Fosdesdenosine sipalabenamide

Fosdesdenosine sipalabenamide

CAS 2348493-39-8

MF C26H29N6O7P, MW=568.5 g/mol

benzyl N-(P-ambo-3′-deoxy-OP-phenyl-5′-adenylyl)-Lalaninate

benzyl (2S)-2-[[[(2S,4R,5R)-5-(6-aminopurin-9-yl)-4-hydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate

3′-Deoxyadenosine 5′-O-phenyl-(benzoxy-L-alaninyl)-phosphatenucleoside analogue, antineoplastic, NUC 7738, Y7BFN2M72F

Fosdesdenosine sipalabenamide is an investigational new drug that is being evaluated for the treatment of advanced solid tumors and lymphoma.^[1] This compound is a phosphoramidate derivative of cordycepin (3′-deoxyadenosine), an adenosine analog originally isolated from the fungus Cordyceps.^[2][3] As a nucleoside analog with potential antineoplastic properties, Fosdesdenosine sipalabenamide is designed to inhibit RNA synthesis and act as an RNA inhibitor.^[1] The drug is being developed by NuCana Plc.^[1]

Fosdesdenosine Sipalabenamide is a phosphoramidate derivative of the monophosphate form of cordycepin (3′-deoxyadenosine; 3′-dA), an adenosine derivative first isolated from Cordyceps sinensis, with potential antineoplastic, antioxidant, and anti-inflammatory activities. Upon administration and cellular uptake of fosdesdenosine sipalabenamide by passive diffusion, cordycepin monophosphate (3′-dAMP) is converted into its active anti-cancer metabolite 3′-deoxyadenosine triphosphate (3′-dATP). 3′-dATP functions as a ribonucleoside analogue and competes with ATP during transcription. Therefore, this agent causes RNA synthesis inhibition, inhibits cellular proliferation, and induces apoptosis. Also, 3′-dAMP activates AMP-activated protein kinase (AMPK) and reduces mammalian target of rapamycin (mTOR) signaling. This prevents the hyperphosphorylation of the translation repressor protein 4E-BP1. This results in the induction of tumor cell apoptosis and a decrease in tumor cell proliferation. mTOR, a serine/threonine kinase belonging to the phosphatidylinositol 3-kinase (PI3K)-related kinase (PIKK) family, plays an important role in the PI3K/AKT/mTOR signaling pathway that regulates cell growth and proliferation, and its expression or activity is frequently dysregulated in human cancers. Compared to cordycepin alone, the addition of the phosphoramidate moiety may overcome cancer resistance and allow for greater cytotoxicity as fosdesdenosine sipalabenamide does not require a nucleoside transporter for cellular uptake, is independent of enzymatic activation by adenosine kinase (AK) and is not susceptible to enzymatic degradation by adenosine deaminase (ADA). Altogether, this may help overcome cancer resistance to cordycepin.

SYN

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

Publication Name: Journal of Medicinal Chemistry

Publication Date: 2022-11-23

PMCID: PMC9743095

PMID: 36417756

DOI: 10.1021/acs.jmedchem.2c01348

R_p)- and (S_p)-3′-Deoxyadenosine 5′-O-phenyl-(benzoxy-l-alaninyl)-phosphate (7a)

Prepared according to general procedure C using 3′-deoxyadenosine (1) (0.05 g, 0.20 mmol) in anhydrous THF (4 mL), N-methyl imidazole (0.080 μL, 1.0 mmol), and phenyl(benzyloxy-l-alaninyl) phosphorochloridate (4a) (0.021 g, 0.6 mmol) in THF (2.4 mL) Purification by Biotage Isolera One (cartridge SNAP 25 g, 25 mL/min, CH₃OH/CH₂Cl₂ 1–8% 10 CV, 8% 5 CV) and preparative TLC (1000 μM, eluent system CH₃OH/CH₂Cl₂ 5/95) afforded the title compound 7a as a white solid (0.032 g, 28%). ³¹P NMR (202 MHz, CD₃OD) δ_P 3.91, 3.73. ¹H NMR (500 MHz, CDCl₃) δ_H 8.26 (s, 0.5H, H-8), 8.24 (s, 0.5H, H-8), 8.22 (s, 0.5H, H-2), 8.21 (s, 0.5H, H-2), 7.34–7.25 (m, 7H, Ar), 7.21–7.13 (m, 3H, Ar), 6.01 (d, J = 1.5 Hz, 0.5H, H-1′), 6.00 (d, J = 1.5 Hz, 0.5H, H-1′), 5.15–5.04 (m, 2H, CH₂Ph), 4.73–4.63 (m, 2H, H-2′, H-4′), 4.43–4.35 (m, 1H, H-5′), 4.27–4.20 (m, 1H, H-5′), 4.03–3.91 (m, 1H, CHCH₃), 2.35–2.28 (m, 1H, H-3′), 2.09–2.02 (m, 1H, H-3′), 1.32 (d, J = 7.4 Hz, 1.5 H, CHCH₃), 1.28 (d, J = 7.4 Hz, 1.5 H, CHCH₃). ¹³C NMR (125 MHz, CD₃OD) δ_C 174.84 (d, ³J_C-P = 4.5 Hz, C=O), 174.63 (d, ³J_C-P = 4.5 Hz, C═O), 157.32 (C-6), 157.31 (C-6), 153.86 (C-2), 153.84 (C-2), 152.13 (C-4), 152.07 (C-4), 150.20 (C-Ar), 150.18 (C-Ar), 140.47 (C-8), 137.26 (C-Ar), 137.19 (C-Ar), 130.76 (CH-Ar), 130.74 (CH-Ar), 129.57 (CH-Ar), 129.32 (CH-Ar), 129.31 (CH-Ar), 129.29 (CH-Ar), 129.26 (CH-Ar), 126.16 (CH-Ar), 126.14 (CH-Ar), 121.46 (d, ³J_C-P = 4.7 Hz, CH-Ar), 121.38 (d, ³J_C-P = 4.7 Hz, CH-Ar) 120.54 (C-5), 120.53 (C-5), 93.24 (C-1′), 93.18 (C-1′), 80.43 (d, ³J_C-P = 3.6 Hz, C-4′), 80.36 (d, ³J_C-P = 3.6 Hz, C-4′), 76.62 (C-2′), 68.62 (d, ²J_C-P = 5.3 Hz, C-5′), 68.30 (d, ²J_C-P = 5.3 Hz, C-5′), 67.95 (CH₂Ph), 67.92 (CH₂Ph), 51.74 (CHCH₃), 51.60 (CHCH₃), 34.91 (C-3′), 34.70 (C-3′), 20.45 (d, ³J_C-P = 7.0 Hz, CHCH₃), 20.28 (d, ³J_C-P = 7.0 Hz, CHCH₃). Reversed-phase HPLC eluting with H₂O/CH₃CN from 100/10 to 0/100 in 30 min, F = 1 mL/min, λ = 254 nm, t_R 13.56 and 13.75 min. C₂₆H₂₉N₆O₇P required m/z 568.2 [M]. MS (ES+) found m/z 569.2 [M + H]⁺, 591.2 [M + Na]⁺, 1159.4 [2M+Na]⁺.

The two diastereoisomers 7a-R_p and 7a-S_p were separated via Biotage Isolera One (cartridge SNAP-Ultra C18 12 g, F: 12 mL/min, isocratic eluent system: H₂O/CH₃OH 45/55 in 30 min, 150 mg sample) to obtain:

7a-R_p as Fast Eluting Isomer (76 mg)

³¹P NMR (202 MHz, CD₃OD) δ_P 3.91. ¹H NMR (500 MHz, CDCl₃) δ_H 8.26 (s, 1H, H-8), 8.22 (s, 1H, H-2), 7.37–7.25 (m, 7H, Ar), 7.22–7.12 (m, 3H, Ar), 6.01 (d, J = 1.5 Hz, 1H, H-1′), 5.12 (AB q, J_AB = 12.0 Hz, 2H, CH₂Ph), 4.74–4.70 (m, 1H, H-2′), 4.69–4.62 (m, 1H, H-4′), 4.44–4.38 (m, 1H, H-5′), 4.28–4.21 (m, 1H, H-5′), 3.99–3.90 (m, 1H, CHCH₃), 2.35–2.27 (m, 1H, H-3′), 2.09–2.02 (m, 1H, H-3′), 1.29 (d, J = 7.0 Hz, 3H, CHCH₃). HPLC reversed-phase HPLC eluting with H₂O/CH₃CN from 90/10 to 0/100 in 30 min, F = 1 mL/min, λ = 254 nm, showed one peak with t_R 13.56 min.

7a-S_p as Slow-Eluting Isomer (61 mg)

³¹P NMR (202 MHz, CD₃OD) δ_P 3.73. ¹H NMR (500 MHz, CDCl₃) δ_H 8.24 (s, 1H, H-8), 8.22 (s, 1H, H-2), 7.36–7.26 (m, 7H, Ar), 7.22–7.13 (m, 3H, Ar), 6.01 (d, J = 1.5 Hz, 1H, H-1′), 5.08 (AB q, J_AB = 12.0 Hz, 2H, CH₂Ph), 4.70–4.67 (m, 1H, H-2′), 4.66–4.60 (m, 1H, H-4′), 4.41–4.35 (m, 1H, H-5′), 4.26–4.19 (m, 1H, H-5′), 4.02–3.94 (m, 1H, CHCH₃), 2.36–2.27 (m, 1H, H-3′), 2.08–2.01 (m, 1H, H-3′), 1.34–1.30 (m, 3H, CHCH₃). HPLC reversed-phase HPLC eluting with H₂O/CH₃CN from 90/10 to 0/100 in 30 min, F = 1 mL/min, λ = 254 nm, t_R 13.75 min.

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Clinical data
Other names	NUC-7738
Identifiers
IUPAC name
CAS Number	2348493-39-8
PubChem CID	166177279
DrugBank	DB19148
UNII	Y7BFN2M72F
ChEMBL	ChEMBL5277528
Chemical and physical data
Formula	C26H29N6O7P
Molar mass	568.527 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

References

1.  “Fosdesdenosine sipalabenamide”. PatSnap.
2.  “Fosdesdenosine Sipalabenamide”. PubChem. U.S. National Library of Medicine.
3.  Serpi M, Ferrari V, McGuigan C, Ghazaly E, Pepper C (December 2022). “Synthesis and Characterization of NUC-7738, an Aryloxy Phosphoramidate of 3′-Deoxyadenosine, as a Potential Anticancer Agent”. Journal of Medicinal Chemistry. 65 (23): 15789–15804. doi:10.1021/acs.jmedchem.2c01348. PMC 9743095. PMID 36417756.

….///////Fosdesdenosine sipalabenamide, antineoplastic, NUC 7738, Y7BFN2M72F