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| Targets |
NUC-3373 targets thymidylate synthase (TS), a key enzyme in the de novo synthesis of thymidylate, which is essential for DNA replication. As a pyrimidine nucleotide analogue, it inhibits TS activity, leading to depletion of thymidine triphosphate (dTTP) and disruption of DNA synthesis. The compound is a prodrug of a cytotoxic metabolite that targets and inhibits cancer cell proliferation by interfering with DNA replication and transcription.
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| ln Vitro |
Damage-associated molecular patterns (DAMPs) are released, cell surface calreticulin (CRT) is expressed more, and nuclear high-mobility group protein 1 (HMGB1) is lost when fosifloxuridine nafalbenamide is administered [1].
NUC-3373 demonstrates in vitro anticancer activity as a thymidylate synthase inhibitor. As a ProTide transformation of 5-FU, it generates higher concentrations of FUDR-MP in cells compared to 5-FU. Its in vitro activity is assessed by measuring inhibition of thymidylate synthase activity, DNA synthesis, and cell proliferation in cancer cell lines. |
| ln Vivo |
The HT-29 nude mouse xenograft model shows antitumor efficacy for fosifloxuridine nafalbenamide [2].
NUC-3373 has demonstrated in vivo anticancer activity in preclinical models. As a novel nucleoside analog, it is being developed for the treatment of cancer. Its in vivo activity is assessed by measuring tumor growth inhibition in xenograft models. The ProTide technology enhances the intracellular delivery of the active metabolite. |
| Enzyme Assay |
The in vitro enzyme assay for NUC-3373 involves measuring its inhibitory activity against thymidylate synthase in cell-free systems. These assays use purified thymidylate synthase enzyme and measure the conversion of dUMP to dTMP in the presence of the compound. Inhibitory potency is determined by assessing the reduction in enzyme activity. The active metabolite FUDR-MP is the species that inhibits TS.
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| Cell Assay |
In vitro cellular assays for NUC-3373 are performed using cancer cell lines. These assays measure the compound's ability to inhibit cell proliferation, induce cell cycle arrest, and cause apoptosis. The intracellular generation of FUDR-MP and inhibition of thymidylate synthase are also assessed. These assays demonstrate the compound's anticancer activity.
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| Animal Protocol |
In vivo animal studies for NUC-3373 are conducted in mouse xenograft models of various cancers. These studies typically involve administration of the compound, followed by assessment of tumor growth inhibition, survival, and pharmacodynamic markers of thymidylate synthase inhibition. The compound's efficacy as a novel nucleoside analog is evaluated in these models.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of NUC-3373 are characterized by its ProTide design, which enhances intracellular delivery of the active metabolite FUDR-MP. The compound has a molecular formula of C₂₉H₃₀F₂N₄O₈P and a molecular weight of 631.54 g/mol. Its pharmacokinetic profile supports its development as an anticancer agent.
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| Toxicity/Toxicokinetics |
Toxicology studies of NUC-3373 have been conducted to support its development as an anticancer agent. As a thymidylate synthase inhibitor and nucleoside analog, its toxicology profile includes effects on rapidly dividing cells, such as bone marrow and gastrointestinal epithelial cells, which are common to this class of compounds.
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| References |
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| Additional Infomation |
Fucy-fluorouridine naphthabenamide is being investigated in the clinical trial NCT03428958 (NUC-3373 Safety Study in Combination with Standard Therapy for Colorectal Cancer). Fucy-fluorouridine naphthabenamide is a phosphoramide ester-based prodrug whose active form is the monophosphate (MP) form of 5-fluoro-2'-deoxyuridine (FUdR; FUDR). FUdR is the active metabolite of fluorouracil (5-FU), an antimetabolite of pyrimidine nucleosides with potential antitumor activity. When the nucleoside analog prodrug fucy-fluorouridine naphthabenamide is administered, tumor cells rapidly absorb the drug. Within the tumor cells, the phosphoramide ester portion is removed, and fucy-fluorouridine naphthabenamide is converted to its active form, FUDR-MP. FUDR-MP, in turn, binds to and inhibits thymidylate synthase (TS), leading to thymidine triphosphate (TTP) depletion and thus inhibiting DNA synthesis. Compared to 5-fluorouracil (5-FU), FUDR-MP, due to the presence of a phosphoramide group, exhibits stronger lipophilicity and can accumulate within cancer cells via passive diffusion without the need for nucleoside transporters, resulting in higher intracellular concentrations. Furthermore, unlike 5-FU, FUDR-MP exerts its activity directly upon entering the cell without phosphorylation. Unlike 5-FU, fucytosine naphthalenebenzamide is not inactivated or converted into toxic metabolites by dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP), thus exhibiting a longer half-life and lower toxicity.
NUC-3373 (CAS: 1332837-31-6), also known as Fosifloxuridine nafalbenamide, is a pyrimidine nucleotide analogue and thymidylate synthase inhibitor with anticancer activity. It is a ProTide transformation of 5-FU that generates higher concentrations of FUDR-MP in cells. The compound has a molecular formula of C₂₉H₃₀F₂N₄O₈P and a molecular weight of 631.54 g/mol. It is for research use only. |
| Molecular Formula |
C29H30F2N4O8P
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| Molecular Weight |
613.527432203293
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| Exact Mass |
613.162
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| CAS # |
1332837-31-6
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| PubChem CID |
53373585
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Index of Refraction |
1.650
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| LogP |
3.04
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
43
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| Complexity |
1100
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| Defined Atom Stereocenter Count |
4
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| SMILES |
C[C@@H](C(=O)OCC1=CC=CC=C1)NP(=O)(OC[C@@H]2[C@H](C[C@@H](O2)N3C=C(C(=O)NC3=O)F)O)OC4=CC=CC5=CC=CC=C54
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| InChi Key |
LYMGFDGRLCYHTR-ICIRLHQFSA-N
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| InChi Code |
InChI=1S/C29H30F2N4O8P/c1-18(26(37)41-16-19-8-3-2-4-9-19)34-44(39,40,23-13-7-11-20-10-5-6-12-21(20)23)42-17-22-25(36)29(30,31)27(43-22)35-15-14-24(32)33-28(35)38/h2-15,18,22,25,27,36H,16-17H2,1H3,(H2,32,33,38)(H2,34,39,40)/t18-,22+,25+,27+/m0/s1
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| Chemical Name |
L-Alanine, N-(-2'-deoxy-2',2'-difluoro-p-1-naphthalenyl-5'-cytidylyl)-, phenylmethyl ester
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| Synonyms |
NUC-3373 NUC 3373 NUC3373
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~162.99 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.07 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.07 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.07 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6299 mL | 8.1496 mL | 16.2991 mL | |
| 5 mM | 0.3260 mL | 1.6299 mL | 3.2598 mL | |
| 10 mM | 0.1630 mL | 0.8150 mL | 1.6299 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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