Design, synthesis, and antitumor evaluation of histone deacetylase inhibitors with l-phenylglycine scaffold

Figures & data

Figure 1 The structures of five approved drugs (A) and HDAC inhibitors in clinical trials (B).

Abbreviations: SAHA, suberoylanilide hydroxamic acid; HDAC, histone deacetylase.

Figure 2 The development of phenylglycine-based HDAC inhibitors.

Abbreviation: HDAC, histone deacetylase.

Figure 3 Reagents and conditions: (a) BTC, dioxane, reflux; (b) Et₃N, DCM; (c) TBTU, Et₃N, DCM; (d) NaBH₃(CN), AcOH, EtOH; (e) NH₂OK, MeOH; (f) HCl, anhydrous EtOAc.

Abbreviations: BTC, bis(trichloromethyl) carbonate; DCM, dichloromethane; TBTU, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate.

Figure 4 Reagents and conditions: (a) CH₃COCl, MeOH; (b) SnCl₂, EtOH; (c) HCl, anhydrous EtOAc; (d) TBTU, Et₃N, DCM; (e) BTC, dioxane, reflux; (f) Et₃N, DCM; (g) NH₂OK, MeOH.

Abbreviations: TBTU, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate; DCM, dichloromethane; BTC, bis(trichloromethyl) carbonate.

Table 1 HDAC inhibitory activities of ureido series compounds

	R1	n	HeLa cell nuclear extract IC50 (nM)a
SAHAb	–	–	145.6
D18b		0	7.5
7a		0	13.3
7b		0	12.6
7c		0	2.3
7d		0	76.1
7e		0	4.1
7f		0	6.3
7g		0	2.7
7h		0	1.2
7i		0	15.0
7j		0	178.2
7k		0	124.5
16a		1	128.0
16b		1	215.2
16c		1	91.7
16d		1	811.0

Notes:

a Values are the mean of three experiments. The standard derivations are <20% of the mean.

b Data from Zhang et al.⁸

Abbreviations: SAHA, suberoylanilide hydroxamic acid; IC₅₀, half-maximal inhibitory concentration; HDAC, histone deacetylase.

Table 2 HDAC inhibitory activities of amide series compounds

Compound	R1	HeLa cell nuclear extract IC50 (nM)a
SAHAb	–	145.6
D3b		14.3
D7b		28.7
8a		168.1
8b		162.6
8c		106.6
8d		53.0
8e		352.6

Notes:

a Values are the mean of three experiments. The standard derivations are <20% of the mean.

b Data from Zhang et al.⁸

Abbreviations: SAHA, suberoylanilide hydroxamic acid; IC₅₀, half-maximal inhibitory concentration; HDAC, histone deacetylase.

Table 3 In vitro antiproliferative activities against U937 cell line of representative ureido and amide series compounds

	Ureido series compounds								Amide series compounds
	D18a	7a	7b	7c	7e	7g	7h	7i	D3a	8a	8b	8c	8d
U937 IC50 (μM)b	1.31	6.1	2.9	4.4	2.0	3.1	5.1	5.7	1.32	10.5	10.5	9.8	8.9

Notes:

a Data from Zhang et al.⁸

b Values are the mean of three experiments. The standard derivations are <20% of the mean.

Abbreviation: IC₅₀, half-maximal inhibitory concentration.

Table 4 HDAC inhibitory activities and antiproliferative activities of secondary amine series compounds

Compound	R3	IC50 (nM)a	IC50 (μM)a
		HeLa cell nuclear extract	U937	U266	KG-1	HeLa	H7402	HCT116
SAHAb	–	145.6	4.2	1.4	2.7	9.0	8.0	4.1
D18b	–	7.5	1.3	5.3	2.8	17.2	>20	4.0
9a		105.0	0.75	1.5	1.1	8.0	4.1	1.4
9b		56.1	1.1	2.4	3.4	6.0	4.2	5.5
9c		12.8	0.84	2.1	1.5	15.0	7.1	2.3
9d		70.0	0.53	0.98	0.90	5.4	3.5	1.3
9e		13.8	0.95	3.0	2.0	15.6	9.6	3.0
9f		50.3	0.98	3.3	2.5	6.8	12.4	3.0
9g		72.0	2.0	4.3	5.6	.20	.20	6.2

Notes:

a Values are the mean of three experiments. The standard derivations are <20% of the mean.

b Data from Zhang et al.⁸

Abbreviations: HDAC, histone deacetylase; SAHA, suberoylanilide hydroxamic acid; IC₅₀, half-maximal inhibitory concentration.

Figure 5 Growth curve of implanted U937 xenograft in nude mice.

Note: Data are expressed as the mean ± standard deviation.
Abbreviations: Ctrl, control; po, per os; SAHA, suberoylanilide hydroxamic acid.

Figure 6 Picture of dissected U937 tumor tissues.

Abbreviations: po, per os; SAHA, suberoylanilide hydroxamic acid.

ZhangLZhangYChouCJHistone deacetylase inhibitors with enhanced enzymatic inhibition effects and potent in vitro and in vivo antitumor activitiesChemMedChem2014963864824227760

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