149647-78-9

Basic information

• Product Name: Vorinostat
• Synonyms: SAHA cpd;UNII-58IFB293JI;Vornostat;Octanediamide, N1-hydroxy-N8-phenyl-;SAHA=N-Hydroxy-N'-phenyloctanediamide;SAHA, N-Hydroxy-Nphenyloctanediamide, Zolinza;Zolinza (See Suberoylanilide Hydroxamic Acid);Vorinostat
• CAS NO: 149647-78-9
• Molecular Formula: C₁₄H₂₀N₂O₃
• Molecular Weight: 264.32
• EINECS: 1308068-626-2
• Product Categories: Aromatics;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;API;Inhibitor;ZOLINZA;Anti-cancer & immunity
• Mol File: 149647-78-9.mol
• Article Data: 39

Chemical Properties

• Melting Point: 161-162°C
• Appearance: white to tan/
• Density: 1.2
• Refractive Index: 1.566
• Storage Temp.: -20°C Freezer
• Solubility: DMSO: ≥15mg/mL
• PKA: 9.48±0.20(Predicted)
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 6 months.
• Merck: 14,10034
• CAS DataBase Reference: Vorinostat(CAS DataBase Reference)
• NIST Chemistry Reference: Vorinostat(149647-78-9)
• EPA Substance Registry System: Vorinostat(149647-78-9)

Safety Data

• Hazard Codes: T
• Statements: 61-68
• Safety Statements: 53-36/37-45
• WGK Germany: 3
• RTECS: RG8835000
• Hazardous Substances Data: 149647-78-9(Hazardous Substances Data)

Usage

Antitumor drugs

Vorinostat is a novel, molecularly targeted antineoplastic agent that causes cell cycle arrest and/or apoptosis by inhibiting histone deacetylase (HDAC). It is the first HDAC inhibitor approved by the US Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma (CTCL) with significant skin involvement that is still progressing, resistant or relapsing after two systemic regimens. On October 6, 2006, the US Food and Drug Administration (FDA) have approved vorinostat capsules (vorinostat) for the treatment of skin cancer drugs. The drug is the first novel type of anti-cancer drugs of histone deacetylase inhibitor developed by the United States Merck for the treatment of skin T cell lymphoma (CTCL). FDA has approved it for the treatment of metastatic skin T-cell lymphoma which is unable to be cured or even worsened or gets recurrent cases. A large number of experimental studies and clinical results have shown that vorinostat has a excellent efficacy on a variety of tumors and have significant synergies when combined with other oncology drugs. The current treatment of other tumors is still undergoing in-depth study; these results show that vorinostat has a broad market prospects. Vorinostat has low toxicity with the evidence of its safety and efficacy being supported by two clinical trials, including 107 patients with CTCL who had gotten relapsed after receiving other drugs. According to the standard analysis of improvement in the grade of skin lesion, 30% of patients treated with Zolinza get symptoms improved, with the average efficacy duration of 168 days. The most common serious adverse events were pulmonary embolism, dehydration, deep venous thrombosis and anemia. Common adverse reactions are gastrointestinal symptoms (including diarrhea, nausea and loss of appetite, vomiting and constipation); fatigue, chills and taste disorders. Animal experiments showed that pregnant women should be banned of using the drug.

Preparation

Suberic acid can undergo the intramolecular dehydration into suberic anhydride under the action of the acetic anhydride. The suberic anhydride, together with aniline can have ring-opening amidation in ethyl acetate at 0 °C to generate suberic acid monoanilide, followed by methanol esterification and hydroxylamine amine aminolysis to obtain the anti-tumor drug in vorinostat with the total yield of about 65%. "Chinese Journal of Pharmaceutical Industry" 2009, Volume 40, No. 7, pages 481-483

Anti-cancer drug Vorinostat was able to clear latent HIV virus

Researchers from the University of North Carolina at Chapel Hill have published a groundbreaking research paper in the July 25, 2012 issue of Nature to confirm that a deacetylase inhibitor drug – vorinostat that can be used to treat certain types of lymphoma-being capable of clearing out the patient's latent HIV virus in vivo. The researchers have conducted a series of experiments to evaluate the potential of this drug to activate and destroy latent HIV viruses. Initially, laboratory experiments for measuring the level of active HIV in CD4 + T cells showed that vorinostat can take off the camouflage of latent HIV viruses in these cells. Then, eight male patients who still kept medically stable HIV infection after antiretroviral therapy, took vorinostat, and then were tested their active HIV levels in the body and compared it to the levels they had before taking the drug. The researchers found that HIV-RNA levels in CD4 + T cells increased by an average of 4.5-fold in those patients who receiving vorinostat, confirming that the HIV virus was disguised. This is the first published study confirming that deacetylase inhibitors have the potential to break down latency in latent virus libraries. The study provides convincing evidence that a new strategy may be used to directly attack and eradicate latent HIV infection. However, getting rid of the latent nature of HIV is only the first step in curing HIV infection.

Description

Vorinostat is the first drug in a new class of anti-cancer agents that inhibit histone deacetylases (HDAC). It was launched as an oral treatment for cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease on or following two systemic therapies. HDACs are enzymes that catalyze the removal of the acetyl modification on lysine residues of proteins, including the core nucleosomal histones. Together with their counterpart histone acetyltransferases (HATs), HDACs regulate the acetylation level of the histones, which plays an important role in the regulation of chromatin plasticity and gene transcription. Hypoacetylation of histones is associated with a condensed chromatin structure resulting in the repression of gene transcription, whereas acetylated histones are associated with a more open chromatin structure and activation of transcription. In some cancer cells, there is an overexpression of HDACs, resulting in hypoacetylation of histones. Inhibitors of HDAC are thought to transcriptionally reactivate dormant tumor-suppressor genes by allowing for the accumulation of acetyl groups on histones and an open chromatin structure. Vorinostat inhibits the enzymatic activity of HDAC1, HDAC2, HDAC3, and HDAC6 at nanomolar concentrations (IC50 ＜86 nM). In vitro, it induces growth arrest, differentiation or apoptosis in a variety of tumor cells. In addition, vorinostat inhibits tumor growth in animal models bearing solid tumors, including breast, prostate, lung and gastric cancers, as well as hematologic malignancies such as multiple myeloma and leukemias.

Chemical Properties

White Crystalline Solid

Originator

Columbia University (US)

Uses

Different sources of media describe the Uses of 149647-78-9 differently. You can refer to the following data:
1. A potent, selective, cell permeable histone deacetylase inhibitor (HDAC). Displays anti-angiogenic activity by interfering with VEGF signaling in human umbilical vein endothelial cells (HUVECs). Induces differentiation in uman breast cancer cells.
2. antineoplastic, histone deacetylase inhibitor
3. Suberoylanilide Hydroxamic Acid is a potent, selective, cell permeable histone deacetylase inhibitor (HDAC). Suberoylanilide Hydroxamic Acid displays anti-angiogenic activity by interfering with VEGF signaling in human umbilical vein endothelial cells (HUVECs). Suberoylanilide Hydroxamic Acid induces differentiation in uman breast cancer cells.
4. A potent HDAC inhibitor; also causes cell cycle arrest at G1
5. Vorinostat, a histone deacetylase (HDAC) inhibitor from Merck, was approved for the treatment of cutaneous T-cell lymphoma (CTCL), a type of non-Hodgkin’s lymphoma. Vorinostat was shown to inhibit HDAC1, HDAC2, HDAC3 and HDAC6 at nanomolar concentrations. HDAC inhibitors are potent differentiating agents toward a variety of neoplasms, including leukemia and breast and prostate cancers.

Definition

ChEBI: A dicarboxylic acid diamide comprising suberic (octanedioic) acid coupled to aniline and hydroxylamine. A histone deacetylase inhibitor, it is marketed under the name Zolinza for the treatment of cutaneous T cell lymphoma (CTCL).

Brand name

Zolinza

General Description

Histones are proteins around which DNA is wound in the process of packing DNA into the nucleus. They also havea role in regulating the transcription of genes, and this iscontrolled by the covalent modifications acetylation, phosphorylation,and methylation to which they are subject.Vorinostat fits the basic pharmacophore for the HDACis, which consists of a hydrophobic cap regionconnected to a zinc coordinating functionality by a hydrophobiclinker.The hydroxamic acid functionality iscapable of bidendate binding to zinc present in the enzymeand is a major factor in the overall binding of the compound.The compound inhibits HDAC1, 2, 3, and 6 classes of thisenzyme with nanomolar (＜86 nM) IC50 values.The agent is given orally and is available in 100-mg capsulesfor the treatment of cutaneous T-cell lymphoma. Thebioavailability is 43%, and the agent is 71% bound toplasma proteins. Extensive metabolism of the agent occursto give the O-glucuronide of the hydroxamic acid functionand 4-anilino-4-oxobutanoic acid with minimal involvementof isozymes of CYP. The metabolites, both of whichare inactive, are eliminated in the urine and the drug has aterminal elimination half-life of 2 hours. The most commonlyreported adverse effects are fatigue, diarrhea, andnausea.

Biochem/physiol Actions

SAHA or Vorinostat facilitates the transcription of genes that result in apoptosis, differentiation and growth arrest. It has been observed to give beneficial results in lymphoma but not in solid tumors.

Synthesis

Commercially available monomethyl ester 125 was reacted with aniline in the presence of DCC and HOBt in DMF to give amide 127 in 89% yield.Methyl ester amide 127 was then reacted with hydroxylamine HCl salt and potassium hydroxide in methanol to give vorinostat (XVI) in 90% yield.

References

1) Vrana et al. (1999), Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-XL, c-Jun and p21CIP1, but independent of p53; Oncogene, 18 7016 2) Butler et al. (2002), The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin; Proc. Natl. Acad. Sci. USA, 99 11700 3) Tang et al. (2012), Sorafenib and HDAC inhibitors synergize to kill CNS tumor cells, 13 567

InChI:InChI=1/C14H20N2O3/c17-13(15-12-8-4-3-5-9-12)10-6-1-2-7-11-14(18)16-19/h3-5,8-9,19H,1-2,6-7,10-11H2,(H,15,17)(H,16,18)

Synthetic route

7-phenylcarbamoyl heptanoic acid methyl ester (162853-41-0) → vorinostat (149647-78-9)

Conditions	Yield
Stage #1: 7-phenylcarbamoyl heptanoic acid methyl ester With hydroxylamine hydrochloride; sodium methylate In methanol; water for 16.1667h; Stage #2: With water; acetic acid In methanol for 0.166667h; pH=8.7 - 12.02;	95.6%
With hydroxylamine hydrochloride; sodium methylate In methanol for 16.1667h;	95.6%
Stage #1: 7-phenylcarbamoyl heptanoic acid methyl ester With hydroxylamine hydrochloride; sodium methylate In methanol for 16.3333h; Stage #2: With sodium methylate In methanol; water for 0.166667h; pH=12.01 - 12.02; Stage #3: With acetic acid In methanol; water pH=8.70 - 8.98; Product distribution / selectivity;	95.6%

C21H24N2O3 → vorinostat (149647-78-9)

Conditions	Yield
With 10 wt% Pd(OH)2 on carbon; hydrogen; trifluoroacetic acid In methanol at 20℃; for 2h;	91%

N-phenylhexanamide (6998-10-3) → vorinostat (149647-78-9)

Conditions	Yield
With hydroxylamine hydrochloride In N,N-dimethyl-formamide at 40℃; for 1h; Reagent/catalyst;	88.5%

8-(hydroxyamino)-8-oxooctanoic acid (149647-86-9) + aniline (62-53-3) → vorinostat (149647-78-9)

Conditions	Yield
With dicyclohexyl-carbodiimide; potassium hydroxide In ethanol at 50℃; for 0.5h;	82.4%
With dicyclohexyl-carbodiimide; 1,1'-carbonyldiimidazole In tetrahydrofuran

suberanilic acid (149648-52-2) → vorinostat (149647-78-9)

Conditions	Yield
With C36H24B4N2O3; hydroxylamine hydrochloride; triethylamine In toluene at 80℃; for 14h; Molecular sieve;	82%
Stage #1: suberanilic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 25 - 30℃; for 0.5h; Stage #2: With hydroxylamine hydrochloride In N,N-dimethyl-formamide for 0.5h;	75%
Stage #1: suberanilic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 25 - 30℃; for 0.5h; Stage #2: With hydroxylamine hydrochloride In N,N-dimethyl-formamide for 0.5h;	75%

7-phenylcarbamoyl heptanoic acid methyl ester (162853-41-0) → suberanilic acid (149648-52-2) + vorinostat (149647-78-9)

Conditions	Yield
With water; hydroxylamine; sodium methylate In methanol at 90℃;	A 15% B 80%

C17H23NO5 → vorinostat (149647-78-9)

Conditions	Yield
With hydroxylamine In methanol
With hydroxylamine hydrochloride; potassium hydroxide In methanol at 20℃; for 0.25h;
Multi-step reaction with 4 steps 1: sodium tetrahydroborate / methanol / 0.5 h / 0 °C 2: Dess-Martin periodane / dichloromethane / 1 h / 20 °C 3: Benzoylformic acid / Petroleum ether / 48 h / 20 °C / Irradiation; Green chemistry 4: hydroxylamine hydrochloride; triethylamine / dichloromethane / 24 h / 20 °C View Scheme
With hydroxylamine hydrochloride In tetrahydrofuran; methanol at 20℃; for 1.5h;
With hydroxylamine hydrochloride; potassium hydroxide In tetrahydrofuran; methanol at 20℃; for 0.5h;	0.14 g

suberic acid monomethyl ester (3946-32-5) → vorinostat (149647-78-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 88.7 percent / 1-hydroxybenzotriazole; dicyclohexylcarbodiimide / dimethylformamide / 1.5 h / 20 °C 2: 90 percent / hydroxylamine; KOH / methanol / 1 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: thionyl chloride / dichloromethane; N,N-dimethyl-formamide / 3 h / Reflux 2: triethylamine / dichloromethane / 1.5 h / 20 °C 3: hydroxylamine hydrochloride; sodium methylate / methanol / 0.67 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: 1-hydroxy-1H-benzotriazole hydrate / N,N-dimethyl-formamide 2: potassium hydroxide; hydroxylamine hydrochloride / methanol View Scheme
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / dichloromethane / 20 °C / Cooling with ice 2.1: lithium hydroxide; water / tetrahydrofuran / 12 h / 20 °C 3.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 °C / Cooling with ice 3.2: 20 °C 4.1: dihydrogen peroxide / aq. phosphate buffer / 4 h / 37 °C / pH 7.4 View Scheme

aniline (62-53-3) + [(Xantphos)2Pd(3-methyl-1-butenyl]OTf → vorinostat (149647-78-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 88.7 percent / 1-hydroxybenzotriazole; dicyclohexylcarbodiimide / dimethylformamide / 1.5 h / 20 °C 2: 90 percent / hydroxylamine; KOH / methanol / 1 h / 20 °C View Scheme

octane-1,8-dioic acid (505-48-6) → vorinostat (149647-78-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: 96 percent / Ac2O / 1 h / Heating 2: 94 percent / tetrahydrofuran / 0.5 h / 20 °C 3: Et3N / tetrahydrofuran / 0.17 h 4: NH2OH / methanol View Scheme
Multi-step reaction with 6 steps 1.1: 0.17 h / 150 - 180 °C 1.2: 0.33 h / 20 °C 2.1: triethylamine / tetrahydrofuran / 0.25 h / -10 °C 3.1: sodium tetrahydroborate / methanol / 0.5 h / 0 °C 4.1: Dess-Martin periodane / dichloromethane / 1 h / 20 °C 5.1: Benzoylformic acid / Petroleum ether / 48 h / 20 °C / Irradiation; Green chemistry 6.1: hydroxylamine hydrochloride; triethylamine / dichloromethane / 24 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: 0.17 h / 185 - 190 °C / Sealed tube 2: Dowex50W-X2 acid resin / 22 h / Reflux 3: methanol; hydroxylamine hydrochloride; sodium View Scheme
Multi-step reaction with 3 steps 1.1: 0.33 h / 175 - 190 °C 1.2: 0.33 h 2.1: 18 h / Heating / reflux 3.1: hydroxylamine hydrochloride; sodium methylate / methanol View Scheme
Multi-step reaction with 3 steps 1.1: acetic anhydride 2.1: tetrahydrofuran 3.1: triethylamine; chloroformic acid ethyl ester / 0 °C 3.2: 20 °C View Scheme

oxonane-2,9-dione (10521-06-9) → vorinostat (149647-78-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 94 percent / tetrahydrofuran / 0.5 h / 20 °C 2: Et3N / tetrahydrofuran / 0.17 h 3: NH2OH / methanol View Scheme
Multi-step reaction with 3 steps 1: copper(l) iodide / 1,4-dioxane; water 2: zinc(II) chloride / 3 h / 50 °C 3: sodium methylate; hydroxylamine hydrochloride / methanol / 3 h / 40 °C View Scheme
Multi-step reaction with 2 steps 1.1: tetrahydrofuran 2.1: triethylamine; chloroformic acid ethyl ester / 0 °C 2.2: 20 °C View Scheme

C16H21NO5 → vorinostat (149647-78-9)

Conditions	Yield
With hydroxylamine In tetrahydrofuran; methanol at 0 - 5℃; for 0.25h;

octane-1,8-dioic acid (505-48-6) + aniline (62-53-3) → vorinostat (149647-78-9)

Conditions	Yield
With hydroxylamine; dicyclohexyl-carbodiimide; 1,1'-carbonyldiimidazole In tetrahydrofuran at 25 - 30℃;
Multi-step reaction with 2 steps 1.1: dicyclohexyl-carbodiimide; 1,1'-carbonyldiimidazole / tetrahydrofuran 2.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 0.5 h / 25 - 30 °C 2.2: 0.5 h View Scheme
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; ethyl 2-(tert-butoxycarbonyloxyimino)-2-cyanoacetate / tetrahydrofuran / 1 h / 0 - 5 °C 2.1: dmap; N-ethyl-N,N-diisopropylamine; ethyl 2-(tert-butoxycarbonyloxyimino)-2-cyanoacetate / tetrahydrofuran / 0.5 h / 0 - 5 °C 2.2: 20 °C View Scheme

suberic acid monomethyl ester (3946-32-5) + aniline (62-53-3) → vorinostat (149647-78-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 0.08 h 1.2: 4 h / 25 °C 2.1: hydroxylamine hydrochloride; potassium hydroxide / methanol / 0.1 h / 80 °C / Microwave irradiation View Scheme
Multi-step reaction with 2 steps 1: boric acid / toluene / 10 h / Reflux; Dean-Stark; Inert atmosphere; Green chemistry 2: potassium hydroxide; hydroxylamine hydrochloride / methanol / 0.5 h / 20 - 40 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 12 h / 20 °C 2: hydroxylamine; potassium hydroxide / methanol / 1.5 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: boric acid / toluene / 10 h / Reflux; Inert atmosphere; Dean-Stark; Green chemistry 2: potassium hydroxide; hydroxylamine hydrochloride / methanol / 1 h / 40 °C / Green chemistry View Scheme

8-oxo-N-phenyloctanamide → vorinostat (149647-78-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: Benzoylformic acid / Petroleum ether / 48 h / 20 °C / Irradiation; Green chemistry 2: hydroxylamine hydrochloride; triethylamine / dichloromethane / 24 h / 20 °C View Scheme

8-hydroxy-N-phenyloctanamide → vorinostat (149647-78-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: Dess-Martin periodane / dichloromethane / 1 h / 20 °C 2: Benzoylformic acid / Petroleum ether / 48 h / 20 °C / Irradiation; Green chemistry 3: hydroxylamine hydrochloride; triethylamine / dichloromethane / 24 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydroxide; potassium permanganate / water / 20 °C 2.1: triethylamine; chloroformic acid ethyl ester / tetrahydrofuran / 0.5 h / 0 °C 2.2: 1 h / 20 °C View Scheme

aniline (62-53-3) → vorinostat (149647-78-9)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: 0.17 h / 150 - 180 °C 1.2: 0.33 h / 20 °C 2.1: triethylamine / tetrahydrofuran / 0.25 h / -10 °C 3.1: sodium tetrahydroborate / methanol / 0.5 h / 0 °C 4.1: Dess-Martin periodane / dichloromethane / 1 h / 20 °C 5.1: Benzoylformic acid / Petroleum ether / 48 h / 20 °C / Irradiation; Green chemistry 6.1: hydroxylamine hydrochloride; triethylamine / dichloromethane / 24 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: copper(l) iodide / 1,4-dioxane; water 2: zinc(II) chloride / 3 h / 50 °C 3: sodium methylate; hydroxylamine hydrochloride / methanol / 3 h / 40 °C View Scheme
Multi-step reaction with 3 steps 1.1: 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine / 24 h / 100 °C 2.1: sodium hydroxide; potassium permanganate / water / 20 °C 3.1: triethylamine; chloroformic acid ethyl ester / tetrahydrofuran / 0.5 h / 0 °C 3.2: 1 h / 20 °C View Scheme

diisopropyl 1-(8-oxo-8-(phenylamino)octanoyl)hydrazine-1,2-dicarboxylate → vorinostat (149647-78-9)

Conditions	Yield
With hydroxylamine hydrochloride; triethylamine In dichloromethane at 20℃; for 24h;

oxonan-2-one (5698-29-3) → vorinostat (149647-78-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine / 24 h / 100 °C 2.1: sodium hydroxide; potassium permanganate / water / 20 °C 3.1: triethylamine; chloroformic acid ethyl ester / tetrahydrofuran / 0.5 h / 0 °C 3.2: 1 h / 20 °C View Scheme

(4-(((8-oxo-8-(phenylamino)octanamido)oxy)methyl)phenyl)boronic acid → vorinostat (149647-78-9)

Conditions	Yield
With dihydrogen peroxide In aq. phosphate buffer at 37℃; for 4h; pH=7.4; Reagent/catalyst;

(4-(((8-oxo-8-(phenylamino)octanamido)oxy)methyl)phenyl)boronic acid → C21H26N2O4 + vorinostat (149647-78-9)

Conditions	Yield
With dihydrogen peroxide In aq. phosphate buffer at 37℃; for 4h; pH=7.4; Reagent/catalyst;

aniline (62-53-3) → C21H26N2O4 + vorinostat (149647-78-9)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / dichloromethane / 20 °C / Cooling with ice 2.1: lithium hydroxide; water / tetrahydrofuran / 12 h / 20 °C 3.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 °C / Cooling with ice 3.2: 20 °C 4.1: dihydrogen peroxide / aq. phosphate buffer / 4 h / 37 °C / pH 7.4 View Scheme

suberic acid monomethyl ester (3946-32-5) → C21H26N2O4 + vorinostat (149647-78-9)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / dichloromethane / 20 °C / Cooling with ice 2.1: lithium hydroxide; water / tetrahydrofuran / 12 h / 20 °C 3.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 °C / Cooling with ice 3.2: 20 °C 4.1: dihydrogen peroxide / aq. phosphate buffer / 4 h / 37 °C / pH 7.4 View Scheme

7-phenylcarbamoyl heptanoic acid methyl ester (162853-41-0) → C21H26N2O4 + vorinostat (149647-78-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: lithium hydroxide; water / tetrahydrofuran / 12 h / 20 °C 2.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 °C / Cooling with ice 2.2: 20 °C 3.1: dihydrogen peroxide / aq. phosphate buffer / 4 h / 37 °C / pH 7.4 View Scheme

suberanilic acid (149648-52-2) → C21H26N2O4 + vorinostat (149647-78-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 °C / Cooling with ice 1.2: 20 °C 2.1: dihydrogen peroxide / aq. phosphate buffer / 4 h / 37 °C / pH 7.4 View Scheme

N-phenylhept-6-enamide → vorinostat (149647-78-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: Hoveyda-Grubbs catalyst second generation / dichloromethane / 3 h / Reflux; Inert atmosphere 2: 10 wt% Pd(OH)2 on carbon; trifluoroacetic acid; hydrogen / methanol / 2 h / 20 °C View Scheme

(E)-methyl 8-(benzyloxyamino)-8-oxooct-6-enoate → vorinostat (149647-78-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: lithium hydroxide monohydrate / tetrahydrofuran; water / 4 h / 20 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0.25 h / 0 °C 2.2: 16 h / 0 - 20 °C 3.1: 10 wt% Pd(OH)2 on carbon; trifluoroacetic acid; hydrogen / methanol / 2 h / 20 °C View Scheme

methyl hept-6-enoate (1745-17-1) → vorinostat (149647-78-9)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: Hoveyda-Grubbs catalyst second generation / dichloromethane / 3 h / Reflux; Inert atmosphere 2.1: lithium hydroxide monohydrate / tetrahydrofuran; water / 4 h / 20 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0.25 h / 0 °C 3.2: 16 h / 0 - 20 °C 4.1: 10 wt% Pd(OH)2 on carbon; trifluoroacetic acid; hydrogen / methanol / 2 h / 20 °C View Scheme

C15H19NO4 → vorinostat (149647-78-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0.25 h / 0 °C 1.2: 16 h / 0 - 20 °C 2.1: 10 wt% Pd(OH)2 on carbon; trifluoroacetic acid; hydrogen / methanol / 2 h / 20 °C View Scheme

vorinostat (149647-78-9) → suberoylanilide hydroxamic acid iron complex

Conditions	Yield
With iron(III) chloride; N-ethyl-N,N-diisopropylamine In ethanol at 20℃; for 16.0833h;	96%

phenyl isocyanate (103-71-9) + vorinostat (149647-78-9) → [(8-anilino-8-oxo-octanoyl)amino] N-phenylcarbamate

Conditions	Yield
In N,N-dimethyl-formamide; acetone at -15 - 20℃;	96%

benzyl isothiocyanate (3173-56-6) + vorinostat (149647-78-9) → [(8-anilino-8-oxo-octanoyl)amino] N-benzylcarbamate

Conditions	Yield
In N,N-dimethyl-formamide; acetone at -15 - 20℃;	94%

vorinostat (149647-78-9) + Isopropyl isocyanate (1795-48-8) → [(8-anilino-8-oxo-octanoyl)amino] N-isopropylcarbamate

Conditions	Yield
In N,N-dimethyl-formamide; acetone at -15 - 20℃;	93%

vorinostat (149647-78-9) + ethyl isocyanate (109-90-0) → [(8-anilino-8-oxo-octanoyl)amino] N-ethylcarbamate

Conditions	Yield
In N,N-dimethyl-formamide; acetone at -15 - 20℃;	92%

C44H74ClN3O11Si3 + vorinostat (149647-78-9) → C58H93N5O14Si3

Conditions	Yield
With pyridine at 0 - 25℃; for 5h;	92%

vorinostat (149647-78-9) + N,N'-dimethyl-N-benzyl-[4-(2,3,4-tri-O-tert-butyldimethylsilyl-β-D-glucopyranosyl)uronate-3-nitrobenzoyloxycarbonyl]ethylenediamine carbamoyl chloride (637330-41-7) → C58H91N5O15Si3

Conditions	Yield
In pyridine at 0 - 25℃; for 5h;	92%
With pyridine at 0 - 20℃; for 5h;	85%

2,3,4,6-tetra-O-acetyl-D-glucopyranosyl 1-(N-phenyl)-2,2,2-trifluoroacetimidate (942428-83-3) + vorinostat (149647-78-9) → 2,3,4,6-tetra-O-acetyl-1-O-7-(phenylcarbamoyl)hepthydroxamoyl-β-D-glucopyranose

Conditions	Yield
With trimethylsilyl trifluoromethanesulfonate In dichloromethane at -20 - 20℃;	90%

2,3,4,6-tetra-O-acetyl-D-mannopyranosyl 1-(N-phenyl)-2,2,2-trifluoroacetimidate (942428-90-2) + vorinostat (149647-78-9) → 2,3,4,6-tetra-O-acetyl-1-O-7-(phenylcarbamoyl)hepthydroxamoyl-α-D-mannopyranose

Conditions	Yield
With trimethylsilyl trifluoromethanesulfonate In dichloromethane at -20 - 20℃;	84%

4-bromomethyl-3-nitrobenzoic acid (55715-03-2) + vorinostat (149647-78-9) → C22H25N3O7

Conditions	Yield
With sodium hydroxide In methanol at 20℃; for 18h;	83%

N1,N2-dimethyl-N1-(2-phenylcyclopropyl)ethane-1,2-diamine dihydrochloride + 1,1'-carbonyldiimidazole (530-62-1) + vorinostat (149647-78-9) → N1-((methyl(2-(methyl(2-phenylcyclopropyl)amino)ethyl)carbamoyl)oxy)-N8-phenyloctanediamide

Conditions	Yield
Stage #1: 1,1'-carbonyldiimidazole; vorinostat In acetonitrile at 10℃; for 0.333333h; Stage #2: N1,N2-dimethyl-N1-(2-phenylcyclopropyl)ethane-1,2-diamine dihydrochloride With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 12h;	82.7%

4-bromomethylbenzoic Acid (6232-88-8) + vorinostat (149647-78-9) → C22H26N2O5

Conditions	Yield
With sodium hydroxide In methanol at 20℃; for 18h;	79%

vorinostat (149647-78-9) → N-[(8-anilino-8-oxooctanoyl)oxy]-N'-phenyloctanediamide

Conditions	Yield
Stage #1: suberanilic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide) for 0.0833333h; Stage #2: vorinostat In DMF (N,N-dimethyl-formamide) for 24h;	77%

O-(methyl 2,3,4-tri-O-acetyl-D-glucuronopyranosyl)-N-phenyl-2,2,2-trifluoroacetimidate (869996-05-4) + vorinostat (149647-78-9) → methyl 2,3,4-tri-O-acetyl-1-O-7-(phenylcarbamoyl)hepthydroxamoyl-β-D-glucopyranosyluronate (931415-42-8)

Conditions	Yield
With trimethylsilyl trifluoromethanesulfonate In dichloromethane at -20 - 20℃;	76%

2-(bromomethyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione + vorinostat (149647-78-9) → N1-phenyl-N8-((2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)methoxy)octanediamide

Conditions	Yield
With sodium hydroxide In methanol at 20℃; for 18h; Inert atmosphere;	74%

vorinostat (149647-78-9) + benzylamine (100-46-9) → C21H27N3O2 (1200803-45-7)

Conditions	Yield
Stage #1: vorinostat With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine In dichloroethane at 0℃; for 1.5h; Lossen rearrangement; Inert atmosphere; Stage #2: benzylamine In dichloroethane at 0 - 84℃; for 15h; Lossen rearrangement; Inert atmosphere;	73%

2,3,5-tri-O-acetyl-D-ribofuranosyl 1-(N-phenyl)-2,2,2-trifluoroacetimidate (942428-91-3) + vorinostat (149647-78-9) → 2,3,5-tri-O-acetyl-1-O-7-(phenylcarbamoyl)hepthydroxamoyl-β-D-ribofuranose

Conditions	Yield
With trimethylsilyl trifluoromethanesulfonate In dichloromethane at -20 - 20℃;	69%

2,3,4,6-tetra-O-acetyl-D-galactosyl 1-(N-phenyl)-2,2,2-trifluoroacetimidate (942428-89-9) + vorinostat (149647-78-9) → 2,3,4,6-tetra-O-acetyl-1-O-7-(phenylcarbamoyl)hepthydroxamoyl-β-D-galactopyranose (931415-43-9)

Conditions	Yield
With trimethylsilyl trifluoromethanesulfonate In dichloromethane at -20 - 20℃;	69%

mono-4-vinylbenzyl succinate (139486-67-2) + vorinostat (149647-78-9) → C27H32N2O6

Conditions	Yield
Stage #1: mono-4-vinylbenzyl succinate With 1,1'-carbonyldiimidazole In dichloromethane for 0.166667h; Stage #2: vorinostat for 2h; Reagent/catalyst;	69%

ethyl 7-(((S)-1-(((S)-1-((4-(bromomethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate + vorinostat (149647-78-9) → ethyl 7-(((S)-3-methyl-1-oxo-1-(((S)-1-oxo-1-((4-(((8-oxo-8-(phenylamino)octanamido)oxy)methyl)phenyl)amino)-5-ureidopentan-2-yl)amino)butan-2-yl)amino)-7-oxoheptanoate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere;	68%

[2,2]bipyridinyl (366-18-7) + copper(II) perchlorate hexahydrate + vorinostat (149647-78-9) → C24H27CuN4O3(1+)*ClO4(1-)

Conditions	Yield
With potassium hydroxide In methanol; water at 25℃; for 0.5h;	67.7%

copper(II) perchlorate hexahydrate + 1,10-phenanthroline-5,6-dione (27318-90-7) + vorinostat (149647-78-9) → Cu-SAHA-Phendio

Conditions	Yield
With potassium hydroxide In methanol; ethanol; water at 25℃; for 0.5h;	67%

6-(3-((4-(bromomethyl)phenyl)thio)-2,5-dioxopyrrolidin-1-yl)-N-(prop-2-yn-1-yl)hexanamide + vorinostat (149647-78-9) → N1-((4-((2,5-dioxo-1-(6-oxo-6-(prop-2-yn-1-ylamino)hexyl)pyrrolidin-3-yl)thio)benzyl)oxy)-N8-phenyloctanediamide

Conditions	Yield
Stage #1: vorinostat With sodium hydroxide In methanol; water Stage #2: 6-(3-((4-(bromomethyl)phenyl)thio)-2,5-dioxopyrrolidin-1-yl)-N-(prop-2-yn-1-yl)hexanamide In methanol; water	67%
With sodium hydroxide In methanol Inert atmosphere;	40%

Upstream product

• 505-48-6 octane-1,8-dioic acid 
• 62-53-3 aniline 
• 1119-60-4 hept-6-enoic acid 
• 1745-17-1 methyl hept-6-enoate 
• 6998-10-3 N-phenylhexanamide 
• 149648-52-2 suberanilic acid 
• 162853-41-0 8-oxo-8-(phenylamino)octanoic acid methyl ester 
• 3946-32-5 suberic acid monomethyl ester 
• 5698-29-3 oxonan-2-one 
• 149647-86-9 8-(hydroxyamino)-8-oxooctanoic acid 
• 10521-06-9 oxonane-2,9-dione 

Downstream Products

• 866824-87-5 N-[(8-anilino-8-oxooctanoyl)oxy]-N'-phenyloctanediamide 

Relevant articles and documents

Novel SAHA analogues inhibit HDACs, induce apoptosis and modulate the expression of microRNAs in hepatocellular carcinoma

In eukaryotes, transcriptional regulation occurs via chromatin remodeling, mainly through post translational modifications of histones that package DNA into structural units. Histone deacetylases (HDACs) are enzymes that play important role in various biological processes by repressing gene expression. Suberoylanilide hydroxamic acid (SAHA) is a known HDAC inhibitor that showed significant anti cancer activity by relieving gene silencing against hematologic and solid tumors. We have designed and synthesized a series of SAHA analogs C1–C4 and performed biological studies to elucidate its anti-cancer effects. It is observed that SAHA analogs significantly inhibited cell proliferation and induced apoptosis in hepatocellular carcinoma (HCC) cell lines HepG2 and SK-HEP-1. These analogs also showed non-toxic activity towards primary human hepatocytes, which describes its tumor specificity. SAHA analogs exhibited strong HDAC inhibition, which is 2–3 fold higher compared to SAHA. Moreover, these molecules induced hyper acetylation of histone H3 at various positions on the lysine residue. Further, it is observed that SAHA analogs are strong inducers of apoptosis, as they regulated the expression of various proteins involved in both extrinsic and intrinsic pathways. Interestingly, SAHA analogs induced upregulation of tumor suppressor miRNAs by activating its biogenesis pathway. Further, it is confirmed by microRNA (miRNA) prediction tools that these miRNAs are capable of targeting various anti-apoptotic genes. Based on these findings we conclude that SAHA analogs could be strong HDAC inhibitors with promising apoptosis inducing nature in HCC.

A nanodelivered Vorinostat derivative is a promising oral compound for the treatment of visceral leishmaniasis

There is currently no satisfactory treatment for visceral leishmaniasis; the disease is thus in desperate need of novel drugs. The ideal candidate should be effective, safe, affordable, and administered via the oral route. Histone deacetylases (HDACs) are involved in silencing critical regulatory pathways, including pro-apoptotic programs, and represent potential therapeutic targets for pharmacological interventions. O-alkyl hydroxamates have traditionally been considered to exert no effect on mammal HDACs. The aim of this study was to evaluate the effect of MDG, a SAHA derivative of the O-alkyl hydroxamate family with no activity on human histone deacetylase enzymes, on the visceral leishmaniasis causative agents and in a murine model of the disease. The effects of vorinostat, tubacin and valproic acid (well-known mammal HDAC inhibitors) on the parasite were also evaluated. MDG was found to be highly active against Leishmania infantum and L. donovani intracellular amastigotes in vitro but not against the promastigote stage. In contrast, vorinostat, tubacin and valproic acid showed no activity against the parasite. Assays investigating hERG and Cav1.2 channels in vitro found no evidence of MDG-driven cardiotoxicity. MDG showed neither hepatotoxicity nor mutagenicity, nor did it exert activity on cytochrome P450 enzymes. MDG was adsorbed onto gold nanoparticles for the in vivo experiments, performed on infected Balb/c mice. MDG was effective at reducing the parasite load in major target tissues (bone marrow, spleen and liver) in more than 70% at 25 mg/kg through both the oral and intraperitoneal route, proving more active than the reference compounds (meglumine antimoniate, MA) without showing toxicity. In addition, the combination of MDG and MA was very effective.

An Endogenous Reactive Oxygen Species (ROS)-Activated Histone Deacetylase Inhibitor Prodrug for Cancer Chemotherapy

Suberoylanilide hydroxamic acid (SAHA, vorinostat) is a potent small-molecule pan-inhibitor of histone deacetylases (HDACs) approved for treatment of cutaneous T-cell lymphoma (CTCL). However, SAHA exhibits poor selectivity for cancer cells over noncancer cells. With an aim to improving its selectivity for cancer cells, we generated a novel SAHA prodrug (SAHA-OBP) that is activated in the presence of hydrogen peroxide, a reactive oxygen species (ROS) known to be overexpressed in cancer cells. The high endogenous ROS content in cancer cells triggers rapid removal of the 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl carbonyl (OBP) cap to release active SAHA. The SAHA-OBP prodrug demonstrates selective activity against multiple cancer cell lines such as HeLa, MCF-7, MDA-MB-231, and B16-F10, while remaining benign toward noncancer cells. The downstream effects of SAHA released from SAHA-OBP in cancer cells is the induction of apoptosis. SAHA-OBP was also found to be effective on multicellular tumor spheroids (MCTS). The SAHA prodrug designed in this study undergoes rapid ROS-dependent activation and imparts much-needed selectivity to SAHA for cancer cells.

Hypoxia-activated pro-drugs of the KDAC inhibitor vorinostat (SAHA)

Hypoxia (lower than normal oxygen) is a characteristic of most solid tumours that results in poor cancer patient prognosis. The difference in cellular environment between normoxia (21percent oxygen) or physoxia (4–7.5percent oxygen) and hypoxia (2.0percent oxygen) causes increased resistance to radio- and chemotherapy, but also provides the opportunity to selectively release hypoxia-activated pro-drugs. This approach potentially allows targeting of chemotherapies, including lysine deacetylase (KDAC) inhibitors, to the hypoxic fraction of cells. Here, we report initial work on the development of KDAC inhibitors that are selectively released in hypoxic conditions. We have shown that the addition of a 4-nitrobenzyl (NB) or 1-methyl-2-nitroimidazole (NI) bioreductive group onto the hydroxamic acid moiety of SAHA, giving NB-SAHA and NI-SAHA, abolishes KDAC inhibition activity. Both NB-SAHA and NI-SAHA undergo enzyme-mediated bioreduction, in a hypoxia-dependent manner, to release SAHA selectively in 0.1percent oxygen. This work provides an important foundation for further investigations into the targeted release of KDAC inhibitors in hypoxic tumours.

A method for utilizing the modified mesoporous material catalytic preparation fu linuo his method (by machine translation)

The invention provides a coupling agent suberic acid bitter wine and modified mesoporous silica coupling/catalytic system for preparing fu linuo his method, the method comprises the following steps: preparation suberic acid bitter wine and coupling agent modified mesoporous silicon dioxide; wherein said hydrophilic modified mesoporous silicon dioxide pre-treatment reactant [...] 1 - 2 h, with aniline or a salt thereof to react to form an intermediate product of bromoxynil aniline acid; in the presence of a modified mesoporous silica obtained bromoxynil aniline acid with hydroxylamine or its salt by the reaction of the fu linuo he. The method of the invention the selectivity and the yield is high, the amidation reaction time is short, the resulting fu linuo he purity as high as 99% or more. (by machine translation)