Design, synthesis and biological evaluation of novel pyrrolo[2,3-d]pyrimidine as tumor-targeting agents with selectivity for tumor uptake by high affinity folate receptors over the reduced folate carrier

Golani, Lalit K.; Islam, Farhana; O’Connor, Carrie; Dekhne, Aamod; Hou, Zhanjun; Matherly, Larry H.; Gangjee, Aleem

doi:10.1016/j.bmc.2020.115544

Cited by 12 publications

(6 citation statements)

References 47 publications

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“…Boc protection of 23 in THF at r.t. yielded tert-butyl(5-hydroxyaphthalen-2-yl)carbamate ( 24 ) in 84% yield, followed by methylation with methyl iodide and sodium hydride to provide 25 . Finally, Boc deprotection [ 49 ] using trifluoracetic acid (TFA) afforded 5-methoxy- N -methylnaphthalen-2-amine ( 26 ) in 91% yield.…”

Section: Resultsmentioning

confidence: 99%

“…The crystal structure PDBs were obtained from the protein database. All docking procedures were performed using various modules of the Schrödinger Maestro suite (Schrödinger, LLC, New York, NY, USA, 2020–2) [ 49 ]. The protein was optimized and prepared for docking using the Maestro Protein Preparation Wizard to assess bond order and add missing hydrogens, followed by energy minimization using the OPLS3e force field.…”

Section: Methodsmentioning

confidence: 99%

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Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents

et al. 2022

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A series of eleven 4-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines were designed and synthesized and their biological activities were evaluated. Synthesis involved the Gewald reaction to synthesize ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate ring, and SNAr reactions. Compound 4 was 1.6- and ~7-fold more potent than the lead compound 1 in cell proliferation and microtubule depolymerization assays, respectively. Compounds 4, 5 and 7 showed the most potent antiproliferative effects (IC50 values < 40 nM), while compounds 6, 8, 10, 12 and 13 had lower antiproliferative potencies (IC50 values of 53–125 nM). Additionally, compounds 4–8, 10 and 12–13 circumvented Pgp and βIII-tubulin mediated drug resistance, mechanisms that diminish the clinical efficacy of paclitaxel (PTX). In the NCI-60 cell line panel, compound 4 exhibited an average GI50 of ~10 nM in the 40 most sensitive cell lines. Compound 4 demonstrated statistically significant antitumor effects in a murine MDA-MB-435 xenograft model.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents

et al. 2022

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“…According to reports, the cellular uptake of 6-substituted pyrrolo [2,3-d] pyrimidines, depend on multiple (folate) transporters like folate receptor alpha (FRα), FRβ, reduced folate carrier (RFC), and proton coupled folate transporter (PCFT). And they found that the role of folylpolyglutamate synthetase (FPGS) in the retention of 6-substituted pyrrolo [2,3-d] pyrimidines intracellularly ( Dekhne et al, 2020 ; Golani et al, 2020 ; Wallace-Povirk et al, 2021 ; Wallace-Povirk et al, 2022 ). Thus, this hypersensitivity maybe explained by the fact that KB cells express high amount of FRα, which may serve as cellular internalization route for glytrexate.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, bioavailability, and plasma protein binding study of glytrexate, a novel multitarget antifolate

Xiang

Wu²,

Wang³

et al. 2022

Front. Pharmacol.

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Glytrexate, developed by our team, as a novel multitarget folate antagonist, has inhibitory effects on a variety of cancer cell types, especially KB tumor cells (IC50 0.078 nM), and thus has antitumor drug development prospects. However, its pharmacokinetics and plasma protein binding properties remain unknown. In this study a selective and sensitive liquid chromatography-tandem mass spectrometry (LC‒MS/MS) method was developed and verified to facilitate biological analysis. The bioanalysis method was applied to evaluate the stability, plasma protein binding, and pharmacokinetics of glytrexate. Glytrexate is more stable in human plasma than in rat plasma and in human liver microsomes. The binding of glytrexate to human plasma proteins was higher than that to rat plasma proteins, both of which were less than 30%, suggesting that glytrexate may be at a higher concentration at the pharmacologic target receptor(s) in tissues. Pharmacokinetic characteristics were determined by noncompartmental analysis after administration of single oral (12.5, 25 and 50 mg/kg) and intravenous (2 mg/kg) doses in rats. According to the rat oral pharmacokinetic characteristics, glytrexate had linear dynamics in a dose range of 12.5–50 mg/kg and a poor oral bioavailability of 0.57–1.15%. The investigation revealed that the intravenous half-life, AUC, and Cmax of glytrexate were higher than those of pemetrexed. Pemetrexed is generally produced as an injection preparation. This provides ideas for the development of glytrexate formulations. Therefore, glytrexate injection has clinical application prospects compared to oral administration. This study provides a basis for further investigations into the pharmacological effects and clinical uses of glytrexate.

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“…One year later, L.K. Golani et al designed and synthesized 47 antitumor agents 40 and 41 via the reaction of aminopyrimidines with α-bromo methyl ketones and refluxing the product with L-glutamate diethyl ester (Scheme 14). The antitumor agents 40 and 41 recorded anticancer activity by inhibition of DHFR using reference standards methotrexate (MTX) and pemetrexed (PMX).…”

Section: Synthesis and Reaction Of Pyrimidines Synthesis And Reaction...mentioning

confidence: 99%

Pyrimidines as Anticancer and Antiviral: Synthesis & Reactions (A Review)

Fatahala

Mohamed²,

Khodair³

et al. 2022

Journal of Advanced Pharmacy Research

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Background:The interest of many medicinal and organic chemists has been attracted to the synthesis of pyrimidines and their analogues due to their highly biological and medicinal properties. Objectives& Methodology: Based on these activities, this review discusses the various recent methods for the synthesis of these heterocyclic compounds during the period of 2017 to 2021 with certain two main medicinal actions. Conclusion: Pyrimidine moiety bearing compounds, are synthesized, and reacted either through one-pot synthesis or multi-step synthesis pathways, in catalytic and solvent free condition or using catalysts and solvent.

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Design, synthesis and biological evaluation of novel pyrrolo[2,3-d]pyrimidine as tumor-targeting agents with selectivity for tumor uptake by high affinity folate receptors over the reduced folate carrier

Cited by 12 publications

References 47 publications

Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents

Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents

Pharmacokinetics, bioavailability, and plasma protein binding study of glytrexate, a novel multitarget antifolate

Pyrimidines as Anticancer and Antiviral: Synthesis & Reactions (A Review)

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