Common name: Chidamide; CS055; HBI-8000; Epidaza
Trademarks: Epidaza
Molecular Formula: C22H19FN4O2
CAS Registry Number: 743420-02-2
CAS Name: N-(2-amino-5-fluorophenyl)-4-[[[1-oxo-3-(3-pyridinyl)-2-propen-1-yl]amino]methyl]-benzamide
Molecular Weight: 390.416
SMILES: O=C(NCC1=CC=C(C(NC2=CC(F)=CC=C2N)=O)C=C1)/C=C/C3=CC=CN=C3
InChI Key: WXHHICFWKXDFOW-BJMVGYQFSA-N
InChI: 1S/C22H19FN4O2/c23-18-8-9-19(24)20(12-18)27-22(29)17-6-3-16(4-7-17)14-26-21(28)10-5-15-2-1-11-25-13-15/h1-13H,14,24H2,(H,26,28)(H,27,29)?/b10-5+
Activity: HDAC Inhibitor; Cancer Drug; Histone Deacetylase Inhibitor; HDAC-1, 2,3,10 Inhibitor; Treatment for Peripheral T-cell Lymphomas; Treatment for PTCL
Status: Launched 2014 (China)
Originator: Shenzhen Chipscreen Biosciences Ltd
Chiamide synthesis: US7244751B2
Procedure:
Step a: To a suspension of 0.33 g (2.01 mmol) of N,N'-carbonyldiimidazole in tetrahydrofunan (10 ml) is added drop-wise a solution of 0.30 g (2.01 mmol) of 3-pyridineacrylic acid at 0 °C. Then, the mixture is stirred at room temperature for 3 hours and added drop-wise to a separately prepared 2.0 ml (2.00 mmol) of 1N aqueous sodium hydroxide solution including 0.30 g (2.00 mmol) of 4-aminomethylbenzoic acid, followed by stirring at room temperature for 8 hours. The reaction mixture is evaporated under vacuum. To the residue is added a saturated solution of sodium chloride (2 ml), then the mixture is neutralized with concentrated hydrochloric acid to pH 5. The deposited white solid is collected by filtration, washed with ice-water, and then dried to give 4-[N-(Pyridin-3-ylacryloyl)aminomethyl]benzoic acid (0.46 g, 82%). HRMS calcd for C16H14N2O3: 282.2988. Found: 282.2990. MA calcd for: C16H14N2O3: C, 68.07%; H, 5.00%; N, 9.92%. Found: C, 68.21%; H, 5.03%; N, 9.90%.
Step b: To a suspension of 0.29 g (1.78 mmol) of N,N'-carbonyldiimidazole in tetrahydrofunan (15 ml) is added 0.50 g (1.78 mmol) of 4-[N-(Pyridin-3-ylacryloyl)aminomethyl]benzoic acid, followed by stirring at 45 °C. for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofiman (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 24 hours, the deposited white solid is collected by filtration, washed with tetrahydrofunan, and then dried to give N-(2-amino-4-fluorophenyl)-4-[N-(Pyridin-3-ylacryloyl)aminomethyl]benzamide (0.40 g, 57%). 1H NMR (300 MHz, DMSO-d6): dppm: 4.49 (2H, d), 4.84 (2H, br.s), 6.60 (1H, t), 6.80 (2H, m),696 (1H, t), 7.18 (1H, d), 7.42 (2H, d), 7.52 (1H, d), 7.95 (2H, d), 8.02 (1H, d), 8.56 (1H, d), 8.72 (1H, br. t), 8.78 (1H, s), 9.60 (1H, br.s). IR (KBr) cm1: 3310, 1655, 1631, 1524, 1305, 750. HRMS calcd for C22H19N4O2F: 390.4170. Found: 390.4172. MA calcd for C22H19N4O2F: C, 67.68%; H, 4.40%; N, 14.35%. Found: C, 67.52%; H, 4.38%; N, 14.42%.
Chiamide synthesis: US7244751B2
Procedure:
Step a: To a suspension of 0.33 g (2.01 mmol) of N,N'-carbonyldiimidazole in tetrahydrofunan (10 ml) is added drop-wise a solution of 0.30 g (2.01 mmol) of 3-pyridineacrylic acid at 0 °C. Then, the mixture is stirred at room temperature for 3 hours and added drop-wise to a separately prepared 2.0 ml (2.00 mmol) of 1N aqueous sodium hydroxide solution including 0.30 g (2.00 mmol) of 4-aminomethylbenzoic acid, followed by stirring at room temperature for 8 hours. The reaction mixture is evaporated under vacuum. To the residue is added a saturated solution of sodium chloride (2 ml), then the mixture is neutralized with concentrated hydrochloric acid to pH 5. The deposited white solid is collected by filtration, washed with ice-water, and then dried to give 4-[N-(Pyridin-3-ylacryloyl)aminomethyl]benzoic acid (0.46 g, 82%). HRMS calcd for C16H14N2O3: 282.2988. Found: 282.2990. MA calcd for: C16H14N2O3: C, 68.07%; H, 5.00%; N, 9.92%. Found: C, 68.21%; H, 5.03%; N, 9.90%.
Step b: To a suspension of 0.29 g (1.78 mmol) of N,N'-carbonyldiimidazole in tetrahydrofunan (15 ml) is added 0.50 g (1.78 mmol) of 4-[N-(Pyridin-3-ylacryloyl)aminomethyl]benzoic acid, followed by stirring at 45 °C. for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofiman (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 24 hours, the deposited white solid is collected by filtration, washed with tetrahydrofunan, and then dried to give N-(2-amino-4-fluorophenyl)-4-[N-(Pyridin-3-ylacryloyl)aminomethyl]benzamide (0.40 g, 57%). 1H NMR (300 MHz, DMSO-d6): dppm: 4.49 (2H, d), 4.84 (2H, br.s), 6.60 (1H, t), 6.80 (2H, m),696 (1H, t), 7.18 (1H, d), 7.42 (2H, d), 7.52 (1H, d), 7.95 (2H, d), 8.02 (1H, d), 8.56 (1H, d), 8.72 (1H, br. t), 8.78 (1H, s), 9.60 (1H, br.s). IR (KBr) cm1: 3310, 1655, 1631, 1524, 1305, 750. HRMS calcd for C22H19N4O2F: 390.4170. Found: 390.4172. MA calcd for C22H19N4O2F: C, 67.68%; H, 4.40%; N, 14.35%. Found: C, 67.52%; H, 4.38%; N, 14.42%.
Activity:
Chidamide is an orally bioavailable, low-nanomolar inhibitor of cancer-associated histone deacetylase (HDAC) enzymes with favorable pharmacology and tolerability profiles relative to existing benzamide and non-benzamide HDAC inhibitors. It targets specifically the subtype 1, 2, 3 of Class I and subtype 10 of Class IIb HDAC and is being studied in multiple clinical trials as a single agent or in combination with chemotherapeutic agents for the treatment of various hematological and solid cancers. In clinically administrated concentrations, it demonstrated a unique epigenetic mechanism of actions against tumor cell development, involving preferential induction of growth arrest and apoptosis in blood and lymphoid-derived tumor cells, activation of NK-mediated and CD8-mediated antigen-specific cellular anti-tumor immunity, differentiation of tumor stem cells, reversal of drug-resisting tumor cells and epithelia to mesenchymal transition, which are hallmarks of treatment resistance, tumor cell metastasis and recurrence.
Chidamide was shown to enhance the cytotoxic effect of human peripheral mononuclear cells ex vivo on K562 target cells, accompanied by the upregulation of proteins involved in NK cell functions. Furthermore, the expression of a number of genes involved in immune cell-mediated antitumor activity was observed to be upregulated in peripheral white blood cells from two T-cell lymphoma patients who responded to chidamide administration [1].
In a reported study, researchers investigated the effects of Chidamide on proliferation, differentiation and apoptosis in human leukaemia cell lines and primary myeloid leukaemia cells. The results showed that
1. At low concentrations ( less than 1 µM), Chidamide induced G1 arrest.
2. At moderate concentrations (0.5 µM-2 µM), Chidamide induced differentiation, as determined by the increased expression of the myeloid differentiation marker CD11b.
3. At relatively high concentrations (2 µM-4 µM), Chidamide potently induced caspase-dependent apoptosis.
4. Co-treatment with the ROS (reactive oxygen species) scavengers N-acetyl-L-cysteine or Tiron blocked Chidamide-induced cell differentiation and apoptosis, suggesting an essential role for ROS in these effects. Cytochrome c release and ROS-mediated mitochondrial dysfunction are involved in Chidamide-induced apoptosis of leukaemia.
5. In addition to cell lines, Chidamide also exhibits therapeutic effects in human primary leukaemia cells.
6. Moreover, daily oral Chidamide treatment of nude mice bearing HL60 cell xenografts suppressed tumour growth, induced tumour cell apoptosis and prolonged the survival of tumour-bearing mice.
In conclusion, findings demonstrate that Chidamide is a novel HDACi with potential chemotherapeutic value in several haematological malignancies, especially leukaemia [2].
References:
1. Ning, Z. Q.; et. al. Chidamide (CS055/HBI-8000): a new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicity. Cancer Chemother Pharmacol 2012, 69(4), 901-909. (activity)
2. Gong, K.; et. al. CS055 (Chidamide/HBI-8000), a novel histone deacetylase inhibitor, induces G1 arrest, ROS-dependent apoptosis and differentiation in human leukaemia cells. Biochem J 2012, 443(3), 735-746. (activity)
Chidamide is an orally bioavailable, low-nanomolar inhibitor of cancer-associated histone deacetylase (HDAC) enzymes with favorable pharmacology and tolerability profiles relative to existing benzamide and non-benzamide HDAC inhibitors. It targets specifically the subtype 1, 2, 3 of Class I and subtype 10 of Class IIb HDAC and is being studied in multiple clinical trials as a single agent or in combination with chemotherapeutic agents for the treatment of various hematological and solid cancers. In clinically administrated concentrations, it demonstrated a unique epigenetic mechanism of actions against tumor cell development, involving preferential induction of growth arrest and apoptosis in blood and lymphoid-derived tumor cells, activation of NK-mediated and CD8-mediated antigen-specific cellular anti-tumor immunity, differentiation of tumor stem cells, reversal of drug-resisting tumor cells and epithelia to mesenchymal transition, which are hallmarks of treatment resistance, tumor cell metastasis and recurrence.
Chidamide was shown to enhance the cytotoxic effect of human peripheral mononuclear cells ex vivo on K562 target cells, accompanied by the upregulation of proteins involved in NK cell functions. Furthermore, the expression of a number of genes involved in immune cell-mediated antitumor activity was observed to be upregulated in peripheral white blood cells from two T-cell lymphoma patients who responded to chidamide administration [1].
In a reported study, researchers investigated the effects of Chidamide on proliferation, differentiation and apoptosis in human leukaemia cell lines and primary myeloid leukaemia cells. The results showed that
1. At low concentrations ( less than 1 µM), Chidamide induced G1 arrest.
2. At moderate concentrations (0.5 µM-2 µM), Chidamide induced differentiation, as determined by the increased expression of the myeloid differentiation marker CD11b.
3. At relatively high concentrations (2 µM-4 µM), Chidamide potently induced caspase-dependent apoptosis.
4. Co-treatment with the ROS (reactive oxygen species) scavengers N-acetyl-L-cysteine or Tiron blocked Chidamide-induced cell differentiation and apoptosis, suggesting an essential role for ROS in these effects. Cytochrome c release and ROS-mediated mitochondrial dysfunction are involved in Chidamide-induced apoptosis of leukaemia.
5. In addition to cell lines, Chidamide also exhibits therapeutic effects in human primary leukaemia cells.
6. Moreover, daily oral Chidamide treatment of nude mice bearing HL60 cell xenografts suppressed tumour growth, induced tumour cell apoptosis and prolonged the survival of tumour-bearing mice.
In conclusion, findings demonstrate that Chidamide is a novel HDACi with potential chemotherapeutic value in several haematological malignancies, especially leukaemia [2].
References:
1. Ning, Z. Q.; et. al. Chidamide (CS055/HBI-8000): a new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicity. Cancer Chemother Pharmacol 2012, 69(4), 901-909. (activity)
2. Gong, K.; et. al. CS055 (Chidamide/HBI-8000), a novel histone deacetylase inhibitor, induces G1 arrest, ROS-dependent apoptosis and differentiation in human leukaemia cells. Biochem J 2012, 443(3), 735-746. (activity)
3. Hu, W.; et. al. N-(2-amino-5-fluorophenyl)-4-[N-(Pyridin-3-ylacryloyl) aminomethyl ]benzamide or other derivatives for treating cancer and psoriasis. US7244751B2
4. Lu, X.; et. al. Crystal form of chidamide, preparation method and use thereof. WO2014082354A1
5. Yin, Z.-H.; et. al. Synthesis of chidamide,a new histone deacetylase (HDAC) inhibitor. Chin J New Drugs 2004, 13(6), 536-538. (starts with basic raw materials)
4. Lu, X.; et. al. Crystal form of chidamide, preparation method and use thereof. WO2014082354A1
5. Yin, Z.-H.; et. al. Synthesis of chidamide,a new histone deacetylase (HDAC) inhibitor. Chin J New Drugs 2004, 13(6), 536-538. (starts with basic raw materials)
