Physiology of Pyrimidines

Cerecedo, Leopold R.

doi:10.1038/146274a0

Cited by 6 publications

(6 citation statements)

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“…This takes us back almost a century, when nucleosides were first identified as physiologically important molecules. For instance, as early as 1927, the metabolism of pyrimidine nucleosides was studied (15,28), whereas the physiological effects of purinergic compounds, including adenosine, on the heart were reported in a landmark paper in 1929 (26). Thus the early history of the study of nucleosides reflects their physiological roles as nutrients and metabolites within cells, tissues, and whole animals.…”

Section: Nucleosides: Metabolites and Drugsmentioning

confidence: 99%

Physiology of Nucleoside Transporters: Back to the Future. . . .

Rose

Coe

2008

Physiology

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Nucleoside transporters (NTs) are integral membrane proteins responsible for mediating and facilitating the flux of nucleosides and nucleobases across cellular membranes. NTs are also responsible for the uptake of nucleoside analog drugs used in the treatment of cancer and viral infections, and they are the target of certain compounds used in the treatment of some types of cardiovascular disease. The important role of NTs as drug transporters and therapeutic targets has necessarily led to intense interest into their structure and function and the relationship between these proteins and drug efficacy. In contrast, we still know relatively little about the fundamental physiology of NTs. In this review, we discuss various aspects of the physiology of NTs in mammalian systems, particularly noting tissues and cells where there has been little recent research. Our central thesis is reference back to some of the older literature, combined with current findings, will provide direction for future research into NT physiology that will lead to a fuller understanding of the role of these intriguing proteins in the everyday lives of cells, tissues, organs, and whole animals.

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Section: Nucleosides: Metabolites and Drugsmentioning

confidence: 99%

Physiology of Nucleoside Transporters: Back to the Future. . . .

Rose

Coe

2008

Physiology

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“…Thus, there are many synthetic pyrimidine derivatives with exhibited several pharmacological actions such as antimicrobial [ 16 , 17 ], anticancer [ 18 , 19 , 20 ], antioxidant [ 18 ], antifungal [ 21 ], antithyroid [ 22 ], antiviral [ 23 , 24 , 25 ], anticonvulsant [ 26 ], anti-inflammatory [ 27 ], antitubercular [ 28 ], antileishmanial [ 29 ], antimalarial [ 30 ], anthelminthic [ 31 ], anti-HIV [ 32 ], antitubercular [ 33 ], and antidepressant activities [ 34 ]. In addition, pyrimidine ring prevails in naturally formed structures such alkaloids [ 35 ], nucleic bases [ 36 ], vitamins [ 37 ], and numerous other pharmacophores. Pyrimidine ring is considered the core scaffold of the genetic material and hence it is crucial for anticancer activity [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity

et al. 2021

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Scaffolds hybridization is a well-known drug design strategy for antitumor agents. Herein, series of novel indolyl-pyrimidine hybrids were synthesized and evaluated in vitro and in vivo for their antitumor activity. The in vitro antiproliferative activity of all compounds was obtained against MCF-7, HepG2, and HCT-116 cancer cell lines, as well as against WI38 normal cells using the resazurin assay. Compounds 1–4 showed broad spectrum cytotoxic activity against all these cancer cell lines compared to normal cells. Compound 4g showed potent antiproliferative activity against these cell lines (IC50 = 5.1, 5.02, and 6.6 μM, respectively) comparable to the standard treatment (5-FU and erlotinib). In addition, the most promising group of compounds was further evaluated for their in vivo antitumor efficacy against EAC tumor bearing mice. Notably, compound 4g showed the most potent in vivo antitumor activity. The most active compounds were evaluated for their EGFR inhibitory (range 53–79 %) activity. Compound 4g was found to be the most active compound against EGFR (IC50 = 0.25 µM) showing equipotency as the reference treatment (erlotinib). Molecular modeling study was performed on compound 4g revealed a proper binding of this compound inside the EGFR active site comparable to erlotinib. The data suggest that compound 4g could be used as a potential anticancer agent.

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“…Nucleobases are divided into two categories depending on the ring structure: those with a single ring (a nitrogen containing heterocyclic, aromatic compound) are called pyrimidines while those with two rings (a pyrimidine ring fused to an imidazole ring) are called purines (Figure 1B,C). Interest in nucleosides began in the early 1920s when Leopold Cerecedo (1927) conducted studies on thymidine and uracil metabolism. Since then, numerous studies have explored the roles of nucleosides in nucleic acid synthesis, purinergic signaling, as energy providers, as therapeutic agents and more (Kalckar, 1950;Geiger et al, 1985;Pastor-Anglada et al, 1998).…”

Section: Nucleosidesmentioning

confidence: 99%

Substrate Dependent Regulation of the Human Equilibrative Nucleoside Transporter 1 (hENT1) in HEK293 Cells

Zafar¹

2021

Preprint

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Nucleosides and nucleoside analog drugs enter cells through nucleoside transporters, such as the human equilibrative nucleoside transporter 1 (hENT1). The regulation of nucleoside transporters is poorly understood. In this study, through fluorescence-activated cell sorting (FACS) analyses, confocal microscopy and radio-ligand binding assays, I show a decrease in hENT1 abundance at the plasma membrane (PM) in HEK cells treated in the presence of a bolus amount of cytidine (40μM) for 6 hours. Kinetic and transport assays indicate that the remaining hENT1 population at the PM has a higher Vmax and Km but there is no change in overall substrate uptake compared to untreated cells. I also show that cytidine pre-treatment leads to an increased cytotoxicity from gemcitabine (a nucleoside analog drug). These are the first data that show direct substrate dependent regulation of a nucleoside transporter by a mechanism that may involve increased recycling/internalization of the transporter.

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Physiology of Pyrimidines

Cited by 6 publications

References 0 publications

Physiology of Nucleoside Transporters: Back to the Future. . . .

Physiology of Nucleoside Transporters: Back to the Future. . . .

Design, Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity

Substrate Dependent Regulation of the Human Equilibrative Nucleoside Transporter 1 (hENT1) in HEK293 Cells

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