Preparation of 6-(bromomethyl)-2,4-pteridinediamine hydrobromide and its use in improved syntheses of methotrexate and related compounds

Piper, James R.; Montgomery, John A.

doi:10.1021/jo00422a005

Cited by 86 publications

(72 citation statements)

References 6 publications

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“…To a solution of methyl 1-(4-aminobenzoyl)piperidine-4-carboxylate (compound 4a, SI Appendix, SI Text) (100 mg, 0.36 mmol) in 3 ml of DMA was added an equimolar amount of 6-bromomethyl-2,4-diaminopteridine hydrobromide (compound 7, SI Text), synthesized as referenced (23)(24)(25). The solution was stirred and kept at room temperature for 90 h. The solvent was removed by evaporation in vacuo (Ͻ1 mm Hg, bath to 45°C).…”

Section: -24)mentioning

confidence: 99%

Discovery of potent pteridine reductase inhibitors to guide antiparasite drug development

Cavazzuti

Paglietti

Hunter³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

143

152

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Pteridine reductase (PTR1) is essential for salvage of pterins by parasitic trypanosomatids and is a target for the development of improved therapies. To identify inhibitors of Leishmania major and Trypanosoma cruzi PTR1, we combined a rapid-screening strategy using a folate-based library with structure-based design. Assays were carried out against folate-dependent enzymes including PTR1, dihydrofolate reductase (DHFR), and thymidylate synthase. Affinity profiling determined selectivity and specificity of a series of quinoxaline and 2,4-diaminopteridine derivatives, and nine compounds showed greater activity against parasite enzymes compared with human enzymes. Compound 6a displayed a Ki of 100 nM toward LmPTR1, and the crystal structure of the LmPTR1:NADPH:6a ternary complex revealed a substrate-like binding mode distinct from that previously observed for similar compounds. A second round of design, synthesis, and assay produced a compound (6b) with a significantly improved Ki (37 nM) against LmPTR1, and the structure of this complex was also determined. Biological evaluation of selected inhibitors was performed against the extracellular forms of T. cruzi and L. major, both wild-type and overexpressing PTR1 lines, as a model for PTR1-driven antifolate drug resistance and the intracellular form of T. cruzi. An additive profile was observed when PTR1 inhibitors were used in combination with known DHFR inhibitors, and a reduction in toxicity of treatment was observed with respect to administration of a DHFR inhibitor alone. The successful combination of antifolates targeting two enzymes indicates high potential for such an approach in the development of previously undescribed antiparasitic drugs.antitrypanosomatid agents ͉ antifolates ͉ drug discovery P rotozoan parasites of the order Kinetoplastida are the causal agents of serious human diseases, including African sleeping sickness, Chagas' disease, and leishmaniasis. There is an urgent need for new, more effective drugs targeting these neglected diseases, because those in current use are toxic, expensive, and often difficult to administer. The problem is compounded by an increase in drug resistance and lack of progress in drug development. Only a single new effective treatment has been developed in the last 25 years, Miltefosine (hexadecylphosphocholine), recently approved in India (1).Enzymes involved in the provision and use of reduced folate cofactors such as dihydrofolate reductase (DHFR) and thymidylate synthase (TS) are valued drug targets for the treatment of bacterial infections (2), cancer (3), and certain parasitic diseases, notably malaria (4). DHFR catalyzes the two-step reduction of folate to tetrahydrofolate, which is then transformed to N 5 ,N 10 -methylene tetrahydrofolate and is used by TS as a methyl donor and reducing agent in the conversion of 2Ј-deoxyuridine-5Ј-monophosphate to 2Ј-deoxythymidine-5Ј-monophosphate. Inhibition of DHFR or TS reduces the cellular pool of 2Ј-deoxythymidine-5Ј-monophosphate, impairing DNA replication and resulting ...

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Section: -24)mentioning

confidence: 99%

Discovery of potent pteridine reductase inhibitors to guide antiparasite drug development

Cavazzuti

Paglietti

Hunter³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

143

152

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“…Our synthetic approach to 6-substituted 2,4-diaminopteridines and pterins stc ll1:ed from 2,4-diamino-6-hydrm,ymethylpteridine , 1 \\'hich can be obtained in a regioselective reaction from 2.-t5,6-tetraaminopyrimidine and 1,3-clihydroxy-acerone 129,30) and can be converted by bromotriphenylphosphonium bromide into the valuable synthon 2,4-dicU11ino-6-bromomethylpteridine (2 ) (27 ). This compound ( 2 ) has recently also been synthesized in a more simple one step reaction from 2,4,S,6-tetraaminopyrimidine dihydrobromide and bromomethyl-glyoxalmonoxime (31) under reflux in methanol.…”

Section: Synthesismentioning

confidence: 99%

“…(2) (27) a). A solution of triphenylphosphane (81.8 g, 0.31 mol) in dimethylacetamide (DMA) (350 ml) was cooled to O-S"C and then under stirring bromine (16 ml, 0.31 mol ) added dropwise to form a colorless precipitate.…”

Section: Synthesismentioning

confidence: 99%

“…> 350"C. (27) According to the general procedure from 2,4-diamino-6-ethm.. -ymethylpteridine (4) b) A suspension of 50 (1.31 g, 3.9 mmole) in EtOH (250 ml) and 1 N HCI (25 ml) was heated to 70°C for 2.5 hours with stirring. After cooling in the icebox overnight the precipitate was collected, washed with EtOH and dried at 10G'C to give 1.0 g (89%) of a yellowish powder of m.p.…”

Section: -Methoxymet/n1pterin (26)mentioning

confidence: 99%

“…Condensation of aminomalononitrile and chloromethylglyoxalmonoxime lead in a regioselective reaction to 2-amino-S-chioromethyl-3-cyanopyrazine i-oxide, which can either clirectly or after deoxygenation been converted into the corresponcling alkoxymethyl derivatives and subsequent reaction with guanidine to give the 6-alkoxymethyl-2,4-cliaminopteridines and 8-oxides, respectively. Also 2,4-diamino-6-bromomethyl-pteridine (27) was used as a versatile intermecliate to react with N-, 0-and 5-nucleophiles in the side chain (28). Alkaline hydrolysis is a known method to transform 2,4-diami- nopterines into pterins in high yields .…”

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Pteridines CX

Traub

Pfleiderer

1999

Pteridines

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SummaryA series of new 6-substituted 2,4-diaminopteridines (3-23) and pterins (26-43) have been synthesized by nucleophilic displacement reactions at the side chain of 6-bromomethyl-2,4-diaminopteridine (2) and 6-bromomethylpterin (25) using various types of 0-, N-and S-nucleophiles. Acid and base hydrolyses allow easy conversion of the 2,4-diaminopteridines (3-5, 7, 9, 10, 12, 19-21 and 23) into the corresponding pterins (26-32, 39-42). Acylations take place at the amino as well as at the functional groups in the side chain (44-46). A versatile protection of the amino group in pterins is its transformation into the N ,N -dimethylaminomethylcnimino function by amide-acetals (47, 50) allowing subsequently selective acylations at the side chain (48, 49).

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Synthesis of tritiated N-[4-(2,4-diaminopteridine-6-methyl)-3,4-dihydro-2H-1,4-benzothiazine-7-carbonyl]-L-homo glutamic acid (MX-68)

Matsuoka¹,

Kuroki²,

Yano³

et al. 1997

J Label Compd Radiopharm

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Preparation of 6-(bromomethyl)-2,4-pteridinediamine hydrobromide and its use in improved syntheses of methotrexate and related compounds

Cited by 86 publications

References 6 publications

Discovery of potent pteridine reductase inhibitors to guide antiparasite drug development

Discovery of potent pteridine reductase inhibitors to guide antiparasite drug development

Pteridines CX

Synthesis of tritiated N-[4-(2,4-diaminopteridine-6-methyl)-3,4-dihydro-2H-1,4-benzothiazine-7-carbonyl]-L-homo glutamic acid (MX-68)

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