Synthesis and characterization of 5,7-dihydroxyflavanone derivatives as novel protein tyrosine phosphatase 1B inhibitors

Figures & data

Scheme 1.  Synthesis of compounds 4a–n. Reagents and conditions: (a) MOMCl, K2CO3, acetone 0°C, rt; (b) corresponding benzaldehyde, 10% KOH, ethanol/H2O, rt; (c) 3 M HCl, MeOH/THF, reflux; (d) NaOAc, EtOH, reflux.

Table 1.  Inhibitory activity of compounds 4a–n against PTP1B.

Compounds	PTP1B
	Inhibition rate^a (%)	IC50^b (μM)
4a	94.23	9.06 ± 2.12
4b	95.65	7.98 ± 0.91
4c	98.43	2.66 ± 0.23
4d	78.24	10.23 ± 2.45
4e	98.02	4.18 ± 0.94
4f	97.04	3.60 ± 0.41
4g	96.34	2.40 ± 0.22
4h	95.80	4.90 ± 0.98
4i	97.19	7.33 ± 1.25
4j	95.45	3.48 ± 0.19
4k	99.13	2.37 ± 0.37
4l	73.66	36.73 ± 7.16
4m	98.78	14.09 ± 1.38
4n	94.26	13.12 ± 1.25
UA^c	98.45	3.20 ± 0.31

^aValues tested at 20 μg/mL concentration.

^bThe pNPP assay. IC₅₀ values were determined by regression analyses and expressed as means ± SD of three replications.

^cPositive control.

Table 2.  Inhibitory activity of compounds 4k against related PTPs.

Cpds	IC50 (μM)^a
	TCPTP	CDC25B	LAR	SHP-1	SHP-2
4k	8.82 ± 1.29	8.54 ± 1.51	NA^b	NA	NA

^aThe pNPP assay. IC₅₀ values were determined by regression analyses and expressed as means ± SD of three replications.

^bNot active at 20 μg/mL concentration.

Figure 1.  Characterization of 4k to PTP1B. (A) At various fixed concentrations of 4k the initial velocity was determined with various concentrations of pNPP. (B) Typical competitive inhibition of 4k shown by Lineweaver-Burk plot. (C) K_i determination.

Figure 2.  Effect of compound 4k on tyrosine phosphorylation of IRβ in CHO/hIR cells. Sodium vanadate (V = 0.5 mM) and DMSO were used as postitive and negative controls. The levels of IRβ and β-actin were used to normalization.

Figure 3.  Docking result of compound 4k in the PTP1B catalytic pocket. (A) Binding pose of 4k in PTP1B active site; (B) Key residues in binding site surrounding 4k.