Fluorocyclopentenyl-cytosine with Broad Spectrum and Potent Antitumor Activity

Choi, Won Jun; Chung, Hwa‐Jin; Chandra, Girish; Alexander, Varughese; Zhao, Long; Lee, Hyuk Woo; Nayak, Akshata; Majik, Mahesh S.; Kim, Hea Ok; Kim, Jinhee; Lee, Young B.; Ahn, Chang Ho; Lee, Sang Kook; Jeong, Lak Shin

doi:10.1021/jm3004009

Cited by 56 publications

(36 citation statements)

References 19 publications

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“…This explains the lack of cross resistance between gemcitabine and RX-3117 and will increase the potential of RX-3117 to be used against these tumors. Along with being active in gemcitabine resistant cell lines in vitro [3, 5], RX-3117 also showed in vivo activity against various tumor types, including gemcitabine resistant tumors [5, 6]. Additionally, this study also showed a relation between UCK2 expression and UCK activity as well as of UCK2 expression and RX-3117 sensitivity, which suggests that UCK2 expression may be used to select patients for their sensitivity to RX-3117.…”

Section: Discussionmentioning

confidence: 67%

“…A cytidine analog, fluorocyclopentenylcytosine (RX-3117) (Fig 1), has shown promise as an anti-cancer drug since it showed considerable anti-tumor activity in various xenograft models [5], including models resistant to gemcitabine [6]. The lack of cross resistance between these two drugs suggests a difference in mechanism of action or method by which they are metabolized in cells.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, this study showed that RX-3117, contrary to a drug such as gemcitabine, is not deaminated by cytidine deaminase (CDA) and that RX-3117 causes both inhibition of DNA and RNA synthesis, although the inhibition of the former is more pronounced. RX-3117 also targets DNA methyltransferase (DNMT) [3, 5] of which there are multiple variants [7]. DNMT3a and DNMT3b establish de novo DNA methylation patterns in DNA, which is important during embryogenesis [7], while DNMT1 differs in that its role is to maintain the established DNA methylation pattern through cell division and thus DNA replication [8].…”

Section: Introductionmentioning

confidence: 99%

“…DNMT3a and DNMT3b establish de novo DNA methylation patterns in DNA, which is important during embryogenesis [7], while DNMT1 differs in that its role is to maintain the established DNA methylation pattern through cell division and thus DNA replication [8]. In two previous studies a decrease in DNMT1 expression was found in cell lines treated with RX-3117 [5], while this was not the case for DNMT3a. This suggests RX-3117 might be an effective demethylating agent, comparable to decitabine (Aza-CdR) and azacytidine (Aza-CR) [1].…”

Section: Introductionmentioning

confidence: 99%

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The Cytidine Analog Fluorocyclopentenylcytosine (RX-3117) Is Activated by Uridine-Cytidine Kinase 2

et al. 2016

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Fluorocyclopentenylcytosine (RX-3117) is an orally available cytidine analog, currently in Phase I clinical trial. RX-3117 has promising antitumor activity in various human tumor xenografts including gemcitabine resistant tumors. RX-3117 is activated by uridine-cytidine kinase (UCK). Since UCK exists in two forms, UCK1 and UCK2, we investigated which form is responsible for RX-3117 phosphorylation. For that purpose we transfected A549 and SW1573 cell lines with UCK-siRNAs. Transfection of UCK1-siRNA efficiently downregulated UCK1-mRNA, but not UCK2-mRNA expression, and did not affect sensitivity to RX-3117. However, transfection of UCK2-siRNA completely downregulated UCK2-mRNA and protein and protected both A549 and SW1573 against RX-3117. UCK enzyme activity in two panels of tumor cell lines and xenograft cells correlated only with UCK2-mRNA expression (r = 0.803 and 0.915, respectively), but not with UCK1-mRNA. Moreover, accumulation of RX-3117 nucleotides correlated with UCK2 expression. In conclusion, RX-3117 is activated by UCK2 which may be used to select patients potentially sensitive to RX-3117.

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Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Cytidine Analog Fluorocyclopentenylcytosine (RX-3117) Is Activated by Uridine-Cytidine Kinase 2

et al. 2016

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“…This can be easily explained by the irreversible inhi-bition of the enzyme caused by this molecule, unlike the neplanocin A, which presents a reversible mechanism [38]. Thus, based on that, their 6′-fluorinated analogs were obtained by Jeong et al (Figure 19) [39].…”

Section: Fluorine In Medicinal Chemistry: Some Fluorinated Carbocyclimentioning

confidence: 98%

Recent Progress for the Synthesis of Selected Carbocyclic Nucleosides

et al. 2015

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Nucleoside analogs are extremely useful for the development of therapeutic agents to control viral diseases and cancer. Among the numerous modifications on the nucleoside skeleton, replacement of the oxygen of the furanose ring by a CH2 group resulted in increased flexibility and higher resistance to phosphorylases and led to carbocyclic nucleoside analogs (or carbanucleosides). The broad spectrum of biological activities of carbocyclic nucleosides led to tremendous research interest in their syntheses. The article documents recent strategies for the synthesis of active carbocyclic nucleosides by presenting individual case studies, such as the neplanocins, entecavir and selected fluorinated carbocyclic nucleosides. Furthermore, it provides new insights into new directions for more potent and active carbocyclic nucleoside analogs.

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Recent Advances in the Synthesis of Carbocyclic Nucleosides via Ring‐Closing Metathesis

2014

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The past decades witnessed the development and the strong potential of nucleoside analogues as therapeutic agents as well as biological tools. Among this, five‐membered carbocyclic nucleosides have shown immense promise in the treatment of cancer and viral infections. The systematic evolution of transition‐metal‐catalyzed CC bond‐forming reactions has widened the scope of olefin metathesis. The development of new catalysts, the selectivity, efficiency, functional‐group compatibility, along with a better know‐how of the catalyst–substrate interactions have encouraged researchers to use this powerful tool for the design of desired target compounds. The aim of this Focus Review is to highlight recently developed synthetic strategies for the synthesis of carbocyclic nucleosides involving ring‐closing metathesis (RCM) as a key step.

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Fluorocyclopentenyl-cytosine with Broad Spectrum and Potent Antitumor Activity

Cited by 56 publications

References 19 publications

The Cytidine Analog Fluorocyclopentenylcytosine (RX-3117) Is Activated by Uridine-Cytidine Kinase 2

The Cytidine Analog Fluorocyclopentenylcytosine (RX-3117) Is Activated by Uridine-Cytidine Kinase 2

Recent Progress for the Synthesis of Selected Carbocyclic Nucleosides

Recent Advances in the Synthesis of Carbocyclic Nucleosides via Ring‐Closing Metathesis

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