Pteridine-2,4-Diamine Derivatives as Radical Scavengers and Inhibitors of Lipoxygenase that can Possess Anti-Inflammatory Properties

Pontiki, Eleni; Hadjipavlou‐Litina, Dimitra; Patsilinakos, Alexandros; Tran, Trang M.; Marson, Charles M.

doi:10.4155/fmc.15.104

Cited by 21 publications

(9 citation statements)

References 49 publications

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“…Many pteridine-containing compounds serve as redox cofactors and possess redox-based activities (e.g., antioxidant, pro-oxidant, and radical scavenging activities). ,, As such, we examined lumazines 7 – 9 for radical scavenging activity against the stable radical 1,1-diphenyl-2-picrylhydrazyl (DPPH) (Figure A). Ascorbic acid was used as a positive control [half-maximum concentration (EC 50 ) = 30 μM].…”

Section: Resultsmentioning

confidence: 99%

Cellular Stress-Induced Metabolites in Escherichia coli

et al. 2022

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Escherichia coli isolates commonly inhabit the human microbiota, yet the majority of E. coli’s small-molecule repertoire remains uncharacterized. We previously employed erythromycin-induced translational stress to facilitate the characterization of autoinducer-3 (AI-3) and structurally related pyrazinones derived from “abortive” tRNA synthetase reactions in pathogenic, commensal, and probiotic E. coli isolates. In this study, we explored the “missing” tryptophan-derived pyrazinone reaction and characterized two other families of metabolites that were similarly upregulated under erythromycin stress. Strikingly, the abortive tryptophanyl-tRNA synthetase reaction leads to a tetracyclic indole alkaloid metabolite (1) rather than a pyrazinone. Furthermore, erythromycin induced two naphthoquinone-functionalized metabolites (MK-hCys, 2; and MK-Cys, 3) and four lumazines (7–10). Using genetic and metabolite analyses coupled with biomimetic synthesis, we provide support that the naphthoquinones are derived from 4-dihydroxy-2-naphthoic acid (DHNA), an intermediate in the menaquinone biosynthetic pathway, and the amino acids homocysteine and cysteine. In contrast, the lumazines are dependent on a flavin intermediate and α-ketoacids from the aminotransferases AspC and TyrB. We show that one of the lumazine members (9), an indole-functionalized analogue, possesses antioxidant properties, modulates the anti-inflammatory fate of isolated TH17 cells, and serves as an aryl-hydrocarbon receptor (AhR) agonist. These three systems described here serve to illustrate that new metabolic branches could be more commonly derived from well-established primary metabolic pathways.

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Section: Resultsmentioning

confidence: 99%

Cellular Stress-Induced Metabolites in Escherichia coli

et al. 2022

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“…Synthetic new compounds developed for cancer or organ transplantation are very attractive and untapped resources for the development of new drugs for neglected diseases such as the strongyloidiasis. Long chain-aminoalcohols and diamines are sphingosine-derivatives that have been considered as target molecules for development of new drugs showing cytotoxicity against neoplastic cells [ 35 ], and possessing anti-inflammatory properties [ 34 , 36 ] and ability to kill infectious agents [ 18 , 24 , 37 ]. However, they have never been used against nematodes such as Strongyloides spp.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo evaluation of 2-aminoalkanol and 1,2-alkanediamine derivatives against Strongyloides venezuelensis

et al. 2016

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BackgroundStrongyloidiasis is a parasitic disease widely present in tropical and subtropical areas. Strongyloides stercoralis represents the main species that infects human beings. Ivermectin is the current drug of choice; however, issues related with treatment failure in patients with diabetes or infected with T-lymphotropic virus-1 make the identification of new molecules for alternative treatment a priority. In the present study, the activity of sphingosine-related aminoalcohol and diamine were evaluated against Strongyloides venezuelensis third-stage larva (L3) cultures and experimental infections in mice.MethodsThe efficacy of each compound against L3 was assessed using both XTT (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) assay and microscopic observation with concentrations ranging from 1 to 350 μM. Cytotoxicity was evaluated using J774.2 macrophage cell line and XTT assay. Lethal concentration 50 (LC50), selectivity index (SI) and structure-activity relationships were established. The activity compounds 4 (2-(ethylamino) hexadecan-1-ol), 6 (2-(butylamino) hexadecan-1-ol), 17 (tert-butyl N-(1-aminododecan-2-yl) carbamate) and 18 (tert-butyl N-(1-aminohexadecan-2-yl) carbamate) were further assessed against experimental S. venezuelensis infections in CD1 mice measuring reductions in the numbers of parthenogenetic females and egg passed in faeces. Mice were infected with 3,000 L3 and treated with 20 mg/kg/day for five days.ResultsIn the screening study of 15 aminoalcohols [lauryl (n = 9); palmityl (n = 13); stearyl (n = 15) and alcohol derivatives], the presence of a palmitol chain was associated with the highest efficacy against L3 (LC50 31.9–39.1 μM). Alkylation of the 2-amino group with medium size fragments as ethyl or n-butyl showed the best larvicidal activity. The dialkylation did not improve efficacy. Aminoalcohols 4 and 6 showed the highest SI (1.5 and 1.6, respectively). With respect to diamine derivative compounds, a chain size of sixteen carbon atoms (palmitoyl chain, n = 13), and the alkylation of the 2-amino group with medium-sized fragments, were associated with the highest lethal activities. The presence of carbamoyl group in diamines 17 and 18 yielded high SI (1.7 and 1.4, respectively). Infected mice treated with aminoalcohol 6 showed reduction in parthenogenetic females (59 %) and eggs in faeces (51 %).ConclusionsThese results support the potentiality of aminoalcohol and diamine sphingosine-related compounds as suitable prototypes for developing new promising drugs against strongyloidiasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1648-5) contains supplementary material, which is available to authorized users.

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“…Pontiki et al synthesized a series of 2,4‐aminopteridines that showed antioxidant activity measured by several approaches, including inhibition of soybean lipoxygenase, where 4‐amino substituents played a crucial role in the inhibitory activity and 6,7‐substituents generally showed lowered potency. Moreover, to gain insight into their anti‐inflammatory activities, some 2‐(4‐methylpiperazin‐1‐yl)pteridin‐4‐amine compounds were tested in a rat model of ulcerative colitis and in the carrageenan paw edema model.…”

Section: Anti‐inflammatory Activitymentioning

confidence: 99%

Therapeutic potential of pteridine derivatives: A comprehensive review

Carmona‐Martínez

Ruiz–Alcaraz

Vera

et al. 2018

Medicinal Research Reviews

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Pteridines are aromatic compounds formed by fused pyrazine and pyrimidine rings. Many living organisms synthesize pteridines, where they act as pigments, enzymatic cofactors, or immune system activation molecules. This variety of biological functions has motivated the synthesis of a huge number of pteridine derivatives with the aim of studying their therapeutic potential. This review gathers the state‐of‐the‐art of pteridine derivatives, describing their biological activities and molecular targets. The antitumor activity of pteridine‐based compounds is one of the most studied and advanced therapeutic potentials, for which several molecular targets have been identified. Nevertheless, pteridines are also considered as very promising therapeutics for the treatment of chronic inflammation‐related diseases. On the other hand, many pteridine derivatives have been tested for antimicrobial activities but, although some of them resulted to be active in preliminary assays, a deeper research is needed in this area. Moreover, pteridines may be of use in the treatment of many other diseases, such as diabetes, osteoporosis, ischemia, or neurodegeneration, among others. Thus, the diversity of the biological activities shown by these compounds highlights the promising therapeutic use of pteridine derivatives. Indeed, methotrexate, pralatrexate, and triamterene are Food and Drug Administration approved pteridines, while many others are currently under study in clinical trials.

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Pteridine-2,4-Diamine Derivatives as Radical Scavengers and Inhibitors of Lipoxygenase that can Possess Anti-Inflammatory Properties

Cited by 21 publications

References 49 publications

Cellular Stress-Induced Metabolites in Escherichia coli

Cellular Stress-Induced Metabolites in Escherichia coli

In vitro and in vivo evaluation of 2-aminoalkanol and 1,2-alkanediamine derivatives against Strongyloides venezuelensis

Therapeutic potential of pteridine derivatives: A comprehensive review

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