Changing the face of kynurenines and neurotoxicity: therapeutic considerations

Abstract

Kynurenines are the products of tryptophan metabolism. Among them, kynurenine and kynurenic acid are generally thought to have neuroprotective properties, while 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid are considered neurotoxic. They participate in immunoregulation and inflammation and possess pro- or anti-excitotoxic properties, and their involvement in oxidative stress has also been suggested. Consequently, it is not surprising that kynurenines have been closely related to neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis. More information about the less-known metabolites, picolinic and cinnabarinic acid, evaluation of new receptorial targets, such as aryl-hydrocarbon receptors, and intensive research on the field of the immunomodulatory function of kynurenines delineated the high importance of this pathway in general homeostasis. Emerging knowledge about the kynurenine pathway provides new target points for the development of therapeutical solutions against neurodegenerative diseases.

Figure 1

Schematic drawing of the common neurotoxic mechanisms in neurodegeneration. The figure attempts to interpret that the involvement and interrelationship of metabolic disturbances, neuroinflammation and excitotoxicity causes neurotoxicity that eventually results in neurodegeneration.

Figure 2

The kynurenine pathway. The metabolism of l-tryptophan is divided into two distinct pathways, the serotonin and the kynurenine pathway (KP). Indoleamine 2,3-dioxygenase 1 and 2 and tryptophan 2,3-dioxygenase convert l-tryptophan to N-formyl-l-kynurenine in the first step of the KP. N-formyl-l-kynurenine is further processed by formamidase to l-kynurenine (l-KYN), the central metabolite of the KP. From l-KYN, three different enzymes produce the next metabolites, forming three branches of the metabolism. The first branch is the kynurenic acid branch, where kynurenine aminotransferases (KATs) produce kynurenic acid from l-KYN. On the second branch, kynureninase converts l-KYN to anthranilic acid, which is further metabolized by anthranilate 3-monoxygenase to 3-hydroxyanthranilic acid (3-HA). On the third branch, kynurenine monooxygenase produces 3-hydroxykynurenine (3-HK), which is further metabolized by kynureninase to 3-HA. 3-HK can be also metabolized by KATs to form xanthurenic acid or be auto-oxidized. 3-HA is converted by 3-hydroxyanthranilic acid oxygenase to 2-amino-3-carboxymuconate semialdehyde or suffers auto-oxidation to form cinnabarinic acid. 2-amino-3-carboxymuconate semialdehyde can be converted by picolinic carboxylase to picolinic acid or can be converted by non-enzymatic cyclisation to quinolinic acid, which, through conversion by quinolinic acid phosphoribosyltransferase, results in the formation of nicotinamide adenine dinucleotide.

Scheme 1

Transformational possibilities to develop kynurenic acid analogues. The transformations of kynurenic acid (KYNA) derivatives can be achieved through modification of the aromatic ring, the synthetically active 4-OH group, conversion of the 2-carboxylic function to pharmacologically interesting ester or amide derivatives of KYNA [139]. The amides of KYNA are pharmacologically and synthetically highly promising synthons in the patent literature. Coupling between KYNA and 2-dimethylaminoethylamine was achieved by using N,N'-diisopropylcarbodiimide (DCI) in the presence of 1-hydroxybenzotriazole hydrate (1-HOBT), yielding 2. Further transformations are also shown in Scheme 1 [140].