Synthesis of classical, three-carbon-bridged 5-substituted furo[2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates.

doi:10.1021/jm040123k

Paper

Synthesis of classical, three-carbon-bridged 5-substituted furo[2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates.

Published 2004 · A. Gangjee, Yibin Zeng, J. McGuire

Journal of medicinal chemistry

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20

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Abstract

Bridge homologation of the previously reported classical two-carbon-bridged antifolates, a 5-substituted 2,4-diaminofuro[2,3-d]pyrimidine (1) [which is a 6-regioisomer of LY231514 (Alimta)] and a 6-subsituted 2-amino-4-oxopyrrolo[2,3-d]pyrimidine, afforded the three-carbon-bridged antifolates analogues 4 and 5, with enhanced inhibitory activity against tumor cells in culture (EC(50) values in the 10(-8)-10(-7) M range or less). These two analogues were synthesized via a 10-step synthetic sequence starting from methyl 4-bromobenzoate (14), which was elaborated to the alpha-chloromethyl ketone (8) followed by condensation with 2,6-diamino-pyrimidin-4-one (7) to afford the substituted furo[2,3-d]pyrimidine 9 and the pyrrolo[2,3-d]pyrimidine 10. Subsequent coupling of each regioisomer with diethyl-l-glutamate followed by saponification afforded 4 and 5. The biological results indicate that elongation of the C8-C9 bridge of the classical 5-substituted 2,4-diaminofuro[2,3-d]pyrimidine and 6-substituted 2-amino-4-oxopyrrolo[2,3-d]pyrimidine are highly conducive to antitumor activity in vitro, despite a lack of increase in inhibitory activity against the target enzymes. This supports our original hypothesis that truncation of the B-ring of a highly potent 6-6 ring system to a 6-5 ring system can be compensated by bridge homologation to restore the overall length of the molecule.

In Vitro Study

Study Snapshot

Three-carbon-bridged antifolates, such as 4-amino-4-oxopyrrolo[2,3-d]pyrimidine, show enhanced inhibitory activity against tumor cells in culture, supporting their potential as antitumor agents.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Synthesis of classical, three-carbon-bridged 5-substituted furo[2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates.

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References

Citations

Design, Synthesis, in Vitro, and in Silico Evaluations of 1,3,4‐Oxadiazole Derivatives Linked to the Pyrrolo[2,3‐d]pyrimidine Moieties as Potent Antimicrobial Targets

1,3,4-oxadiazole derivatives linked to pyrrolo[2,3-d]pyrimidine moieties show excellent antimicrobial inhibitory activity, with compounds 6 f and 7 a showing potent antifungal activity against C. albicans.

Review on synthetic approaches towards barbituric acids‐based furo[2,3‐d]pyrimidines

Barbituric acids-based furo[2,3d]pyrimidines can be synthesized using various methods, including multicomponent reactions and Cloke-Wilson rearrangements, for pharmaceutical discovery research.

Biology and therapeutic applications of the proton-coupled folate transporter

PCFT-targeted therapeutics show promise for treating hereditary folate malabsorption and various cancers, with promising future and potential challenges.

Microwave assisted synthesis of 2,3-dihydro-4H-benzo[4,5]thiazolo[3,2-a]furo[2,3-d] pyrimidin-4-ones by radical addition of 2-hydroxy-4H-benzo[4,5]thiazolo[3,2-a] pyrimidin-4-ones to various conjugated alkenes and dienes mediated Mn(OAc)3

Microwave irradiation effectively synthesizes novel 2,3-dihydro-4H-benzo[4,5]thiazolo[3,2-a]furo[2,3-d] pyrimidin-4-ones in good to excellent yields.

One-pot synthesis of highly substituted poly(furopyrimidine)s via catalyst-free multicomponent polymerizations of diisocyanides, N,N′-dimethylbarbituric acid, and dialdehyde

Catalyst-free multicomponent polymerization of diisocyanides, N,N′-dimethylbarbituric acid, and dialdehyde allows for the synthesis of highly substituted poly(furopyrimidine)s with excellent yields and a decomposition temperature of

An efficient diastereoselective synthesis of novel fused 5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-ones via one-pot three-component reaction

This one-pot three-component reaction efficiently synthesizes novel fused 5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-ones with good-to-excellent yields, making it a convenient and safe method for synthesising complex organic compounds.

Novel pyrrolo[2,3-d]pyrimidine derivatives: Design, synthesis, structure elucidation and in vitro anti-BVDV activity

Novel pyrrolo[2,3-d]pyrimidine derivatives show excellent anti-BVDV activity, with compounds 11, 13, 16, and 17 showing high activity compared to those with Cl or CH3 on C2.

Synthesis of some novel phenylfuro[3,2-d]pyrimidine glycosides derivatives with expected antimicrobial activity

Novel phenylfuro[3,2-d]pyrimidine glycosides derivatives with expected antimicrobial activity have been synthesized and reported.