Discovery of a series of small molecules as potent histone deacetylase inhibitors

Figures & data

Figure 1. Design of new scaffold from the lead structure.

Scheme 1. Reagents and conditions: (a) CH₃COCl, CH₃OH; (b) (Boc)₂O, Et₃N, MeOH/H₂O; (c) RSO₂Cl, NaHCO₃, THF/H₂O; (d) TBTU, Et₃N, THF; (e) NH₂OK, MeOH; (f) EtOAc, HCl.

Table 1. The inhibitory activities of derived molecules.*

Compounds	IC50‡ (μM)	HCT116 (inhib%)†,‡	K562 (inhib%)	MDA-MB-231 (inhib%)	ES-2 (inhib%)
4a	0.28	3.36	24.59	24.35	1.48
4b	0.74	3.77	22.75	11.40	5.07
4c	0.33	17.49	50.79	28.55	23.49
4d	1.42	20.51	55.63	21.98	13.33
4e	0.23	8.12	56.77	36.99	44.16
4f	1.05	8.31	8.22	3.05	16.73
4g	2.11	3.04	27.86	3.71	13.59
4h	0.14	22.32	57.79	35.98	50.01
4hb	0.18	8.66	50.44	9.73	32.71
h3	2.60	7.33	41.35	8.21	12.33
h4	3.79	4.65	34.88	5.06	9.55
SAHA	0.17	35.11	56.84	44.68	47.19

*The method for in vitro activity assay has been described in our previous work20.

†Each value is the mean of at least three experiments (all SDs are within 10% of the mean).

‡The acitivity was described as inhibition%, the concentration of the molecules is 5 μM.

Table 2. The tumor cell growth inhibitory activities of 4h compared with SAHA.*

Compounds	U937	HCT116	K562	HL60	MCF7	PC3
4h	1.85	12.12	2.67	2.02	12.70	4.93
SAHA	0.99	4.21	2.99	1.86	5.09	6.33

*Each value is the mean of at least three experiments (all SDs are within 10% of the mean).

Figure 2. Binding patterns of 4h and 4hb in the active site of HDAC2: (a) 4h and 4hb were shown using the wire model, the residues were displayed as sticks; carbon atoms of 4h were colored magenta, carbon atoms of 4hb were colored green, the gray ball is zinc ion, the H-bonds were represented as dash lines (in black--white mode, 4h is the structure containing Boc group); (b) 4h was shown using the ball–stick model.

Zhang YJ, Feng JH, Liu CX, et al. Design, synthesis and preliminary activity assay of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as novel histone deacetylases (HDACs) inhibitors. Bioorg Med Chem 2010;18:1761–72

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