Methotrexate analogs. 3. Synthesis and biological properties of some side-chain altered analogs

Chaykovsky, Michael; Rosowsky, A.; Papathanasopoulos, Nickolas; Chen, Katherine K. N.; Modest, Edward J.; Kisliuk, Roy L.; Gaumont, Y.

doi:10.1021/jm00257a015

Cited by 37 publications

(19 citation statements)

References 16 publications

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“…These were archival samples with a purity of Ն90% as determined by thin-layer chromatography. The compounds in entries 1 to 6 were made from 4-[N-(2,4-diaminopteridin-6-yl)methyl-N-methyl]aminobenzoic acid and amines by the mixed anhydride method using isobutyl chloroformate and triethylamine (6,7), whereas those in entries 7 to 15 were made by reaction of amines with diethyl N- [4-(2,4-diaminopteridin-6-yl)methyl-N-methyl]aminobenzoyl-L-glutamate (methotrexate diethyl ester) (30). 2,4-Diamino-6-methylpteridine (entry 16) and its 7-isomer (entry 17) were synthesized from 2,4,5,6-tetraaminopyrimidine and 1,3-dihydroxyacetone as described previously (43).…”

Section: Methodsmentioning

confidence: 99%

Efficacies of Lipophilic Inhibitors of Dihydrofolate Reductase against Parasitic Protozoa

Lau

Ferlan

Brophy

et al. 2001

Antimicrob Agents Chemother

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Competitive inhibitors of dihydrofolate reductase (DHFR) are used in chemotherapy or prophylaxis of many microbial pathogens, including the eukaryotic parasites Plasmodium falciparum and Toxoplasma gondii. Unfortunately, point mutations in the DHFR gene can confer resistance to inhibitors specific to these pathogens. We have developed a rapid system for testing inhibitors of DHFRs from a variety of parasites. We replaced the DHFR gene from the budding yeast Saccharomyces cerevisiae with the DHFR-coding region from humans, P. falciparum, T. gondii, Pneumocystis carinii, and bovine or human-derived Cryptosporidium parvum. We studied 84 dicyclic and tricyclic 2,4-diaminopyrimidine derivatives in this heterologous system and identified those most effective against the DHFR enzymes from each of the pathogens. Among these compounds, six tetrahydroquinazolines were effective inhibitors of every strain tested, but they also inhibited the human DHFR and were not selective for the parasites. However, two quinazolines and four tetrahydroquinazolines were both potent and selective inhibitors of the P. falciparum DHFR. These compounds show promise for development as antimalarial drugs.The treatment of diseases caused by eukaryotic pathogens is particularly difficult because of the similarity between their cell biology and that of their human host. The selection for pathogens resistant to currently effective drugs and the increase in immunocompromised individuals have added urgency to the search for new therapies directed specifically against these pathogens. One fruitful avenue for identification of chemotherapeutic drugs is to screen compounds that have already been synthesized in order to identify those that might be active against these increasingly important pathogens. We have adopted this strategy and screened a large library of compounds that are directed against the enzyme dihydrofolate reductase (DHFR) (EC 1.5.1.3). DHFR is a central enzyme in nucleic acid and amino acid synthesis in all cells, but the active sites of enzymes from different organisms show subtle differences that allow the identification of inhibitors specific for a particular species (3,(16)(17)(18)24). For example, pyrimethamine is a selective inhibitor that is effective in the nanomolar range against the DHFRs from Plasmodium falciparum and Toxoplasma gondii, but the human enzyme is relatively insensitive to the drug (8,14,24). Thus, pyrimethamine has been used in malaria and toxoplasmosis therapy for many years (9, 49).We have designed an easy and inexpensive system to test in budding yeast (Saccharomyces cerevisiae) potential DHFR inhibitors against the enzymes from a variety of parasites. Function of the endogenous dfr1 gene was eliminated from the yeast (15), and the defect was complemented by expression of a heterologous DHFR gene from P. falciparum, T. gondii, Pneumocystis carinii, Cryptosporidium parvum, or humans (4). DHFR inhibitors function principally as competitive inhibitors of the enzyme. We have shown that the sensitivity of our engi...

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Section: Methodsmentioning

confidence: 99%

Efficacies of Lipophilic Inhibitors of Dihydrofolate Reductase against Parasitic Protozoa

Lau

Ferlan

Brophy

et al. 2001

Antimicrob Agents Chemother

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“…All derivatives show inhibitory activity except oxide derivatives, rather these showed deleterious effect. This detrimental effect may be due to decrease in basicity of pteridine ring (Table 22) [39].…”

Section: Coormentioning

confidence: 99%

A comprehensive review of synthesized derivatives of methotrexate in relation to their anticancer potential.

Nemat¹,

Iqbal²,

Mehmood³

2020

medical-oncology

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Methotrexate (MTX) is a chemotherapeutic agent with certain side effects. Efforts were made to synthesize analogues of MTX to enhance the activity and reduce side effects. Various derivatives were synthesized by structural modification of parent drug and mainly assayed for anticancer activity and binding affinity with dihydrofolatereductase (DHFR) and folylpolyglutamate synthetase (FPGS). In vitro study was carried out on cell lines CCRF. CEM, ATCC8, L. Casei, P388, L1210, L1210/R81, and H35. These synthesized derivatives have been assayed for human squamous cell carcinoma namely SSC25, SSC68, SSC78, SSC25/R1, SSC68/R1, and SSC78/R1. Some modification proved to enhance anticancer activity while others are detrimental. Some of derivatives were also tested for other biological activity like anti-malarial, anti-bacterial and anti-diabetic and show better activity. This article deals with a comprehensive overview of the synthesized derivatives by structural modifications and the impact of these modifications on its activity.

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“…A linear NaCl gradient of 1 L each of 0-0.5 M NaCl in 0.005 M phosphate buffer, pH 7, was used to elute the column. (1) Preparation of 3-[p-(Carbomethoxy)-thiophenoxylpropionic Acid (20). A mixture of equimolar amounts of 3-bromopropionic acid and p-(carbomethoxy)thiophenol was placed in a round-bottom flask.…”

Section: P R E P a R A T I O N Of 1-[ N-(2-amino-4-hydroxy-5-nitropyrmentioning

confidence: 99%

Folate analogs altered in the C9-N10 bridge region: 11-thiohomofolic acid

Nair¹,

Chen²,

Kisliuk³

et al. 1979

J. Med. Chem.

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The synthesis of 11-thiohomofolic acid (2) has been accomplished by an unambiguous procedure. Reaction of 1-chloro-4-[p-(carbomethoxy)thiophenoxy]-2-butanone (10) with hydroxylamine under carefully controlled conditions gave the corresponding oxime 33. Conversion of this oxime to 1-phthalimido-4-[p-(carbomethoxy)thiophenoxy]-2-butanone oxime (4) was carried out by its reaction with potassium phthalimide using crown 18 ether as a catalyst. Hydrazinolysis of compound 4 gave 1-amino-4-[p-(carbomethoxy)thiophenoxy]-2-butanone oxime (5), which was used for the construction of the title compound 2 by modification of the Boon and Leigh procedure. An alternate synthesis utilizing 1-hydroxy-4-[p-(carbomethoxy)thiophenoxy]-2-butanone (11) and 4-hydroxy-2,5,6-triaminopyrimidine has also been carried out. Compound 2 did not exhibit any antifolate activity against Lactobacillus casei or Streptococcus faecium. The dithionite reduction product, 7,8-dihydro-11-thiohomofolic acid, was able to function as a substrate of L. casei dihydrofolate reductase. The catalytic reduction product of 2, consisting of a mixture of diastereomers, exhibited powerful antifolate activity against both these organisms.

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Methotrexate analogs. 3. Synthesis and biological properties of some side-chain altered analogs

Cited by 37 publications

References 16 publications

Efficacies of Lipophilic Inhibitors of Dihydrofolate Reductase against Parasitic Protozoa

Efficacies of Lipophilic Inhibitors of Dihydrofolate Reductase against Parasitic Protozoa

A comprehensive review of synthesized derivatives of methotrexate in relation to their anticancer potential.

Folate analogs altered in the C9-N10 bridge region: 11-thiohomofolic acid

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