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Parasitology 1997Leishmania and other trypanosomatid protozoa require reduced pteridines (pterins and folates) for growth, suggesting that inhibition of these pathways could be targeted... (Review)
Review
Leishmania and other trypanosomatid protozoa require reduced pteridines (pterins and folates) for growth, suggesting that inhibition of these pathways could be targeted for effective chemotherapy. This goal has not yet been realized, indicating that pteridine metabolism may be unusual in this lower eukaryote. We have investigated this possibility using both wild type and laboratory-selected antifolate-resistant strains, and with defined genetic knockouts of several pteridine metabolic genes. In Leishmania, resistance to the antifolate methotrexate is mediated through several mechanisms singly or in combination, including alterations in transport leading to reduced drug influx, overproduction (R-region amplification) or point mutation of dihydrofolate reductase-thymidylate synthase (DHFR-TS), and amplification of a novel pteridine reductase (PTR1, encoded by the H-region). All of the proteins involved are potential targets for antifolate chemotherapy. Notably, parasites in which the gene encoding dihydrofolate reductase (DHFR) has been deleted (dhfr-ts- knockouts) do not survive in animal models, validating this enzyme as a target for effective chemotherapy. However, the properties of pteridine reductase 1 (PTR1) suggest a reason why antifolate chemotherapy has so far not been successful in trypanosomatids. PTR1, by its ability to provide reduced pterins and folates, has the potential to act as a by-pass and/or modulator of DHFR inhibition under physiological conditions. Moreover, PTR1 is less sensitive to many antifolates targeted primarily against DHFR. These findings suggest that successful antifolate chemotherapy in Leishmania will have to target simultaneously both DHFR and PTR1.
Topics: Animals; Drug Resistance; Folic Acid Antagonists; Leishmania; Leishmaniasis; Methotrexate; Oxidoreductases; Pteridines
PubMed: 9309772
DOI: No ID Found -
Acta Crystallographica. Section F,... Nov 2017The pteridine glycosyltransferase (PGT) found in Chlorobium tepidum (CtPGT) catalyzes the conversion of L-threo-tetrahydrobiopterin to...
The pteridine glycosyltransferase (PGT) found in Chlorobium tepidum (CtPGT) catalyzes the conversion of L-threo-tetrahydrobiopterin to 1-O-(L-threo-biopterin-2'-yl)-β-N-acetylglucosamine using UDP-N-acetylglucosamine. The gene for CtPGT was cloned, and selenomethionine-derivatized protein was overexpressed and purified using various chromatographic techniques. The protein was crystallized by the hanging-drop vapour-diffusion method using 0.24 M triammonium citrate pH 7.0, 14%(w/v) PEG 3350 as a reservoir solution. Multiple-wavelength anomalous diffraction data were collected to 2.15 Å resolution from a single CtPGT crystal. The crystal belonged to the monoclinic space group C2, with unit-cell parameters a = 189.61, b = 79.98, c = 105.92 Å, β = 120.5°.
Topics: Chlorobium; Crystallization; Crystallography, X-Ray; Glycosyltransferases; Protein Conformation; Pteridines
PubMed: 29095157
DOI: 10.1107/S2053230X17015515 -
Biomarkers in Medicine Oct 2013
Topics: Biomarkers, Tumor; Humans; Neoplasms; Pteridines
PubMed: 24044558
DOI: 10.2217/bmm.13.88 -
Journal of Natural Products Jul 2019Natural products containing a lumazine motif were first isolated from natural sources in 1940. These natural products are relatively rare, with fewer than 100 lumazines... (Review)
Review
Natural products containing a lumazine motif were first isolated from natural sources in 1940. These natural products are relatively rare, with fewer than 100 lumazines known to occur in Nature. This review discusses the isolation of lumazines, their biological activity, and their biosynthesis, where known.
Topics: Biological Products; Molecular Structure; Pteridines
PubMed: 31317731
DOI: 10.1021/acs.jnatprod.9b00351 -
European Journal of Medicinal Chemistry May 2023In accordance with WHO statistics, leishmaniasis is one of the top neglected tropical diseases, affecting around 700 000 to one million people per year. To that end, a...
In accordance with WHO statistics, leishmaniasis is one of the top neglected tropical diseases, affecting around 700 000 to one million people per year. To that end, a new series of coumarin-1,2,3-triazole hybrid compounds was designed and synthesized. All new compounds exerted higher activity than miltefosine against L. major promastigotes and amastigotes. Seven compounds showed single digit micromolar IC values whereas three compounds (13c, 14b and 14c) displayed submicromolar potencies. A mechanistic study to elucidate the antifolate-dependent activity of these compounds revealed that folic and folinic acids abrogated their antileishmanial effects. These compounds exhibited high safety margins in normal VERO cells, expressed as high selectivity indices. Docking simulation studies on the folate pathway enzymes pteridine reductase and DHFR-TS imparted strong theoretical support to the observed biological activities. Besides, docking experiments on human DHFR revealed minimal binding interactions thereby highlighting the selectivity of these compounds. Predicted in silico physicochemical and pharmacokinetic parameters were adequate. In view of this, the structural characteristics of these compounds demonstrated their suitability as antileishmanial lead compounds.
Topics: Animals; Humans; Antiprotozoal Agents; Chlorocebus aethiops; Coumarins; Leishmania; Pteridines; Triazoles; Vero Cells
PubMed: 37031526
DOI: 10.1016/j.ejmech.2023.115333 -
Molecular and Biochemical Parasitology Apr 2001Protozoan parasites of the trypanosomatid genus Leishmania are pteridine auxotrophs, and have evolved an elaborate and versatile pteridine salvage network capable of...
Protozoan parasites of the trypanosomatid genus Leishmania are pteridine auxotrophs, and have evolved an elaborate and versatile pteridine salvage network capable of accumulating and reducing pteridines. This includes biopterin and folate transporters (BT1 and FT1), pteridine reductase (PTR1), and dihydrofolate reductase-thymidylate synthase (DHFR-TS). Notably, PTR1 is a novel alternative pteridine reductase whose activity is resistant to inhibition by standard antifolates. In cultured promastigote parasites, PTR1 can function as a metabolic by-pass under conditions of DHFR inhibition and thus reduce the efficacy of chemotherapy. To test whether pteridine salvage occurred in the infectious stage of the parasite, we examined several pathogenic species of Leishmania and the disease-causing amastigote stage that resides within human macrophages. To accomplish this we developed a new sensitive HPLC-based assay for PTR1 activity. These studies established the existence of the pteridine salvage pathway throughout the infectious cycle of Leishmania, including amastigotes. In general, activities were not well correlated with RNA transcript levels, suggesting the occurrence of at least two different modes of post-transcriptional regulation. Thus, pteridine salvage by amastigotes may account for the clinical inefficacy of antifolates against leishmaniasis, and ultimately provide insights into how this may be overcome in the future.
Topics: Animals; Biopterins; Carrier Proteins; Chromatography, High Pressure Liquid; Folic Acid; Folic Acid Antagonists; Gene Expression Regulation, Developmental; Humans; Leishmania; Leishmaniasis; Membrane Transport Proteins; Molecular Sequence Data; Multienzyme Complexes; Oxidoreductases; Protozoan Proteins; Pteridines; RNA, Messenger; Tetrahydrofolate Dehydrogenase; Thymidylate Synthase
PubMed: 11295174
DOI: 10.1016/s0166-6851(01)00213-4 -
Journal of the American Chemical Society Sep 1948
Topics: Pteridines
PubMed: 18882534
DOI: 10.1021/ja01189a058 -
Bioorganic & Medicinal Chemistry Letters Nov 2022Cyclin-dependent kinases play an important role in the regulation of cell cycle and transcription. Selective CDK4/6 inhibitors have been demonstrated to be effective in...
Cyclin-dependent kinases play an important role in the regulation of cell cycle and transcription. Selective CDK4/6 inhibitors have been demonstrated to be effective in the treatment of cancer. In this article, we described the design and synthesis of a series of pteridine-7(8H)-one derivatives as dual CDK4/6 inhibitors. Among them, the most promising compound L2 exhibited significant inhibitory activity against CDK4 and CDK6 with IC values of 16.7 nM and 30.5 nM respectively and showed excellent selectivity to CDK1/2/7/9. Moreover, compound L2 displayed potent antiproliferative activities at low digital micromolar range via inducing apoptosis in breast and colon cancer cells. In all, we developed a new series of pteridine-7(8H)-one derivatives which exhibited promising antitumor activities as selective CDK4/6 inhibitors.
Topics: Pteridines; Cyclin-Dependent Kinase 4; Cell Proliferation; Cell Cycle; Apoptosis; Protein Kinase Inhibitors; Antineoplastic Agents; Cell Line, Tumor; Structure-Activity Relationship
PubMed: 36130661
DOI: 10.1016/j.bmcl.2022.128991 -
Journal of Medicinal Chemistry Jul 2022The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present a systematic, multidisciplinary...
The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present a systematic, multidisciplinary approach to the development of selective antiparasitic compounds. Computational fragment-based design of novel pteridine derivatives along with iterations of crystallographic structure determination allowed for the derivation of a structure-activity relationship for multitarget inhibition. The approach yielded compounds showing apparent picomolar inhibition of pteridine reductase 1 (PTR1), nanomolar inhibition of PTR1, and selective submicromolar inhibition of parasite dihydrofolate reductase (DHFR) versus human DHFR. Moreover, by combining design for polypharmacology with a property-based on-parasite optimization, we found three compounds that exhibited micromolar EC values against while retaining their target inhibition. Our results provide a basis for the further development of pteridine-based compounds, and we expect our multitarget approach to be generally applicable to the design and optimization of anti-infective agents.
Topics: Leishmania major; Oxidoreductases; Pteridines; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase; Trypanosoma brucei brucei
PubMed: 35675511
DOI: 10.1021/acs.jmedchem.2c00232 -
Medicinal Chemistry (Shariqah (United... 2022Pteridine-based scaffolds have been widely prevalent in pharmaceuticals, such as kinase inhibitors targeting EGFR, FLT3 and PI3K/mTOR which are attractive targets for...
BACKGROUND
Pteridine-based scaffolds have been widely prevalent in pharmaceuticals, such as kinase inhibitors targeting EGFR, FLT3 and PI3K/mTOR which are attractive targets for the anticancer therapy.
OBJECTIVE
This work aimed at designing and synthesizing 6-2,2,2-trifluoroethoxy functionalized pteridine-based derivatives for investigation of their anti-cancer activities as EGFR inhibitor.
METHODS
Pteridine-based derivatives were synthesized in 6 steps involving amination, bromination, cyclization, alkoxylation, chlorination and coupling reactions. Cellular anti-proliferative activities and inhibition activities on EGFR signaling of these pteridine derivatives in vitro were determined by the MTT assay and western blot analysis, respectively. Molecular docking simulation studies were carried out by the crystallographic structure of the erlotinib/EGFR kinase domain [Protein Data Bank (PDB) code: 1M17].
RESULTS
The compound 7m, with IC50 values of 27.40 μM on A549 cell line, exhibited comparable anti-proliferative activity relative to the positive control. Besides, western blots showed its obvious down-regulation of p-EGFR and p-ERK expression at 0.8 μM. The molecular docking model displayed a hydrogen bond between Met-769 amide nitrogen and N-1 in pteridine motif of 7m which lied at the ATP binding site of EGFR kinase domain.
CONCLUSION
The inhibition of 7m on cellular growth was comparable to that of the positive control. The inhibitory activities of 7m on EGFR phosphorylation and ERK phosphorylation in A549 cell line were relatively superior to that of the positive control. Both results suggested that the antiproliferative activity of 7m against A549 cell line was caused by inhibition of EGFR signaling pathway, providing a new perspective for the modification of pteridine-based derivatives as EGFR inhibitor.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; ErbB Receptors; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors; Pteridines; Structure-Activity Relationship
PubMed: 34097593
DOI: 10.2174/1573406417666210604105923