149647-78-9 Usage
Description
Vorinostat, also known as Suberoylanilide Hydroxamic Acid (SAHA), is a potent, selective, and cell-permeable histone deacetylase (HDAC) inhibitor. It is the first drug in a new class of anti-cancer agents that inhibit histone deacetylases. Vorinostat 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. It is a white crystalline solid and is marketed under the brand name Zolinza.
Uses
Used in Oncology:
Vorinostat is used as an antineoplastic agent for the treatment of cutaneous T-cell lymphoma (CTCL), a type of non-Hodgkin’s lymphoma. It inhibits HDAC1, HDAC2, HDAC3, and HDAC6 at nanomolar concentrations, leading to the reactivation of dormant tumor-suppressor genes and promoting an open chromatin structure. This results in the inhibition of tumor growth and the induction of growth arrest, differentiation, or apoptosis in various tumor cells.
Used in Drug Development:
Vorinostat is used as a research tool for the development of new HDAC inhibitors and the study of their effects on gene transcription, chromatin plasticity, and cancer cell behavior. It has been shown to inhibit 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.
Used in Combination Therapy:
Vorinostat is used in combination with conventional chemotherapeutic drugs to enhance chemo-sensitivity and efficacy in resistant cases. It has been shown to display synergistic anticancer effects when combined with other treatments, making it a valuable component in the development of novel drug delivery systems and cancer treatment strategies.
Used in Angiogenesis Inhibition:
Vorinostat is used as an anti-angiogenic agent by interfering with VEGF signaling in human umbilical vein endothelial cells (HUVECs). This activity contributes to its anti-cancer properties by inhibiting the formation of new blood vessels that supply nutrients to tumors, thereby limiting their growth and progression.
Used in Cell Cycle Regulation:
Vorinostat is used as a cell cycle regulator, causing cell cycle arrest at the G1 phase. This effect contributes to its anti-cancer properties by preventing the proliferation of cancer cells and promoting their differentiation or apoptosis.
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.
Originator
Columbia
University (US)
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
Check Digit Verification of cas no
The CAS Registry Mumber 149647-78-9 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,4,9,6,4 and 7 respectively; the second part has 2 digits, 7 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 149647-78:
(8*1)+(7*4)+(6*9)+(5*6)+(4*4)+(3*7)+(2*7)+(1*8)=179
179 % 10 = 9
So 149647-78-9 is a valid CAS Registry Number.
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)
149647-78-9Relevant articles and documents
Novel SAHA analogues inhibit HDACs, induce apoptosis and modulate the expression of microRNAs in hepatocellular carcinoma
Srinivas, Chatla,Swathi,Priyanka,Anjana Devi,Subba Reddy,Janaki Ramaiah,Bhadra, Utpal,Bhadra, Manika Pal
, p. 1249 - 1264 (2016)
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
Corpas-López, Victoriano,Díaz-Gavilán, Mónica,Franco-Montalbán, Francisco,Merino-Espinosa, Gemma,López-Viota, Margarita,López-Viota, Julián,Belmonte-Reche, Efres,Pérez-del Palacio, José,de Pedro, Nuria,Gómez-Vidal, José Antonio,Morillas-Márquez, Francisco,Martín-Sánchez, Joaquina
, p. 375 - 383 (2019)
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
Bhagat, Somnath D.,Singh, Usha,Mishra, Ram Kumar,Srivastava, Aasheesh
, p. 2073 - 2079 (2018)
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)
Calder, Ewen D. D.,Conway, Stuart J.,Folkes, Lisa K.,Hammond, Ester M.,Mistry, Ishna N.,Skwarska, Anna,Sneddon, Deborah
supporting information, (2020/04/24)
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)
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Paragraph 0034; 0037, (2019/01/23)
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)