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Synthesis and Characterization of NUC-7738, an Aryloxy Phosphoramidate of 3'-Deoxyadenosine, as a Potential Anticancer Agent.

ABSTRACT: 3'-Deoxyadenosine (3'-dA, Cordycepin, 1) is a nucleoside analogue with anticancer properties, but its clinical development has been hampered due to its deactivation by adenosine deaminase (ADA) and poor cellular uptake due to low expression of the human equilibrative transporter (hENT1). Here, we describe the synthesis and characterization of NUC-7738 (7a), a 5'-aryloxy phosphoramidate prodrug of 3'-dA. We show in vitro evidence that 7a is an effective anticancer drug in a panel of solid and hematological cancer cell lines, showing its preferential cytotoxic effects on leukemic stem cells. We found that unlike 3'-dA, the activity of 7a was independent of hENT1 and kinase activity. Furthermore, it was resistant to ADA metabolic deactivation. Consistent with these findings, 7a showed increased levels of intracellular 3'-deoxyadenosine triphosphate (3'-dATP), the active metabolite. Mechanistically, levels of intracellular 3'-dATP were strongly associated with in vitro potency. NUC-7738 is now in Phase II, dose-escalation study in patients with advanced solid tumors.

SUBMITTER: Serpi M

PROVIDER: S-EPMC9743095 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Synthesis and Characterization of NUC-7738, an Aryloxy Phosphoramidate of 3'-Deoxyadenosine, as a Potential Anticancer Agent.

Serpi Michaela M Ferrari Valentina V McGuigan Christopher C Ghazaly Essam E Pepper Chris C

Journal of medicinal chemistry 20221123 23

3'-Deoxyadenosine (3'-dA, Cordycepin, 1) is a nucleoside analogue with anticancer properties, but its clinical development has been hampered due to its deactivation by adenosine deaminase (ADA) and poor cellular uptake due to low expression of the human equilibrative transporter (hENT1). Here, we describe the synthesis and characterization of NUC-7738 (7a), a 5'-aryloxy phosphoramidate prodrug of 3'-dA. We show in vitro evidence that 7a is an effective anticancer drug ...[more]

PMID: 36417756

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Project description:The failure of current chemotherapeutic agents for pancreatic cancer (PCa) makes it the most aggressive soft tissue tumor with a 5-year survival of slightly above 10% and is estimated to be the second leading cause of cancer death by 2030.ObjectiveThe main aim was to synthesize, characterize and evaluate the anticancer activity of 1,3-bistetrahydrofuran-2yl-5FU (MFU).MethodsMFU was synthesized by using 5-fluorouracil (5-FU) and tetrahydrofuran acetate, and characterized by nuclear magnetic resonance (NMR), micro-elemental analysis, high-performance liquid chromatography (HPLC), and liquid chromatography with mass spectrophotometry (LC-MS). MFU and Gemcitabine hydrochloride (GemHCl) were tested for antiproliferative activity against MiaPaca-2 and Panc-1 cell lines.ResultsThe half-minimum inhibitory concentration (IC50) of MFU was twice lower than that of GemHCl when used in both cell lines. MiaPaca-2 cells (MFU-IC50 = 4.5 ± 1.2 μM vs. GemHCl-IC50 = 10.3 ± 1.1 μM); meanwhile similar trend was observed in Panc-1 cells (MFU-IC50 = 3.0 ± 1 μM vs. GemHCl-IC50 = 6.1 ± 1.03 μM). The MFU and GemHCl effects on 3D spheroids showed a similar trend (IC50-GemHCl = 14.3 ± 1.1 μM vs. IC50-MFU = 7.2 ± 1.1 μM) for MiaPaca-2 cells, and (IC50-GemHCl = 16.3 ± 1.1 μM vs. IC50-MFU = 9.2 ± 1.1 μM) for Panc-1 cells. MFU significantly inhibited clonogenic cell growth, and induced cell death via apoptosis. Cell cycle data showed mean PI for GemHCl (48.5-55.7) twice higher than MFU (24.7 to 27.9) for MiaPaca-2 cells, and similarly to Panc-1 cells. The in-vivo model showed intensely stained EGFR (stained brown) in all control, GemHCl and MFU-treated mice bearing subcutaneous PDX tumors, however, HER2 expression was less stained in MFU-treated tumors compared to GemHCl-treated tumors and controls. Mean tumor volume of MFU-treated mice (361 ± 33.5 mm3) was three-fold lower than GemHCl-treated mice (1074 ± 181.2 mm3) bearing pancreatic PDX tumors.ConclusionMFU was synthesized with high purity and may have potential anticancer activity against PCa.

Dataset Information

Synthesis and Characterization of NUC-7738, an Aryloxy Phosphoramidate of 3'-Deoxyadenosine, as a Potential Anticancer Agent.

Publications

Synthesis and Characterization of NUC-7738, an Aryloxy Phosphoramidate of 3'-Deoxyadenosine, as a Potential Anticancer Agent.

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