Givinostat free base

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WARNING: This product is for research use only, not for human or veterinary use.

Description:Givinostat or gavinostat, aslo known as ITF2357, is a potent and orally active histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities. It is a hydroxamate used in the form of its hydrochloride.Inhibition of HDAC activity by ITF2357 ameliorates joint inflammation and prevents cartilage and bone destruction in experimental arthritis.ITF2357 reduces cytokines and protects islet β cells in vivo and in vitro. 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.

Price and Availability

Givinostat free base is not in stock, may be available through custom synthesis. For cost-effective reason, minimum 1 gram order is requested. The product will be characterized by NMR, HPLC and MS analysis. Purity (HPLC) is usually >98%. CoA, QC data, MSDS will be provided when product is successfully made. The estimated lead time is 2-3 months. Please send email to sales@medkoo.com to inquire quote.

Chemical Structure

Theoretical Analysis

MedKoo Cat#: 205774Name: Givinostat free baseCAS#: 497833-27-9 (free base)Chemical Formula: C24H27N3O4Exact Mass: 421.20016Molecular Weight: 421.49Elemental Analysis:C, 68.39; H, 6.46; N, 9.97; O, 15.18

Related CAS #:497833-27-9 (free base)199657-29-9 (HCl)732302-99-7 (HCl hydrate)

Synonym:Givinostat ; gavinostat; ITF2357; ITF 2357; ITF-2357.

IUPAC/Chemical Name:(6-((diethylamino)methyl)naphthalen-2-yl)methyl (4-(hydroxycarbamoyl)phenyl)carbamate

InChi Key:YALNUENQHAQXEA-UHFFFAOYSA-N

InChi Code:InChI=1S/C24H27N3O4/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)

SMILES Code:O=C(OCC1=CC=C2C=C(CN(CC)CC)C=CC2=C1)NC3=CC=C(C(NO)=O)C=C3

Technical Data

Additional Information

Givinostat inhibits class I and class II histone deacetylases (HDACs) and several pro-inflammatory cytokines. This reduces expression of tumour necrosis factor (TNF), interleukin 1α and β, and interleukin 6.  It also has activity against cells expressing JAK(2V617F), a mutated form of the janus kinase 2 (JAK2) enzyme that is implicated in the pathophysiology of many myeloproliferative diseases, including polycythaemia vera.  In patients with polycythaemia, the reduction of mutant JAK2 concentrations by givinostat is believed to slow down the abnormal growth of erythrocytes and ameliorate the symptoms of the disease. (Source: http://en.wikipedia.org/wiki/Givinostat).   

References

1: Zappasodi R, Cavanè A, Iorio MV, Tortoreto M, Guarnotta C, Ruggiero G, PiovanC, 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.

2: 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.

3: 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.

4: Li S, Fossati G, Marchetti C, Modena D, Pozzi P, Reznikov LL, Moras ML, Azam T, Abbate A, Mascagni P, Dinarello CA. Specific inhibition of histone deacetylase 8 reduces gene expression and production of proinflammatory cytokines in vitro and in vivo. J Biol Chem. 2015 Jan 23;290(4):2368-78. doi: 10.1074/jbc.M114.618454. Epub 2014 Dec 1. PubMed PMID: 25451941; PubMed Central PMCID: PMC4303687.

5: 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. PubMedPMID: 21193899; PubMed Central PMCID: PMC3105153.

6: 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 andinflammatory pathways in the HL-60 model: a gene expression study. Anticancer Res. 2010 Nov;30(11):4525-35. PubMed PMID: 21115902.

7: Galli M, Salmoiraghi S, Golay J, Gozzini A, Crippa C, Pescosta N, Rambaldi A.A phase II multiple dose clinical trial of histone deacetylase inhibitor ITF2357in patients with relapsed or progressive multiple myeloma. Ann Hematol. 2010 Feb;89(2):185-90. doi: 10.1007/s00277-009-0793-8. Epub 2009 Jul 25. PubMed PMID:19633847.

8: 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.

9: 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 May1;54(1):1-9. doi: 10.1097/QAI.0b013e3181d3dca3. PubMed PMID: 20300007; PubMed Central PMCID: PMC3534976.

10: 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.

11: 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.

12: Todoerti K, Barbui V, Pedrini O, Lionetti M, Fossati G, Mascagni P, RambaldiA, Neri A, Introna M, Lombardi L, Golay J. Pleiotropic anti-myeloma activity of ITF2357: inhibition of interleukin-6 receptor signaling and repression of miR-19a and miR-19b. Haematologica. 2010 Feb;95(2):260-9. doi: 10.3324/haematol.2009.012088. Epub 2009 Aug 27. PubMed PMID: 19713220; PubMed Central PMCID: PMC2817029.

13: Del Bufalo D, Desideri M, De Luca T, Di Martile M, Gabellini C, Monica V, Busso S, Eramo A, De Maria R, Milella M, Trisciuoglio D. Histone deacetylase inhibition synergistically enhances pemetrexed cytotoxicity through induction ofapoptosis and autophagy in non-small cell lung cancer. Mol Cancer. 2014 Oct 9;13:230. doi: 10.1186/1476-4598-13-230. PubMed PMID: 25301686; PubMed Central PMCID: PMC4198757.

14: 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. PubMed PMID: 16557334; PubMed Central PMCID: PMC1449516.

15: Guerini V, Barbui V, Spinelli O, Salvi A, Dellacasa C, Carobbio A, Introna M, Barbui T, Golay J, Rambaldi A. The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2(V617F). Leukemia. 2008 Apr;22(4):740-7. Epub 2007 Dec 13. PubMed PMID: 18079739.

16: Furlan A, Monzani V, Reznikov LL, Leoni F, Fossati G, Modena D, Mascagni P, Dinarello CA. Pharmacokinetics, safety and inducible cytokine responses during aphase 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.

17: Golay J, Cuppini L, Leoni F, Micò C, Barbui V, Domenghini M, Lombardi L, Neri A, Barbui AM, Salvi A, Pozzi P, Porro G, Pagani P, Fossati G, Mascagni P, Introna M, Rambaldi A. The histone deacetylase inhibitor ITF2357 has anti-leukemic activity in vitro and in vivo and inhibits IL-6 and VEGF production by stromal cells. Leukemia. 2007 Sep;21(9):1892-900. Epub 2007 Jul 19. PubMed PMID: 17637810.

18: 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.

19: Armeanu S, Pathil A, Venturelli S, Mascagni P, Weiss TS, Göttlicher M, Gregor M, Lauer UM, Bitzer M. Apoptosis on hepatoma cells but not on primary hepatocytes by histone deacetylase inhibitors valproate and ITF2357. J Hepatol. 2005 Feb;42(2):210-7. PubMed PMID: 15664246.

20: Barbetti V, Gozzini A, Rovida E, Morandi A, Spinelli E, Fossati G, Mascagni P, Lübbert M, Dello Sbarba P, Santini V. Selective anti-leukaemic activity of low-dose histone deacetylase inhibitor ITF2357 on AML1/ETO-positive cells. Oncogene. 2008 Mar 13;27(12):1767-78. Epub 2007 Sep 24. PubMed PMID: 17891169.