Synthesis of a novel series of L-isoserine derivatives as aminopeptidase N inhibitors

Figures & data

Scheme 1.  Reagents and conditions: a. CH₃OH, HCl; b. (Boc)₂O, CH₃OH, NaOH; c. i) K₂CO₃, KI, TBAI, benzyl chloride, CH₃COCH₃; ii) HCl/anhydrous EtOAc; d. EDCI, HOBt/anhydrous, DCM, 2a∼2b,4a∼4b, 0°C to room temperature; e. HCl/anhydrous EtOAc.

Scheme 2.  Reagents and conditions: a. (Boc)₂O, CH₃OH, NaOH; b. EDCI, HOBt/anhydrous, DCM, 2a∼2b,4a∼4b,6a∼6d, 0°C to room temperature; c. HCl/anhydrous EtOAc; d. i) 15% Pd/C, CH₃OH. ii) HCl/anhydrous EtOAc.

Table 1.  The structures and IC₅₀ values of target compounds against APN and MMP-2.

Compound	R1	R2	APN/IC50^a (μM)	MMP/IC50^a (μM)
11a		-CH3	301.9 ± 1.3	>1000
11b		CH3	229.2 ± 0.6	681.7 ± 2.8
11c		-Bn	99.5 ± 2.1	328.5 ± 1.9
11d		-Bn	195.1 ± 0.7	>1000
12a		-H	249.1 ± 0.9	710.3 ± 2.3
12b		-H	199.2 ± 3.1	364.2 ± 4.0

Table

Compound	R3	R4	R5	APN /IC50 (μM)	MMP/IC50 (μM)
13a			-CH3	139.6 ± 0.5	125.6 ± 2.4
13b			-Bn	65.1 ± 0.7	225.4 ± 1.1
13c			-CH3	69.1 ± 1.4	236..6 ± 3.3
13d			-Bn	32.2 ± 2.3	333.7 ± 2.7
14a			-H	20.9 ± 0.8	115.0 ± 0.9
14b			-H	12.2 ± 1.6	203.4 ± 2.9
Bestatin				7.3 ± 0.2	167 ± 2.8

a. Each value represents the mean of three experiments, standard deviation is given.

Table 2.  In vitro antiproliferative inhibiting potency of compounds 11c, 13c, 13d and 14b.

Compound	HL-60 IC50^a (mM)	SKOV3 IC50 ^a(mM)
11c	0.33 ± 0.06	0.28 ± 0.03
13c	0.31 ± 0.05	0.07 ± 0.02
13d	>1000	>1000
14b	0.17 ± 0.03	0.38 ± 0.07
Bestatin	0.87 ± 0.07	1.98 ± 0.09

Each value represents the mean values with S.E values for 5 independent experiments.

Figure 1.  The docking result for 14b with the active site of APN (PDB: 2DQM).

Figure 2.  The docking results for 14b with APN showed by LIGPLOT.