Abstract: Hydroxyindoles are organic compounds characterized by the presence of a hydroxy group attached to an indole ring (six-membered benzene ring fused to a five-membered pyrrole ring). These compounds are naturally occurring and play a role in the synthesis of various medicinal drugs. One notable example is 4-Hydroxyindole (4-HI), which contains a hydroxy group at the fourth position of the indole ring. In a recent study, we tested various hydroxyindole compounds for their antiferroptotic activity, including 3-hydroxyindole, which demonstrated strong resistance to ferroptosis. Ferroptosis is a regulated form of cell death that occurs due to uncontrolled phospholipid peroxidation and is associated with the development of degenerative conditions, such as neurodegenerative diseases. Here, we tested the hypothesis that 4-HI could protect against ferroptosis, similar to other hydroxyindole compounds. To induce ferroptosis, we utilized established modulators, including erastin, RSL3, and FINO2. We assessed cytotoxicity using the calcein AM assay and measured lipid peroxidation caused by ferroptosis inducers with the C11-BODIPY assay. Our results indicated that 4-HI protects various brain-related cell types, including HT-22, N27, and RBE4 cells, from ferroptosis. We also utilized our newly developed cell-free assay, in which combined iron and arachidonic acid were used to oxidize C11-BODIPY, allowing us to investigate the radical scavenging activity of 4-HI. We discovered that 4-HI exhibits antioxidant effects in cell-free assays, suggesting that its protective action against ferroptosis is likely due to its radical-scavenging capabilities. Interestingly, we found that 4-hydroxyindole-3-carbaldehyde, a structural analog of 4-HI, did not effectively prevent ferroptosis. This suggests that the carbaldehyde group, which is an electron-withdrawing group, may reduce the antiferroptotic activity of 4-HI. In summary, 4-HI appears to be a promising inhibitor of ferroptosis, warranting further research to explore its potential in protecting against neurotoxicity and neurodegeneration associated with this type of cell death.

Purchased from AmBeed: 81779-27-3

Product Details of 4-Hydroxy-1H-indole-3-carbaldehyde

CAS No. :	81779-27-3
Formula :	C₉H₇NO₂
M.W :	161.16
SMILES Code :	OC1=C2C(=CC=C1)[NH]C=C2C=O
Synonyms :	4-Hydroxyindole-3-carboxaldehyde
MDL No. :	MFCD05864721
InChI Key :	QLBZIZLLMNWTHG-UHFFFAOYSA-N
Pubchem ID :	9815282

Safety of 4-Hydroxy-1H-indole-3-carbaldehyde

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Application In Synthesis of 4-Hydroxy-1H-indole-3-carbaldehyde

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 81779-27-3 ]

[ 81779-27-3 ] Synthesis Path-Downstream 1~54

1
[ 72527-73-2 ]
[ 81779-27-3 ]

References: [1]Heterocycles,1986,vol. 24,p. 3065 - 3069.

2
[ 141692-10-6 ]
[ 81779-27-3 ]

References: [1]Heterocycles,1986,vol. 24,p. 3065 - 3069.

3
[ 81779-27-3 ]
[ 106-95-6 ]
[ 109523-70-8 ]

References: [1]Heterocycles,1986,vol. 24,p. 3065 - 3069.

4
[ 81779-27-3 ]
[ 106-89-8 ]
[ 109523-75-3 ]
[ 109523-76-4 ]

References: [1]Heterocycles,1986,vol. 24,p. 3065 - 3069.

5
[ 81779-27-3 ]
[ 74-88-4 ]
[ 109523-69-5 ]

References: [1]Heterocycles,1986,vol. 24,p. 3065 - 3069.

6
[ 487-89-8 ]
[ 81779-27-3 ]

References: [1]Heterocycles,1996,vol. 43,p. 1855 - 1858.

7
[ 81779-27-3 ]
4-Hydroxy-7-nitro-1H-indole-3-carbaldehyde [ No CAS ]
[ 183621-60-5 ]

References: [1]Heterocycles,1996,vol. 43,p. 1855 - 1858.

8
[ 7042-71-9 ]
[ 81779-27-3 ]

References: [1]Chemical and pharmaceutical bulletin,2002,vol. 50,p. 92 - 99.

9
[ 24424-99-5 ]
[ 81779-27-3 ]
[ 404888-00-2 ]

Yield	Reaction Conditions	Operation in experiment
74%	With dmap; In acetonitrile; at 0℃; for 3h;	EXAMPLE 2 OF REFERENCE 3-Formyl-4-hydroxyindole-1-carboxylic Acid tert-butyl Ester (2-1) (R7=R11=H) A mixture of the 3-formyl-4-hydroxyindole (1-1) 323 mg, di-tert-butyldicarbonate 458 mg, dimethylaminopyridine 12.5 mg and acetonitrile 25 ml was stirred under cooling in ice for 3 h.The solvent was removed under reduced pressure and the residue obtained was recrystallized from acetone-isopropyl ether to give the titled compound as pale yellow crystals, m.p. 159-161 C.(dec.), 389 mg.Yield 74%. 1H-NMR(CDCl3): 1.71 (9H, s), 6.84 (1H, dd, J=8.1, 0.9 Hz), 7.31 (1H, t, J=8.1 Hz), 7.61 (1H, dd, J=8.1, 0.9 Hz), 8.25 (1H, s), 9.76 (1H, d, J=0.6 Hz), 10.13 (1H, s).

References: [1]Chemical and pharmaceutical bulletin,2002,vol. 50,p. 92 - 99.
[2]Patent: US2003/236295,2003,A1 .Location in patent: Page 9.

10
[ 81779-27-3 ]
5-bromo-4-hydroxyindole-3-carbaldehyde [ No CAS ]
[ 404887-98-5 ]

References: [1]Chemical and pharmaceutical bulletin,2002,vol. 50,p. 92 - 99.

11
[ 81779-27-3 ]
5-bromo-4-hydroxyindole-3-carbaldehyde [ No CAS ]

References: [1]Chemical and pharmaceutical bulletin,2002,vol. 50,p. 92 - 99.

12
[ 81779-27-3 ]
[ 404888-04-6 ]

References: [1]Chemical and pharmaceutical bulletin,2002,vol. 50,p. 92 - 99.

13
[ 81779-27-3 ]
[ 404888-02-4 ]

References: [1]Chemical and pharmaceutical bulletin,2002,vol. 50,p. 92 - 99.

14
[ 81779-27-3 ]
4-benzyloxy-5-bromoindole-3-acetonitrile [ No CAS ]

References: [1]Chemical and pharmaceutical bulletin,2002,vol. 50,p. 92 - 99.

15
[ 81779-27-3 ]
4-benzyloxy-1-tert-butoxycarbonylindole-3-carbaldehyde [ No CAS ]

References: [1]Chemical and pharmaceutical bulletin,2002,vol. 50,p. 92 - 99.

16
[ 81779-27-3 ]
1-benzyl-4-benzyloxy-7-bromindole-3-carbaldehyde [ No CAS ]

References: [1]Chemical and pharmaceutical bulletin,2002,vol. 50,p. 92 - 99.

17
[ 81779-27-3 ]
[ 404888-03-5 ]

References: [1]Chemical and pharmaceutical bulletin,2002,vol. 50,p. 92 - 99.

18
[ 81779-27-3 ]
[ 135531-93-0 ]

References: [1]Heterocycles,1996,vol. 43,p. 1855 - 1858.

19
[ 81779-27-3 ]
[ 183621-63-8 ]

References: [1]Heterocycles,1996,vol. 43,p. 1855 - 1858.

20
[ 81779-27-3 ]
1,4-dihydroxy-5-nitroindole [ No CAS ]

References: [1]Heterocycles,1996,vol. 43,p. 1855 - 1858.

21
[ 81779-27-3 ]
[ 183621-62-7 ]

References: [1]Heterocycles,1996,vol. 43,p. 1855 - 1858.

22
[ 81779-27-3 ]
4-Acetoxy-1-acetyl-5-nitro-1H-indole-3-carboxylic acid [ No CAS ]

References: [1]Heterocycles,1996,vol. 43,p. 1855 - 1858.

23
[ 81779-27-3 ]
[ 109523-71-9 ]

References: [1]Heterocycles,1986,vol. 24,p. 3065 - 3069.

24
[ 81779-27-3 ]
[ 109523-74-2 ]

References: [1]Heterocycles,1986,vol. 24,p. 3065 - 3069.

25
[ 81779-27-3 ]
[ 109523-77-5 ]

References: [1]Heterocycles,1986,vol. 24,p. 3065 - 3069.

26
[ 81779-27-3 ]
[ 109523-78-6 ]

References: [1]Heterocycles,1986,vol. 24,p. 3065 - 3069.

27
[ 2380-94-1 ]
[ 68-12-2 ]
[ 81779-27-3 ]

Yield	Reaction Conditions	Operation in experiment
82%		EXAMPLE 1 OF REFERENCE 4-Hydroxyindole-3-carbaldehyde (1-1) (R7=R11=H) phosphorous oxychloride 7.35 ml was added dropwise to dry dimethylformamide 15 ml under cooling in ice-methanol bath and the mixture was stirred for 15 min.Then, a solution of the 4-hydroxyindole 5.0 g in dry dimethylformamide 10 ml was added dropwise to the mixture under cooling in ice and the mixture was stirred for 2 h at room temperature.water was added under cooling in ice to the mixture, which was made alkaline with a 30% aqueous sodium hydroxide solution and was stirred for 15 min.Then, the mixture was acidified to PH 4 with 5N-HCl and the precipitate was collected by filtration, washed with water and dried to give the titled compound 4.99 g as crude crystalline materials.Yield 82%.Crude crystalline materials are recrystallized from methanol to give yellow crystals m.p. 190-193 C. 1H-NMR(DMSO-d6): 6.54 (1H, dd, J=8.1, 0.9 Hz), 6.95 (1H, dd, J=8.1, 0.9 Hz), 7.13 (1H, t, J=8.1 Hz), 8.37 (1H, s), 9.64 (1H, s), 10.54 (1H, br s), 12.35 (1H, br s).

References: [1]Patent: US2003/236295,2003,A1 .Location in patent: Page 9.

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 3 4-Hydroxy-3-formylindole 17.2 g. 4-Benzyloxy-3-formylindole (see Can. J. Chem., 42, 514/1964) are dissolved in 700 ml. methanol, 5 ml. triethylamine are added thereto and the reaction mixture is mixed with 3 g. 10% palladium-active charcoal and hydrogenated at ambient temperature and 1 bar hydrogen pressure. After removal of the catalyst, the reaction mixture is evaporated to give 11 g. (98% of theory) 4-hydroxy-3-formylindole; m.p. 196-200 C.

29
[ 2380-94-1 ]
[ 81779-27-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; trichlorophosphate; In N-methyl-acetamide; water;	4-Hydroxyindole-3-carbaldehyde(1-1) (R7=R11=H) Phosphorous oxychloride 7.35 ml was added dropwise to dry dimethylformamide 15 ml under cooling in ice-methanol bath and the mixture was stirred for 15 min. Then, a solution of the 4-hydroxyindole 5.0 g in dry dimethylformamide 10 ml was added dropwise to the mixture under cooling in ice and the mixture was stirred for 2 h at room temperature. Water was added under cooling in ice to the mixture, which was made alkaline with a 30% aqueous sodium hydroxide solution and was stirred for 15 min. Then, the mixture was acidified to pH 4 with 5N-HCl and the precipitate was collected by filtration, washed with water and dried to give the titled compound 4.99 g as crude crystalline materials. Yield 82%. Crude crystalline materials are recrystallized from methanol to give yellow crystals m.p. 190-193 ØC. 1H-NMR(DMSO-d6): 6.54 (1H, dd, J = 8.1, 0.9 Hz), 6.95 (1H, dd, J = 8.1, 0.9 Hz), 7.13 (1H, t, J = 8.1 Hz), 8.37 (1H, s), 9.64 (1H, s), 10.54 (1H, br s), 12.35 (1H, br s).

References: [1]Patent: EP1325909,2003,A1 .

30
[ 1346151-06-1 ]
[ 81779-27-3 ]
[ 1346151-07-2 ]

Yield	Reaction Conditions	Operation in experiment
64%	With piperidine; In methanol; at 60℃; for 2h;	(b) Step 2 A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.056 g, 0.016 mmol) in methanol (2.0 mL) was added with <strong>[81779-27-3]4-hydroxy-1H-indole-3-carboxaldehyde</strong> (0.026 g, 0.016 mmol). Then, the mixture was added with 5 drops of piperidine, and then the mixture was stirred at 60C for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain tert-butyl (Z)-4-({6-hydroxy-2-[(4-hydroxy-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.050 g, 64%). 1H NMR (300 MHz, DMSO-d6) delta 1.38 (s, 9H), 2.53 (m, 4H), 3.38 (m, 4H), 3.88 (s, 2H), 6.55 (d, J = 7.3 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 6.91-7.04 (m, 2H), 7.52 (d, J = 8.1 Hz, 1H), 7.69 (s, 1H), 8.06 (d, J = 2.9 Hz, 1H), 11.87 (s, 1H).

References: [1]Patent: EP2565192,2013,A1 .Location in patent: Paragraph 0197.

31
[ 81779-27-3 ]
N-(2,7,8,9-tetrahydro-6-oxa-2-azabenzo[c,d]azulen-8-yl)hydrazinecarboxylic acid tert-butyl ester [ No CAS ]