NSC77674
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MedKoo CAT#: 555535

CAS#: 737-86-0

Description: NSC77674, also known as Pyridoxal isonicotinoyl hydrazone and PIH is a lipophilic, nontoxic, iron-chelating agent that shows high iron chelation efficacy both in vitro in cell culture models and in vivo in rats and mice.

Chemical Structure

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NSC77674
CAS# 737-86-0
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 555535
Name: NSC77674
CAS#: 737-86-0
Chemical Formula: C14H14N4O3
Exact Mass: 286.11
Molecular Weight: 286.291
Elemental Analysis: C, 58.74; H, 4.93; N, 19.57; O, 16.77

Price and Availability

Size Price Availability Quantity
100mg USD 550
200mg USD 950
500mg USD 1950
1g USD 2750
2g USD 3950
5g USD 4950
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Synonym: NSC 77674; NSC-77674; NSC77674; PIH; Pyridoxal isonicotinoyl hydrazone;

IUPAC/Chemical Name: 4-pyridinecarboxylic acid, 2-[[3-hydroxy-5-(hydroxymethyl)-2-methyl-4-pyridinyl]methylene]hydrazide

InChi Key: BQYIXOPJPLGCRZ-REZTVBANSA-N

InChi Code: InChI=1S/C14H14N4O3/c1-9-13(20)12(11(8-19)6-16-9)7-17-18-14(21)10-2-4-15-5-3-10/h2-7,19-20H,8H2,1H3,(H,18,21)/b17-7+

SMILES Code: O=C(C1=CC=NC=C1)N/N=C/C2=C(O)C(C)=NC=C2CO

Appearance: 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: >3 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

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Product Data:
Product Data
Instruction:
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Biological target: Pyridoxal isonicotinoyl hydrazone (PIH) is a lipophilic, tridentate Fe-chelating agent that shows high Fe chelation efficacy.
In vitro activity: Compared with hydroxyl radical scavengers (DMSO, salicylate and mannitol), PIH (pyridoxal isonicotinoyl hydrazone) was about two orders of magnitude more active in protecting 2-deoxyribose from degradation, which was comparable with some of its analogues and DFO. 400 microM PIH was equally effective in preventing degradation of both 15 mM and 1.5 mM 2-deoxyribose. Taken together, these results indicate that PIH (and its analogues) works by a mechanism different than the hydroxyl radical scavengers. Reference: Biochim Biophys Acta. 2000 Oct 18;1523(2-3):154-60. https://pubmed.ncbi.nlm.nih.gov/11042379/
In vivo activity: In vivo, mice treated with PIH after ICH attenuated neurological deficit scores. Additionally, this study found PIH reduced ROS production, iron accumulation, and lipid peroxidation around the hematoma peripheral tissue. Meanwhile, ICH mice treated with PIH showed an upregulation of the key ferroptosis enzyme, glutathione peroxidase 4, and downregulation of cyclooxygenase-2. Moreover, PIH administration inhibited proinflammatory polarization and reduced interleukin-1 beta and tumor necrosis factor alpha in ICH mice. Reference: Biomed Res Int. 2021 Sep 8;2021:9916328. https://pubmed.ncbi.nlm.nih.gov/34541001/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMF 1.0 3.49
DMSO 9.9 34.42
Ethanol 0.5 1.75

Preparing Stock Solutions

The following data is based on the product molecular weight 286.29 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.

Recalculate based on batch purity %
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: 1. Brewer CT, Yang L, Edwards A, Lu Y, Low J, Wu J, Lee RE, Chen T. The Isoniazid Metabolites Hydrazine and Pyridoxal Isonicotinoyl Hydrazone Modulate Heme Biosynthesis. Toxicol Sci. 2019 Mar 1;168(1):209-224. doi: 10.1093/toxsci/kfy294. PMID: 30517741; PMCID: PMC6390808. 2. Hermes-Lima M, Ponka P, Schulman HM. The iron chelator pyridoxal isonicotinoyl hydrazone (PIH) and its analogues prevent damage to 2-deoxyribose mediated by ferric iron plus ascorbate. Biochim Biophys Acta. 2000 Oct 18;1523(2-3):154-60. doi: 10.1016/s0304-4165(00)00115-x. PMID: 11042379. 3. Zhang H, Wen M, Chen J, Yao C, Lin X, Lin Z, Ru J, Zhuge Q, Yang S. Pyridoxal Isonicotinoyl Hydrazone Improves Neurological Recovery by Attenuating Ferroptosis and Inflammation in Cerebral Hemorrhagic Mice. Biomed Res Int. 2021 Sep 8;2021:9916328. doi: 10.1155/2021/9916328. PMID: 34541001; PMCID: PMC8445720. 4. Zhang G, Chen L, Wen Y, Rao Z, Wei Y, Wu X. Pyridoxal isonicotinoyl hydrazone inhibition of FXR is involved in the pathogenesis of isoniazid-induced liver injury. Toxicol Appl Pharmacol. 2020 Sep 1;402:115134. doi: 10.1016/j.taap.2020.115134. Epub 2020 Jul 14. PMID: 32673658.
In vitro protocol: 1. Brewer CT, Yang L, Edwards A, Lu Y, Low J, Wu J, Lee RE, Chen T. The Isoniazid Metabolites Hydrazine and Pyridoxal Isonicotinoyl Hydrazone Modulate Heme Biosynthesis. Toxicol Sci. 2019 Mar 1;168(1):209-224. doi: 10.1093/toxsci/kfy294. PMID: 30517741; PMCID: PMC6390808. 2. Hermes-Lima M, Ponka P, Schulman HM. The iron chelator pyridoxal isonicotinoyl hydrazone (PIH) and its analogues prevent damage to 2-deoxyribose mediated by ferric iron plus ascorbate. Biochim Biophys Acta. 2000 Oct 18;1523(2-3):154-60. doi: 10.1016/s0304-4165(00)00115-x. PMID: 11042379.
In vivo protocol: 1. Zhang H, Wen M, Chen J, Yao C, Lin X, Lin Z, Ru J, Zhuge Q, Yang S. Pyridoxal Isonicotinoyl Hydrazone Improves Neurological Recovery by Attenuating Ferroptosis and Inflammation in Cerebral Hemorrhagic Mice. Biomed Res Int. 2021 Sep 8;2021:9916328. doi: 10.1155/2021/9916328. PMID: 34541001; PMCID: PMC8445720. 2. Zhang G, Chen L, Wen Y, Rao Z, Wei Y, Wu X. Pyridoxal isonicotinoyl hydrazone inhibition of FXR is involved in the pathogenesis of isoniazid-induced liver injury. Toxicol Appl Pharmacol. 2020 Sep 1;402:115134. doi: 10.1016/j.taap.2020.115134. Epub 2020 Jul 14. PMID: 32673658.

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1: Brewer CT, Yang L, Edwards A, Lu Y, Low J, Wu J, Lee RE, Chen T. The Isoniazid Metabolites Hydrazine and Pyridoxal Isonicotinoyl Hydrazone Modulate Heme Biosynthesis. Toxicol Sci. 2019 Mar 1;168(1):209-224. doi: 10.1093/toxsci/kfy294. PubMed PMID: 30517741; PubMed Central PMCID: PMC6390808.

2: Sarno F, Papulino C, Franci G, Andersen JH, Cautain B, Melardo C, Altucci L, Nebbioso A. 3-Chloro-N'-(2-hydroxybenzylidene) benzohydrazide: An LSD1-Selective Inhibitor and Iron-Chelating Agent for Anticancer Therapy. Front Pharmacol. 2018 Sep 7;9:1006. doi: 10.3389/fphar.2018.01006. eCollection 2018. PubMed PMID: 30245629; PubMed Central PMCID: PMC6137965.

3: Chen YL, Kong X, Xie Y, Hider RC. The interaction of pyridoxal isonicotinoyl hydrazone (PIH) and salicylaldehyde isonicotinoyl hydrazone (SIH) with iron. J Inorg Biochem. 2018 Mar;180:194-203. doi: 10.1016/j.jinorgbio.2017.12.007. Epub 2017 Dec 21. PubMed PMID: 29329026.

4: Fratz-Berilla EJ, Breydo L, Gouya L, Puy H, Uversky VN, Ferreira GC. Isoniazid inhibits human erythroid 5-aminolevulinate synthase: Molecular mechanism and tolerance study with four X-linked protoporphyria patients. Biochim Biophys Acta Mol Basis Dis. 2017 Feb;1863(2):428-439. doi: 10.1016/j.bbadis.2016.11.011. Epub 2016 Nov 10. PubMed PMID: 27838491.

5: Merlot AM, Sahni S, Lane DJ, Fordham AM, Pantarat N, Hibbs DE, Richardson V, Doddareddy MR, Ong JA, Huang ML, Richardson DR, Kalinowski DS. Potentiating the cellular targeting and anti-tumor activity of Dp44mT via binding to human serum albumin: two saturable mechanisms of Dp44mT uptake by cells. Oncotarget. 2015 Apr 30;6(12):10374-98. PubMed PMID: 25848850; PubMed Central PMCID: PMC4496362.

6: Ellis S, Kalinowski DS, Leotta L, Huang ML, Jelfs P, Sintchenko V, Richardson DR, Triccas JA. Potent antimycobacterial activity of the pyridoxal isonicotinoyl hydrazone analog 2-pyridylcarboxaldehyde isonicotinoyl hydrazone: a lipophilic transport vehicle for isonicotinic acid hydrazide. Mol Pharmacol. 2014 Feb;85(2):269-78. doi: 10.1124/mol.113.090357. Epub 2013 Nov 15. PubMed PMID: 24243647; PubMed Central PMCID: PMC6067633.

7: Merlot AM, Pantarat N, Menezes SV, Sahni S, Richardson DR, Kalinowski DS. Cellular uptake of the antitumor agent Dp44mT occurs via a carrier/receptor-mediated mechanism. Mol Pharmacol. 2013 Dec;84(6):911-24. doi: 10.1124/mol.113.088393. Epub 2013 Oct 1. PubMed PMID: 24085840.

8: DeRuisseau KC, Park YM, DeRuisseau LR, Cowley PM, Fazen CH, Doyle RP. Aging-related changes in the iron status of skeletal muscle. Exp Gerontol. 2013 Nov;48(11):1294-302. doi: 10.1016/j.exger.2013.08.011. Epub 2013 Aug 29. PubMed PMID: 23994517; PubMed Central PMCID: PMC3812819.

9: Pelle E, Jian J, Declercq L, Dong K, Yang Q, Pourzand C, Maes D, Pernodet N, Yarosh DB, Huang X. Protection against ultraviolet A-induced oxidative damage in normal human epidermal keratinocytes under post-menopausal conditions by an ultraviolet A-activated caged-iron chelator: a pilot study. Photodermatol Photoimmunol Photomed. 2011 Oct;27(5):231-5. doi: 10.1111/j.1600-0781.2011.00604.x. PubMed PMID: 21950626.

10: Pasáková I, Gladziszová M, Charvátová J, Stariat J, Klimeš J, Kovaříková P. Use of different stationary phases for separation of isoniazid, its metabolites and vitamin B6 forms. J Sep Sci. 2011 Jun;34(12):1357-65. doi: 10.1002/jssc.201100081. Epub 2011 May 13. PubMed PMID: 21567949.

11: Kovacevic Z, Yu Y, Richardson DR. Chelators to the rescue: different horses for different courses! Chem Res Toxicol. 2011 Mar 21;24(3):279-82. doi: 10.1021/tx100435c. Epub 2011 Jan 7. PubMed PMID: 21214214.

12: Merlot AM, Pantarat N, Lovejoy DB, Kalinowski DS, Richardson DR. Membrane transport and intracellular sequestration of novel thiosemicarbazone chelators for the treatment of cancer. Mol Pharmacol. 2010 Oct;78(4):675-84. doi: 10.1124/mol.110.066126. Epub 2010 Jul 6. PubMed PMID: 20605952.

13: Bendova P, Mackova E, Haskova P, Vavrova A, Jirkovsky E, Sterba M, Popelova O, Kalinowski DS, Kovarikova P, Vavrova K, Richardson DR, Simunek T. Comparison of clinically used and experimental iron chelators for protection against oxidative stress-induced cellular injury. Chem Res Toxicol. 2010 Jun 21;23(6):1105-14. doi: 10.1021/tx100125t. PubMed PMID: 20521781.

14: Stariat J, Kovaríková P, Klimes J, Lovejoy DB, Kalinowski DS, Richardson DR. HPLC methods for determination of two novel thiosemicarbazone anti-cancer drugs (N4mT and Dp44mT) in plasma and their application to in vitro plasma stability of these agents. J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Jan 15;877(3):316-22. doi: 10.1016/j.jchromb.2008.11.044. Epub 2008 Dec 6. PubMed PMID: 19097949.

15: Whitnall M, Suryo Rahmanto Y, Sutak R, Xu X, Becker EM, Mikhael MR, Ponka P, Richardson DR. The MCK mouse heart model of Friedreich's ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation. Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9757-62. doi: 10.1073/pnas.0804261105. Epub 2008 Jul 9. PubMed PMID: 18621680; PubMed Central PMCID: PMC2474513.

16: Szuber N, Buss JL, Soe-Lin S, Felfly H, Trudel M, Ponka P. Alternative treatment paradigm for thalassemia using iron chelators. Exp Hematol. 2008 Jul;36(7):773-85. doi: 10.1016/j.exphem.2008.01.006. Epub 2008 May 5. PubMed PMID: 18456387.

17: Hershko C, Abrahamov A, Konijn AM, Breuer W, Cabantchik IZ, Pootrakul P, Link G. Objectives and methods of iron chelation therapy. Bioinorg Chem Appl. 2003:151-68. doi: 10.1155/S1565363303000128. PubMed PMID: 18365050; PubMed Central PMCID: PMC2267048.

18: Kovaríková P, Mrkvicková Z, Klimes J. Investigation of the stability of aromatic hydrazones in plasma and related biological material. J Pharm Biomed Anal. 2008 Jun 9;47(2):360-70. doi: 10.1016/j.jpba.2008.01.011. Epub 2008 Jan 16. PubMed PMID: 18294799.

19: Simunek T, Sterba M, Popelova O, Kaiserova H, Potacova A, Adamcova M, Mazurova Y, Ponka P, Gersl V. Pyridoxal isonicotinoyl hydrazone (PIH) and its analogs as protectants against anthracycline-induced cardiotoxicity. Hemoglobin. 2008;32(1-2):207-15. doi: 10.1080/03630260701680276. PubMed PMID: 18274998.

20: Kalinowski DS, Richardson DR. Future of toxicology--iron chelators and differing modes of action and toxicity: the changing face of iron chelation therapy. Chem Res Toxicol. 2007 May;20(5):715-20. Epub 2007 Apr 3. PubMed PMID: 17402750.