A convenient synthesis of aminopterin and homologs <i>via</i> 6‐(bromomethyl)‐2,4‐diaminopteridine hydrobromide

Piper, James R.

doi:10.1002/jhet.5570110237

Cited by 33 publications

(7 citation statements)

References 11 publications

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“…In nal step, the nitrogen atom of N-(4-methylaminbenzoyl)glutamic acid 494 was alkylated with the already prepared, bromide 501 to afford the desired target methotrexate 502 (Scheme 70). [516][517][518][519][520][521][522][523] A notorious morphine 522 as a legal medication is actually a strong pain killer. 524 Morphine was initially isolated from the unripe seed pods of opium poppy, Papaver somniferum.…”

Section: Five-membered Heterocyclesmentioning

confidence: 99%

Prescribed drugs containing nitrogen heterocycles: an overview

2020

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Section: Five-membered Heterocyclesmentioning

confidence: 99%

Prescribed drugs containing nitrogen heterocycles: an overview

2020

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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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“…This was followed by condensation with 2,4-diamino-6-bromomethylpteridine (16) 5 and saponification of the resulting ester 17 with Ba(OH) 2 . Although it proved expedient to run through the sequence from 13 to 17 with only partial purification of the intermediates 14 and 15, the end product 9 was obtained in very pure state by a two-stage process consisting of preparative HPLC on C 18 silica gel followed by ion-exchange chromatography on DEAE-cellulose.…”

Section: Chemistrymentioning

confidence: 99%

“…Compound 15 (200 mg, 0.58 mmol, as the crude product of reduction of 14 with SnCl2) 4 and 16‚HBr (212 mg, 0.58 mmol, assumed to be solvated with i-PrOH as reported in the literature) 5 were dissolved in DMAC (5 mL), and the solution was heated at 50°C for 7 days. The reaction mixture, containing diester 17, was diluted with 95% EtOH (30 mL) and H 2O (20 mL), and solid Ba(OH)2‚8H2O (1.26 g, 4.0 mmol) was added.…”

Section: -S-[5-[(24-diaminopteridin-6-yl)methylamino]-23-dihydro-1mentioning

confidence: 99%

Synthesis and in Vitro Antifolate Activity of Rotationally Restricted Aminopterin and Methotrexate Analogues

2004

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Heretofore unknown analogues of aminopterin (AMT) and methotrexate (MTX) in which free rotation of the amide bond between the phenyl ring and amino acid side chain is prevented by a CH(2) bridge were synthesized and tested for in vitro antifolate activity. The K(i) of the AMT analogue (9) against human dihydrofolate reductase (DHFR) was 34 pM, whereas that of the MTX analogue (10) was 2100 pM. Both compounds were less potent than the parent drugs. However, although the difference between AMT and MTX was <2-fold, the difference between 9 and 10 was 62-fold, suggesting that the effect of N(10)-methyl substitution is amplified in the bridged compounds. The K(i) values of 9 and 10 as inhibitors of [(3)H]MTX influx into CCRF-CEM human leukemia cells via the reduced folate carrier (RFC) were 0.28 and 1.1 muM, respectively. The corresponding K(i) and K(t) values determined earlier for AMT and MTX were 5.4 and 4.7 muM, respectively. Thus, in contrast to its unfavorable effect on DHFR binding, the CH(2) bridge increased RFC binding. In a 72 h growth assay with CCRF-CEM cells, the IC(50) values of 9 and 10 were 5.1 and 140 nM, respectively, a 27-fold difference that was qualitatively consistent with the observed combination of weaker DHFR binding and stronger RFC binding. Although rotationally restricted inhibitors of other enzymes of folate pathway enzymes have been described previously, 9 and 10 are the first reported examples of DHFR inhibitors of this type.

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A convenient synthesis of aminopterin and homologs via 6‐(bromomethyl)‐2,4‐diaminopteridine hydrobromide

Cited by 33 publications

References 11 publications

Prescribed drugs containing nitrogen heterocycles: an overview

Prescribed drugs containing nitrogen heterocycles: an overview

Discovery of potent pteridine reductase inhibitors to guide antiparasite drug development

Synthesis and in Vitro Antifolate Activity of Rotationally Restricted Aminopterin and Methotrexate Analogues

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