WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H526293
CAS#: 732302-99-7 (HCl hydrate)
Description: Givinostat hydrochloride is a novel histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities.
Hodoodo Cat#: H526293
Name: Givinostat HCl hydrate
CAS#: 732302-99-7 (HCl hydrate)
Chemical Formula: C24H30ClN3O5
Exact Mass: 0.00
Molecular Weight: 475.970
Elemental Analysis: C, 60.56; H, 6.35; Cl, 7.45; N, 8.83; O, 16.81
Related CAS #: 732302-99-7 (HCl hydrate) 497833-27-9 (free base) 199657-29-9 (HCl)
Synonym: ITF2357, ITF-2357, ITF 2357, ITF2357 HCl, ITF2357 hydrochloride, Givinostat HCl, gavinostat, Givinostat HCl hydrate
IUPAC/Chemical Name: (6-((diethylamino)methyl)naphthalen-2-yl)methyl (4-(hydroxycarbamoyl)phenyl)carbamate hydrochloride hydrate
InChi Key: FKGKZBBDJSKCIS-UHFFFAOYSA-N
InChi Code: InChI=1S/C24H27N3O4.ClH.H2O/c1-3-27(4-2)15-17-5-7-21-14-18(6-8-20(21)13-17)16-31-24(29)25-22-11-9-19(10-12-22)23(28)26-30;;/h5-14,30H,3-4,15-16H2,1-2H3,(H,25,29)(H,26,28);1H;1H2
SMILES Code: ONC(C1=CC=C(C=C1)NC(OCC2=CC3=C(C=C2)C=C(CN(CC)CC)C=C3)=O)=O.[H]Cl.[H]O[H]
Appearance: White to beige solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
More Info:
| Biological target: | Givinostat hydrochloride monohydrate (ITF-2357 hydrochloride monohydrate) is a HDAC inhibitor with an IC50 of 198 and 157 nM for HDAC1 and HDAC3, respectively. |
| In vitro activity: | Givinostat significantly inhibited JS-1 cell proliferation and promoted cell apoptosis, leading to cell cycle arrest in G0/G1 phases. Treatment with givinostat downregulated protein expression of CDK4, CDK6, and cyclin D1, whereas expression of p21 and p57 was significantly increased. The givinostat-induced apoptosis of hepatic stellate cells was mainly mediated through p38 and extracellular signal-regulated kinase 1/2. Givinostat treatment increased intracellular reactive oxygen species production, decreased mitochondrial membrane potential, and promoted mitochondrial permeability transition pore opening. Acetylation of superoxide dismutase (acetyl K68) and nuclear factor-κB p65 (acetyl K310) was upregulated, while there was no change in protein expression. Moreover, the notable beneficial effect of givinostat on liver fibrosis was also confirmed in the mouse models. Reference: World J Gastroenterol. 2015 Jul 21;21(27):8326-39. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/26217084/ |
| In vivo activity: | Mice were given 100 μL water or ITF2357 (5 mg/kg) by gavage and, after 1 h, injected intravenously with 200 μg/mouse of ConA. Control mice received an intravenous injection of saline. Mice were bled 24 h later for evaluation of serum ALT levels as described previously (33,34). As shown in Figure 15, ALT levels were reduced by more than 80% by ITF2357 pretreatment. In another experiment, a comparison was made between 1 and 10 mg/kg of oral ITF2357. As shown in Figure 16, a dose of 1 mg/kg ITF2357 was as effective as a dose of 10 mg/kg in reducing ConA hepatitis as measured by ALT levels. Reference: Mol Med. 2005 Jan-Dec;11(1-12):1-15. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/16557334/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 95.0 | 199.59 |
The following data is based on the product molecular weight 475.97 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | |
| In vitro protocol: | 1. Wang YG, Xu L, Wang T, Wei J, Meng WY, Wang N, Shi M. Givinostat inhibition of hepatic stellate cell proliferation and protein acetylation. World J Gastroenterol. 2015 Jul 21;21(27):8326-39. doi: 10.3748/wjg.v21.i27.8326. PMID: 26217084; PMCID: PMC4507102. 2. Leoni F, Fossati G, Lewis EC, Lee JK, Porro G, Pagani P, Modena D, Moras ML, Pozzi P, Reznikov LL, Siegmund B, Fantuzzi G, Dinarello CA, Mascagni P. The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol Med. 2005 Jan-Dec;11(1-12):1-15. doi: 10.2119/2006-00005.Dinarello. PMID: 16557334; PMCID: PMC1449516. |
| In vivo protocol: | 1. Leoni F, Fossati G, Lewis EC, Lee JK, Porro G, Pagani P, Modena D, Moras ML, Pozzi P, Reznikov LL, Siegmund B, Fantuzzi G, Dinarello CA, Mascagni P. The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol Med. 2005 Jan-Dec;11(1-12):1-15. doi: 10.2119/2006-00005.Dinarello. PMID: 16557334; PMCID: PMC1449516. |
1: Lim RR, Tan A, Liu YC, Barathi VA, Mohan RR, Mehta JS, Chaurasia SS. ITF2357 transactivates Id3 and regulate TGFβ/BMP7 signaling pathways to attenuate corneal fibrosis. Sci Rep. 2016 Feb 11;6:20841. doi: 10.1038/srep20841. PubMed PMID: 26865052; PubMed Central PMCID: PMC4750002.
2: Zheng J, van de Veerdonk FL, Crossland KL, Smeekens SP, Chan CM, Al Shehri T, Abinun M, Gennery AR, Mann J, Lendrem DW, Netea MG, Rowan AD, Lilic D. Gain-of-function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC). Eur J Immunol. 2015 Oct;45(10):2834-46. doi: 10.1002/eji.201445344. Epub 2015 Sep 1. PubMed PMID: 26255980.
3: Zappasodi R, Cavanè A, Iorio MV, Tortoreto M, Guarnotta C, Ruggiero G, Piovan C, Magni M, Zaffaroni N, Tagliabue E, Croce CM, Zunino F, Gianni AM, Di Nicola M. Pleiotropic antitumor effects of the pan-HDAC inhibitor ITF2357 against c-Myc-overexpressing human B-cell non-Hodgkin lymphomas. Int J Cancer. 2014 Nov 1;135(9):2034-45. doi: 10.1002/ijc.28852. Epub 2014 Mar 26. PubMed PMID: 24648290.
4: Regna NL, Chafin CB, Hammond SE, Puthiyaveetil AG, Caudell DL, Reilly CM. Class I and II histone deacetylase inhibition by ITF2357 reduces SLE pathogenesis in vivo. Clin Immunol. 2014 Mar;151(1):29-42. doi: 10.1016/j.clim.2014.01.002. Epub 2014 Jan 15. PubMed PMID: 24503172; PubMed Central PMCID: PMC3963170.
5: Glauben R, Sonnenberg E, Wetzel M, Mascagni P, Siegmund B. Histone deacetylase inhibitors modulate interleukin 6-dependent CD4+ T cell polarization in vitro and in vivo. J Biol Chem. 2014 Feb 28;289(9):6142-51. doi: 10.1074/jbc.M113.517599. Epub 2014 Jan 13. PubMed PMID: 24421314; PubMed Central PMCID: PMC3937680.
6: Hara N, Alkanani AK, Dinarello CA, Zipris D. Histone deacetylase inhibitor suppresses virus-induced proinflammatory responses and type 1 diabetes. J Mol Med (Berl). 2014 Jan;92(1):93-102. doi: 10.1007/s00109-013-1078-1. Epub 2013 Aug 28. PubMed PMID: 23982318.
7: Yu WJ, Wang L, You LS, Mei C, Ma QL, Jin J. [ITF-2357 on inhibition myeloid leukemic cell lines cells proliferation in vitro and its mechanism]. Zhonghua Xue Ye Xue Za Zhi. 2012 May;33(5):366-70. Chinese. PubMed PMID: 22781793.
8: Grabiec AM, Korchynskyi O, Tak PP, Reedquist KA. Histone deacetylase inhibitors suppress rheumatoid arthritis fibroblast-like synoviocyte and macrophage IL-6 production by accelerating mRNA decay. Ann Rheum Dis. 2012 Mar;71(3):424-31. doi: 10.1136/ard.2011.154211. Epub 2011 Sep 27. PubMed PMID: 21953341; PubMed Central PMCID: PMC3277722.
9: Vojinovic J, Damjanov N, D'Urzo C, Furlan A, Susic G, Pasic S, Iagaru N, Stefan M, Dinarello CA. Safety and efficacy of an oral histone deacetylase inhibitor in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2011 May;63(5):1452-8. doi: 10.1002/art.30238. PubMed PMID: 21538322.
10: Furlan A, Monzani V, Reznikov LL, Leoni F, Fossati G, Modena D, Mascagni P, Dinarello CA. Pharmacokinetics, safety and inducible cytokine responses during a phase 1 trial of the oral histone deacetylase inhibitor ITF2357 (givinostat). Mol Med. 2011 May-Jun;17(5-6):353-62. doi: 10.2119/molmed.2011.00020. Epub 2011 Feb 22. PubMed PMID: 21365126; PubMed Central PMCID: PMC3105139.
11: Glauben R, Siegmund B. Inhibition of histone deacetylases in inflammatory bowel diseases. Mol Med. 2011 May-Jun;17(5-6):426-33. doi: 10.2119/molmed.2011.00069. Epub 2011 Feb 22. Review. PubMed PMID: 21365125; PubMed Central PMCID: PMC3105130.
12: Joosten LA, Leoni F, Meghji S, Mascagni P. Inhibition of HDAC activity by ITF2357 ameliorates joint inflammation and prevents cartilage and bone destruction in experimental arthritis. Mol Med. 2011 May-Jun;17(5-6):391-6. doi: 10.2119/molmed.2011.00058. Epub 2011 Feb 11. PubMed PMID: 21327299; PubMed Central PMCID: PMC3105133.
13: Vojinovic J, Damjanov N. HDAC inhibition in rheumatoid arthritis and juvenile idiopathic arthritis. Mol Med. 2011 May-Jun;17(5-6):397-403. doi: 10.2119/molmed.2011.00030. Epub 2011 Feb 4. Review. PubMed PMID: 21308151; PubMed Central PMCID: PMC3105145.
14: Shein NA, Shohami E. Histone deacetylase inhibitors as therapeutic agents for acute central nervous system injuries. Mol Med. 2011 May-Jun;17(5-6):448-56. doi: 10.2119/molmed.2011.00038. Epub 2011 Jan 25. Review. PubMed PMID: 21274503; PubMed Central PMCID: PMC3105144.
15: Bodar EJ, Simon A, van der Meer JW. Effects of the histone deacetylase inhibitor ITF2357 in autoinflammatory syndromes. Mol Med. 2011 May-Jun;17(5-6):363-8. doi: 10.2119/molmed.2011.00039. Epub 2011 Jan 25. PubMed PMID: 21274502; PubMed Central PMCID: PMC3105134.
16: Lewis EC, Blaabjerg L, Størling J, Ronn SG, Mascagni P, Dinarello CA, Mandrup-Poulsen T. The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet β cells in vivo and in vitro. Mol Med. 2011 May-Jun;17(5-6):369-77. doi: 10.2119/molmed.2010.00152. Epub 2010 Dec 22. PubMed PMID: 21193899; PubMed Central PMCID: PMC3105153.
17: Galimberti S, Canestraro M, Savli H, Palumbo GA, Tibullo D, Nagy B, Piaggi S, Guerrini F, Cine N, Metelli MR, Petrini M. ITF2357 interferes with apoptosis and inflammatory pathways in the HL-60 model: a gene expression study. Anticancer Res. 2010 Nov;30(11):4525-35. PubMed PMID: 21115902.
18: Rambaldi A, Dellacasa CM, Finazzi G, Carobbio A, Ferrari ML, Guglielmelli P, Gattoni E, Salmoiraghi S, Finazzi MC, Di Tollo S, D'Urzo C, Vannucchi AM, Barosi G, Barbui T. A pilot study of the Histone-Deacetylase inhibitor Givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms. Br J Haematol. 2010 Aug;150(4):446-55. doi: 10.1111/j.1365-2141.2010.08266.x. Epub 2010 Jun 15. PubMed PMID: 20560970.
19: Matalon S, Palmer BE, Nold MF, Furlan A, Kassu A, Fossati G, Mascagni P, Dinarello CA. The histone deacetylase inhibitor ITF2357 decreases surface CXCR4 and CCR5 expression on CD4(+) T-cells and monocytes and is superior to valproic acid for latent HIV-1 expression in vitro. J Acquir Immune Defic Syndr. 2010 May 1;54(1):1-9. doi: 10.1097/QAI.0b013e3181d3dca3. PubMed PMID: 20300007; PubMed Central PMCID: PMC3534976.
20: Shein NA, Grigoriadis N, Alexandrovich AG, Simeonidou C, Lourbopoulos A, Polyzoidou E, Trembovler V, Mascagni P, Dinarello CA, Shohami E. Histone deacetylase inhibitor ITF2357 is neuroprotective, improves functional recovery, and induces glial apoptosis following experimental traumatic brain injury. FASEB J. 2009 Dec;23(12):4266-75. doi: 10.1096/fj.09-134700. Epub 2009 Sep 1. PubMed PMID: 19723705; PubMed Central PMCID: PMC2812044.
