29769-49-1Relevant academic research and scientific papers
Drugging the Folate Pathway in Mycobacterium tuberculosis: The Role of Multi-targeting Agents
Hajian, Behnoush,Scocchera, Eric,Shoen, Carolyn,Krucinska, Jolanta,Viswanathan, Kishore,G-Dayanandan, Narendran,Erlandsen, Heidi,Estrada, Alexavier,Miku?ová, Katarína,Korduláková, Jana,Cynamon, Michael,Wright, Dennis
, p. 781 - 6,791 (2019/06/18)
The folate biosynthetic pathway offers many druggable targets that have yet to be exploited in tuberculosis therapy. Herein, we have identified a series of small molecules that interrupt Mycobacterium tuberculosis (Mtb) folate metabolism by dual targeting of dihydrofolate reductase (DHFR), a key enzyme in the folate pathway, and its functional analog, Rv2671. We have also compared the antifolate activity of these compounds with that of para-aminosalicylic acid (PAS). We found that the bioactive metabolite of PAS, in addition to previously reported activity against DHFR, inhibits flavin-dependent thymidylate synthase in Mtb, suggesting a multi-targeted mechanism of action for this drug. Finally, we have shown that antifolate treatment in Mtb decreases the production of mycolic acids, most likely due to perturbation of the activated methyl cycle. We conclude that multi-targeting of the folate pathway in Mtb is associated with highly potent anti-mycobacterial activity. Hajian et al. have investigated the inhibitory activity of a series of small-molecule antifolates and para-aminosalicylic acid against Mycobacterium tuberculosis, the causative agent of tuberculosis, and show that these compounds exert their activity by acting on multiple targets within the folate biosynthetic pathway.
Synthesis and analysis of bacterial folate metabolism intermediates and antifolates
Dawadi, Surendra,Kordus, Shannon L.,Baughn, Anthony D.,Aldrich, Courtney C.
, p. 5220 - 5223 (2017/11/06)
The mechanism of action of para-aminosalicylic acid (PAS), a drug used to treat drug-resistant tuberculosis (TB), has been confirmed through the first synthesis and biochemical characterization of its active metabolite 7. The synthesis features the coupling of N2-acetyl-6-formylpterin obtained from the degradation of folic acid and appropriately functionalized arylamines to form Schiff bases. The sequential chemoselective reduction of the imine and pterin ring led to the formation of dihydrofolate analogue 7 and two other dihydropteroate species.
Pterin–sulfa conjugates as dihydropteroate synthase inhibitors and antibacterial agents
Zhao, Ying,Shadrick, William R.,Wallace, Miranda J.,Wu, Yinan,Griffith, Elizabeth C.,Qi, Jianjun,Yun, Mi-Kyung,White, Stephen W.,Lee, Richard E.
, p. 3950 - 3954 (2016/08/01)
The sulfonamide class of antibiotics has been in continuous use for over 70?years. They are thought to act by directly inhibiting dihydropteroate synthase (DHPS), and also acting as prodrugs that sequester pterin pools by forming dead end pterin–sulfonamide conjugates. In this study, eight pterin–sulfonamide conjugates were synthesized using a novel synthetic strategy and their biochemical and microbiological properties were investigated. The conjugates were shown to competitively inhibit DHPS, and inhibition was enhanced by the presence of pyrophosphate that is crucial to catalysis and is known to promote an ordering of the DHPS active site. The co-crystal structure of Yersinia pestis DHPS bound to one of the more potent conjugates revealed a mode of binding that is similar to that of the enzymatic product analog pteroic acid. The antimicrobial activities of the pterin–sulfonamide conjugates were measured against Escherichia coli in the presence and absence of folate precursors and dependent metabolites. These results show that the conjugates have appreciable antibacterial activity and act by an on target, anti-folate pathway mechanism rather than as simple dead end products.
Oxidative removal of heterocyclic alkyl or sugar side chain by microwave: A simple step to xanthopterin, 6-formylpterin, and 3-hydroxymethyl-2(1H)- quinoxalinone
Goswami, Shyamaprosad,Maity, Annada C.
, p. 1118 - 1119 (2008/02/10)
One-step microwave-assisted oxidative removal of 3-methyl and 3-sugar side chain in 2(lH)-quinoxalinone system by selenium dioxide and sodium periodate respectively resulting 2(1H)quinoxalinone has been reported. Similarly xanthopterin (as acetyl derivative 11) was isolated from selenium dioxide oxidation of 7-methylxanthopterin. In the absence of adjacent lactam moiety, sodium periodate efficiently oxidizes 2-acetylaminopterin tetrols 7 and 8 to 2-acetylamino-6-formylpterin (16) and the quinoxaline tetrols 9 and 10 respectively to quinoxaline aldehyde 17. However, all the compounds remained unchanged on refluxing with selenium dioxide. The new quinoxalone compounds 15 and 18 were simply synthesized by manganese dioxide oxidation of the completely unprotected 3-substituted sugar of 2(lH)-quinoxalinone 5 and quinoxaline 10 respectively under microwave condition. Copyright
Syntheses of labeled vitamers of folic acid to be used as internal standards in stable isotope dilution assays
Freisleben, Achim,Schieberle, Peter,Rychlik, Michael
, p. 4760 - 4768 (2007/10/03)
[2H4]Folic acid was synthesized by deuterating p-aminobenzoic acid, which was then coupled to glutamic acid and 6-formylpterin, Using [2H4]folic acid as starting component enabled the preparation of labeled vitamers tetrahydrofolate, 5-formyltetrahydrofolate, 5-methyltetrahydrofolate, and 10-formylfolate which were characterized by electrospray mass spectrometry and collision-induced dissociation. The mass spectrometric studies confirmed that the compounds could be used as internal standards in stable isotope dilution assays.
The synthesis of folic acid, multiply labelled with stable isotopes, for bio-availability studies in human nutrition
Maunder, Peter,Finglas, Paul M.,Mallet, Anthony I.,Mellon, Fred A.,Aaqib Razzaque,Ridge, Brian,Vahteristo, Liisa,Witthoeft, Cornelia
, p. 1311 - 1323 (2007/10/03)
Two different methods for the synthesis of folic acid, which are suitable for the incorporation of compounds multiply labelled with stable isotopes, are described. The first method is based on the use of a novel reductive amination to link 2-acetyIamino-4-hydroxy-6-formylpteridine withp-aminobenzoyl-L-glutamic acid. The second method is based on the penultimate formation of an amide bond between Ar-2-acetyl-Ar-10-trifluoroacetyIpteroic acid and dimethyl L-glutamate. Both methods have been used to transform [13C6]aniline into folic acid, labelled with [13C6] in the p-aminobenzoate moiety, and [3,3,4,4-2H4]-L-glutamic acid into folic acid, labelled with [2H4] in the glutamate moiety. Doubly labelled [13C6,2H 4]-p-aminobenzoyl-L-glutamate has also been prepared by the former method.
Preparation of [2',3',5',6'-2H4]pteroylglutamic acid
Dueker,Jones,Smith,Clifford
, p. 981 - 991 (2007/10/02)
Folic acid plays a key role in nucleic acid biosynthesis, essential for normal cell proliferation and function. Localized folate deficiencies may be related to changes in cytology associated with cancer development; analogs of folic acid, such as methotrexate, are potent chemotherapeutic agents and are widely used either alone or in combination therapy for many types of cancer. In this report we describe the synthesis of a tetra-deuterated folic acid from perdeuterated toluene. The primary intermediate, N-(4-amino [2,3,5,6-2H4]benzoyl)-L-glutamic acid diethyl ester was coupled to N(2')-acetyl-6-formylpterin to create [2',3',5',6'-2H4]folic acid. A similar scheme can be used for the preparation of F [1',2',3',4',5',6'-13C6]folic acid from [13C6] ring labeled toluene.
The Synthesis of 6-Aminomethyl-5,6,7,8-tetrahydropterin
Waring, Paul
, p. 667 - 676 (2007/10/02)
6-Aminomethyl-5,6,7,8-tetrahydropterin has been prepared by reduction of 2-acetamido-6-cyanopteridin-4(3H)-one to 2-acetamido-6-aminomethyl-5,6,7,8-tetrahydropteridin-4(3H)-one followed by acid hydrolysis.The hitherto undescribed 6-cyanopterin was prepared by careful hydrolysis of the 2-acetamido compound prepared by dehydration of the oxime derived from 2-acetamido-6-formylpteridin-4(3H)-one.The latter was prepared by selenium dioxide oxidation of the methyl compound.Oxidation of 6-aminomethyl-5,6,7,8-tetrahydropterin at neutral pH appears to proceed with significant side-chain loss in Tris buffer but not in phosphate buffer.
N2'-Acetyl-6-diacetoxymethylpterin
Boyle, Peter H.,O'Mahony, Mary J.
, p. 909 (2007/10/02)
Treatment of folic acid with bromine in 48 percent hydrobromic acid gives the hydrobromide salt of 6-formylpterin (1), and acetylation of 1 with recovered acetic anhydride leads to N2'-acetyl-6-diacetoxymethylpterin (3).
