Applicability of the Hammett Equation to the Indole System: Acidity of Indole-3-carboxylic Acids<sup>1</sup>

Melzer, Marvin S.

doi:10.1021/jo01049a038

Cited by 24 publications

(3 citation statements)

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“…Some years ago the pK's of six 5or 6-substituted indole-3-carboxylic acids were treated with the one-term Hammett equation, and it was concluded that no transmission occurred through the nitrogen atom. 16 In contrast, the report16 cited a study of substituted indole-2-carboxylic acid systems which showed good correlations with a linear combination of am and values for substituents in the 6 position by the expression log K/K0 = Pch0> + PNH<7m, where Pch/Pnh was close to unity. These later results are indicative of equally effective transmission of electronic effects by carbon and nitrogen.…”

Section: Resultsmentioning

confidence: 99%

Transmission of substituent effects in heterocyclic systems by carbon-13 nuclear magnetic resonance. Benzothiazoles

Sawhney¹,

Boykin²

1979

J. Org. Chem.

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Section: Resultsmentioning

confidence: 99%

Transmission of substituent effects in heterocyclic systems by carbon-13 nuclear magnetic resonance. Benzothiazoles

Sawhney¹,

Boykin²

1979

J. Org. Chem.

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“…The second-order rate constant for the reaction of MLT with ONOOH is relatively small (159 M -1 s -1 ) and very close to that of tryptophan (160 M -1 s -1 ) (31), indicating that the methoxy group at C-5 does not activate MLT toward peroxynitrite. The insensitivity of the peroxynitrite/melatonin reaction to electron-donating groups (MLT bears a methoxy substituent on C-5, while tryptophan bears a hydrogen atom on the same position) is substantiated by a Hammett study of 5-substituted indole-3-carboxylic acids, where σ m was used and electrondonating groups had only small effects on the pK of the carboxylic acids (32). These facts taken together support a mechanism in which an electron is transferred from MLT to ONOOH, and the reaction center is the 3-position of MLT.…”

Section: Reaction Ofmentioning

confidence: 99%

Reaction of Peroxynitrite with Melatonin: A Mechanistic Study

Zhang

Squadrito

Uppu

et al. 1999

Chem. Res. Toxicol.

109

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The pH profile of the peroxynitrite/melatonin reaction suggests that both peroxynitrous acid (ONOOH) and its anion (ONOO-) are reactive toward melatonin, but at physiological pH most of the reaction with melatonin involves ONOOH and the activated form of peroxynitrous acid (ONOOH). The formation of hydroxylated products (mainly 6-hydroxymelatonin) suggests that melatonin also reacts with ONOOH. The overall peroxynitrite/melatonin reaction is first-order in melatonin and first-order in peroxynitrite, but the hydroxylation of melatonin is presumed to be zero-order in melatonin. Melatonin is metabolized in the liver, mainly to 6-hydroxymelatonin, so we do not think this metabolite is a useful biomarker for melatonin's antioxidant activity; however, 6-hydroxymelatonin is a better chain-breaking antioxidant than melatonin and may contribute to the beneficial effects of melatonin in vivo. As is now well-known, CO2 modulates the reactions of peroxynitrite. The reaction of peroxynitrite with melatonin in the absence of added bicarbonate produces mainly 6-hydroxymelatonin and 1,2,3,3a,8, 8a-hexahydro-1-acetyl-5-methoxy-8a-hydroxypyrrolo[2,3-b]indole, with some isomeric 1,2,3,3a,8, 8a-hexahydro-1-acetyl-5-methoxy-3a-hydroxypyrrolo[2,3-b]indole. In the presence of added bicarbonate, product yields decrease and 6-hydroxymelatonin is not formed. These facts suggest that melatonin scavenges reactive species (such as CO3*- and *NO2) that are produced from the peroxynitrite/CO2 reaction. The spectrum of the melatoninyl radical cation is observed both in the absence and in the presence of added bicarbonate, suggesting that the melatoninyl radical cation is the initial product and the hydroxypyrrolo[2, 3-b]indole products are derived from it. Unlike tyrosine, where both nitrated and hydroxylated products can be isolated, nitromelatonin is not found in the final products from the melatonin/peroxynitrite reaction in either the absence or presence of added bicarbonate. However, we suggest that 2-hydroxy-3-nitro- and/or 2-hydroxy-3-peroxynitro-2,3-dihydromelatonin are formed as intermediates and subsequently decompose to give 1,2,3,3a,8, 8a-hexahydro-1-acetyl-5-methoxy-8a-hydroxypyrrolo[2,3-b]indole. Since peroxynitrite/CO2 governs the reactions of peroxynitrite in vivo, we suggest that the hydroxypyrrolo[2,3-b]indole products are the main products from the oxidation of melatonin by peroxynitrite-derived species in vivo, and that these products may serve as indexes for melatonin's antioxidant activity.

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“…The aqueous phase was acidified with concentrated HCl and the product was filtered. [22][23][24] Finally, compounds 4a-c (5 mmol) were dissolved in THF (25 mL), then 1,3-dicyclohexylcarbodiimide (DCC) (1.24 g, 6 mmol) and 4-dimethylaminopyridin (DMAP; 0.12 g, 1 mmol) were slowly added. After stirring for 30 min at rt, compound 2 (5 mmol) was added and the mixture was stirred for 7-9 h at rt.…”

Section: Synthesis Of (1h-benzoimidazol-2-yl)methyl 1h-indole-3-carbomentioning

confidence: 99%

Design, synthesis, and antitumor activity of novel benzoheterocycle derivatives as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase

Ding

Zhao

et al. 2020

Journal of Chemical Research

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The vascular endothelial growth factor receptor-2 signaling pathway promotes the formation of new blood vessels, and vascular endothelial growth factor receptor-2 tyrosine kinase exists in both active and inactive conformations. Novel indole–benzimidazole and indole–benzothiazole derivatives joined by different linkers are designed and synthesized as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. All the synthesized compounds were evaluated for their cytotoxicity against four human cancer cell lines (HeLa, HT29, A549, and MDA-MB-435) and human umbilical vein endothelial cell. Meanwhile, the inhibitory activities against vascular endothelial growth factor receptor-2 are estimated in vitro and the binding interactions with dual conformations of vascular endothelial growth factor receptor-2 tyrosine kinase are evaluated by molecular docking. Compounds 5a–c and 14 show inhibitory activity against vascular endothelial growth factor receptor-2 tyrosine kinase and promising cytotoxicity, specifically with IC50 values ranging between 0.1 and 1 μM, which imply broad-spectrum antitumor activity. These results provide a deep insight into potential structural modifications for developing potent vascular endothelial growth factor receptor-2 tyrosine kinase inhibitors.

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Applicability of the Hammett Equation to the Indole System: Acidity of Indole-3-carboxylic Acids¹

Cited by 24 publications

References 0 publications

Transmission of substituent effects in heterocyclic systems by carbon-13 nuclear magnetic resonance. Benzothiazoles

Transmission of substituent effects in heterocyclic systems by carbon-13 nuclear magnetic resonance. Benzothiazoles

Reaction of Peroxynitrite with Melatonin: A Mechanistic Study

Design, synthesis, and antitumor activity of novel benzoheterocycle derivatives as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase

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Applicability of the Hammett Equation to the Indole System: Acidity of Indole-3-carboxylic Acids1

Cited by 24 publications

References 0 publications

Transmission of substituent effects in heterocyclic systems by carbon-13 nuclear magnetic resonance. Benzothiazoles

Transmission of substituent effects in heterocyclic systems by carbon-13 nuclear magnetic resonance. Benzothiazoles

Reaction of Peroxynitrite with Melatonin: A Mechanistic Study

Design, synthesis, and antitumor activity of novel benzoheterocycle derivatives as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase

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Applicability of the Hammett Equation to the Indole System: Acidity of Indole-3-carboxylic Acids¹