Dihydrofolate reductase inhibition effect of 5-substituted pyrido[2,3-d]pyrimidines: Synthesis, antitumor activity and molecular modeling study

Abdelaziz, Ola A.; Husseiny, Walaa M. El; Selim, Khalid B.; Eisa, Hassan M.

doi:10.1016/j.bioorg.2019.103076

Cited by 32 publications

(8 citation statements)

References 42 publications

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“…29) showed the highest antitumor effects and were tested for enzymatic inhibition of the dihydrofolate reductase [compared to the reference medication methotrexate (MTX)] to explain the likely mechanism of action of the observed anticancer activity. 94 Molecule 115 had the highest inhibitory activity at IC 50 of 6.5 mM among all the tested molecules (IC 50 of MTX = 5.57 mM, Table 4).…”

Section: Targeted Inhibition Of Dihydrofolate Reductasementioning

confidence: 99%

Medicinal chemistry perspective of pyrido[2,3-d]pyrimidines as anticancer agents

et al. 2023

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Section: Targeted Inhibition Of Dihydrofolate Reductasementioning

confidence: 99%

Medicinal chemistry perspective of pyrido[2,3-d]pyrimidines as anticancer agents

et al. 2023

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“… 29 The crystal structure of the DHFR interacting with its inhibitor MTX was obtained from the RSC Protein Data Bank (PDB code 1U72 ). 30 , 31 Construction of the three DHFR inhibitors ( 20 , 22 , and 23 ) was performed using the library of fragments in the MOE program. The “Amber force field” was used to minimize the energy of the inhibitors.…”

Section: Methodsmentioning

confidence: 99%

Synthesis, Antitumor Activity, and In Silico Drug Design of New Thieno[2,3-d]Pyrimidine-4-One Derivatives as Nonclassical Lipophilic Dihydrofolate Reductase Inhibitors

et al. 2022

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Synthesis of a new series of 20 compounds bearing the thieno [2,3-d]pyrimidine-4-one scaffold was achieved. The inhibitory activity of these compounds was performed over 60 cell lines of human tumor at single and five dose concentrations. Compounds 20, 22, and 23 exhibited potent growth inhibitions toward the majority of the tested NCI 60 cell lines. Compounds 20 and 23 were the most active compounds with (MG-MID) TGI, GI 50 , and LC 50 values of 16.2, 3.3, 50.1 and 67.7, 6.6, 100, respectively. Also, both compounds showed 7-and 4-fold better activity, respectively, than the standard antitumor agent 5-fluorouracil. Therefore, compounds 20 and 23 were selected to measure their ability to inhibit the dihydrofolate reductase enzyme (DHFR) in comparison to methotrexate (MTX) as a reference drug. Compound 20 was a more potent inhibitor of DHFR (IC 50 = 0.20 μM) than MTX (IC 50 = 0.22 μM). Molecular modeling studies were performed in the DHFR active site, and it showed compatibility with the results obtained from biological studies. Finally, the results showed that compound 20 is a strong antitumor agent and potent inhibitor of DHFR. In addition, this compound induced cell-cycle arrest in SNB-75 cells in the G2/M phase and the apoptosis process in the Pre-G phase. Compound 20 also increased the level of both caspases-3 and 9 by 11.8-and 50.3-fold, respectively.

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“…The structure-activity relationship revealed that electron-withdrawing groups such as nitro and fluorine lowered anticancer ChemistrySelect activity whereas electron-donating compounds such as methoxy groups increased it. [32] Geo and coworker synthesized 6-substituted pyrrolo[2,3-d] pyrimidine conjugates (Scheme 14) and evaluated for their anticancer and in vitro DHFR inhibition activity using MTT assay and DHFR inhibition assay respectively. Methotrexate and pemetrexed were taken as standard drugs for anticancer activity and Methotrexate for DHFR inhibition activity.…”

Section: Biological Activity Of Dihydrofolate Reductase (Dhfr) Enzymementioning

confidence: 99%

An Insight into Synthetic Strategies and Recent Developments of Dihydrofolate Reductase Inhibitors

et al. 2021

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The dihydrofolate reductase (DHFR) is a significant target in cancer, microbial infection, fungal infection, malaria, leishmaniasis, and tuberculosis, among other diseases. The DHFR gene was discovered in prokaryotes and eukaryotes in the late 1950s and is found in all dividing cells. DHFR inhibitors are used for a variety of medicinal purposes. Increased resistance to therapeutic agents such as anticancer, antibiotic, anti‐tuberculosis, and antifungal sparked interest in the development of potent, broad‐spectrum medicines to address the issues. DHFR is a critical target in the development of innovative solutions to address the issues. Methotrexate, trimethoprim, sulfonamides, pyrimethamine, aminopterin, methotrexate, edatrexate, and pralatrexate are only a few of the medications that target DHFR. These medications are known as DHFR inhibitors. These inhibitors block the enzyme dihydrofolate reductase, resulting in a folic acid synthesis pathway that is compromised. The DHFR is involved in the conversion of dihydrofolate to tetrahydrofolate. Purine, pyrazole, pyrimidine, triazole, oxadiazole, and other heterocyclic motifs have shown to have a potential effect on the DHFR. In the medicinal chemistry community, a better understanding of the so‐called enzyme and biochemical underpinnings responsible for enzyme selectivity has led to the development of improved, unique, and new treatments. Several researchers are working on DHFR inhibitors intensely, using a variety of synthetic techniques, molecular modelling, mechanistic studies, in‐vitro and in‐vivo biological evaluations, and structure‐activity relationships (SAR). This review, compiles the findings of several research groups during the last five years. The molecular biology of DHFR, its biosynthetic pathway, and the powerful structure of DFHR inhibitors discovered during the search are all included in this review. The study also includes the latest developments in synthetic methods, molecular docking, and structure‐activity relationships.

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Dihydrofolate reductase inhibition effect of 5-substituted pyrido[2,3-d]pyrimidines: Synthesis, antitumor activity and molecular modeling study

Cited by 32 publications

References 42 publications

Medicinal chemistry perspective of pyrido[2,3-d]pyrimidines as anticancer agents

Medicinal chemistry perspective of pyrido[2,3-d]pyrimidines as anticancer agents

Synthesis, Antitumor Activity, and In Silico Drug Design of New Thieno[2,3-d]Pyrimidine-4-One Derivatives as Nonclassical Lipophilic Dihydrofolate Reductase Inhibitors

An Insight into Synthetic Strategies and Recent Developments of Dihydrofolate Reductase Inhibitors

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