptoacetic acid, SiCl₄, CH₂Cl₂, reflux, 6 h.

Figure 3. Mimetic binding mode of compound 10a (yellow sticks) within HGFR (PDB ID: 3LQ8). The H-bonds were represented by green dotted line and the H-π was represented by red dotted lines.

Table 1. The structures of target compounds 10a–i and 19 and their inhibitory activity against HGFR, MST1R, HT-29, HCT-116 and COLO 205 cells.

Compd.	R	X	Y	IC50 (μM)
				HGFR^a	MST1R^a	HT-29^b	HCT-116^b	COLO 205^b
10a		O	CH	0.11	0.045	1.3 ± 0.11	0.87 ± 0.11	0.11 ± 0.024
10b		O	CH	0.18	0.085	3.0 ± 0.24	3.7 ± 0.34	0.31 ± 0.021
10c		O	CH	0.14	0.072	4.1 ± 0.27	5.9 ± 0.53	0.44 ± 0.038
10d		O	CH	0.90	0.44	2.9 ± 0.19	2.4 ± 0.26	4.9 ± 0.38
10e		O	CH	0.61	0.15	7.7 ± 0.56	2.4 ± 0.26	0.48 ± 0.042
10f		O	CH	0.14	0.078	1.9 ± 0.11	2.6 ± 0.27	0.42 ± 0.034
10g		O	CH	0.18	0.11	6.9 ± 0.47	4.8 ± 0.44	0.59 ± 0.045
10h		O	CH	0.22	0.16	6.5 ± 0.43	–	0.85 ± 0.073
10i		NH	CH	–	–	>10.0	>10.0	–
19		O	N	–	–	8.6 ± 0.67	–	5.3 ± 0.47
BC2021-104511-15i		O	CH	0.27^c	0.11^c	0.79 ± 0.058^c	4.8 ± 0.44	0.72 ± 0.065
Fruquintinib	–	–	–	–	–	1.57	2.2 ± 0.17	>10.0
Regorafenib	–	–	–	–	–	8.49	8.2 ± 0.75	>10.0
Cabozantinib	–	–	–	0.0019		–	–	–
Foretinib	–	–	–		0.0024	–	–	–

^aThe IC₅₀ values are expressed as the mean of two independent experiments. ^bThe IC₅₀ values were an average of three separate determinations and standard deviations were shown. ^cReported IC₅₀ values were 0.20 μM (HGFR), 0.092 μM (MST1R) and 0.19 μM (HT-29 cells), respectively.

Table 2. The cytotoxicity of selected compounds against FHC cells.

Cells	IC50 (μM)^a
	10a	10b	10d	10f	10h
FHC	>10.0	>10.0	>10.0	>10.0	>10.0

^aThe IC₅₀ values were an average of three separate determinations.

Table 3. The kinase inhibitory activity of compounds 10a and 10b against ABL, PDGFRβ, AXL, FLT3, RET, c-Src and VEGFR-2.

Compd.	IC50 (μM)^a
	ABL	RET	AXL	FLT3	PDGFRβ	VEGFR-2	c-Src
10a	1.68 ± 0.13	1.27 ± 0.10	0.95 ± 0.086	6.93 ± 0.73	1.13 ± 0.12	1.16 ± 0.11	0.42 ± 0.035
10b	3.28 ± 0.26	1.52 ± 0.14	1.50 ± 0.15	>10.0	1.20 ± 0.095	2.36 ± 0.18	0.69 ± 0.057

^aValues are expressed as the mean of two independent experiments and standard deviations were shown.

Figure 4. Cell apoptosis analyses of COLO 205 cells treated with compound 10a for 72 h.

Figure 5. Cell cycle arrest analyses of COLO 205 cells treated with compound 10a for 24 h.