Synthesis, bioevaluation and docking study of 5-substitutedphenyl-1,3,4-thiadiazole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents

Figures & data

Figure 1. Structures of some HDAC inhibitors.

Figure 2. A pharmacophore motif of HDACIs (A) and benzothiazole/5-substitutedphenyl-1,3,4-thiadiazole-based hydroxamic acids as HDACIs (B and C).

Scheme 1. Synthetic pathway for N¹-hydroxy-N⁸-(5-substitutedphenyl-1,3,4-thiadiazol-2-yl)octandiamides (5a–o).

Table 1. HDAC inhibition and cytotoxicity of the compounds synthesized.

			Cytotoxicity (IC50,* µM)/Cell lines†
Compound code	R	Molecular weight	SW620	MCF-7	PC3	AsPC-1	NCI-H460	Log p‡
5a	H	384.42	0.70	1.80	0.88	2.71	1.07	1.35
5b	2-Cl	382.86	0.34	1.23	0.42	0.63	0.11	1.99
5c	3-Cl	382.86	0.45	1.23	1.76	1.10	1.94	1.99
5d	4-Cl	382.86	1.62	0.73	0.84	1.34	1.50	1.99
5e	4-F	366.41	3.58	8.05	2.92	1.88	4.79	1.55
5f	4-Br	427.32	0.72	1.27	0.83	0.08	1.42	2.24
5g	4-CH3	362.45	11.52	20.78	14.90	6.38	13.16	1.90
5h	4-OCH3	378.45	1.46	2.46	1.63	0.80	1.97	1.43
5i	4-N(CH3)2	391.49	6.61	6.67	7.35	7.16	8.18	1.53
5j	2-NO2	393.42	19.23	31.18	14.69	33.47	16.69	1.17
5k	4-NO2	393.42	26.71	76.25	25.57	76.25	76.25	1.17
5l	2,6-Cl2	417.31	16.21	16.29	15.18	14.95	14.38	2.64
5m	3,4-CH2OCH2-	390.46	1.89	2.15	2.54	3.04	3.34	1.41
5n	2,3,4-(OCH3)3	438.50	2.29	4.15	1.77	2.11	3.21	0.86
5o	3,4,5-(OCH3)3	438.50	4.31	3.50	1.89	6.02	10.20	0.86
SAHA¶		264.32	3.70	6.42	4.31	3.66	2.77	1.44

*The concentrations (µM) of compounds that produce a 50% reduction in cell growth, the numbers represent the averaged results from triplicate experiments with deviation of less than 10%.

†Cell lines: SW620, colon cancer; MCF-7, breast cancer; PC3, prostate cancer; AsPC-1, pancreatic cancer; and NCI-H460, lung cancer.

‡Estimated by Software Kowwin v1.67 (US EPA, EPI suite v 4.0).

¶SAHA, suberoylanilide hydroxamic acid, a positive control.

Figure 3. Effect of the compounds synthesized on histone acetylation in SW620 cells. Cells were treated with compounds (10 µM) for 24 h. Levels of acetylated histone-H3 and -H4 in total cell lysates were determined by Western immunoblot analysis. VH denotes vehicle treatment (blank control). SAHA (suberoylanilide hydroxamic acid) is a positive control.

Figure 4. Stereoview of the actual binding pose of SAHA and simulated docking pose of compound 5b (A) and 5c (B) to HDAC8. SAHA, compounds 5b, 5c, and the interaction parts of the HDAC8 were shown as a stick model.