AZ20 Chemical Properties

Boiling point:

634.6±55.0 °C(Predicted)

Density 

1.42±0.1 g/cm3(Predicted)

storage temp. 

-20°

solubility 

Soluble in DMSO (up to 20 mg/ml).

form 

solid

pka

15.65±0.30(Predicted)

color 

Off-white

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 1 month.

InChIKey

SCGCBAAYLFTIJU-CQSZACIVSA-N

SMILES

N1C2=C(C(C3=NC(C4(S(C)(=O)=O)CC4)=CC(N4CCOC[C@H]4C)=N3)=CC=C2)C=C1

AZ20 Usage And Synthesis

Description

AZ20 (1233339-22-4) is a potent and highly selective inhibitor of Ataxia telangiectasia mutated and RAD3-related (ATR) kinase (IC50?= 5 nM in vitro; IC50?= 50 nM in HT29 colorectal adenocarcinoma cells).1?Combination therapy with AZ20 and gemcitabine resulted in synergistic inhibition of tumor cell growth and cell death initiation in pancreatic cancer cell lines.2

Uses

AZ20 is a potent and selective inhibitor of ATR (ATM-Rad3-related) kinase with in vivo antitumor activity.

Definition

ChEBI: (3R)-4-[2-(1H-indol-4-yl)-6-(1-methylsulfonylcyclopropyl)-4-pyrimidinyl]-3-methylmorpholine is a member of indoles.

Synthesis

The general steps for the synthesis of (R)-4-(2-(1H-indol-4-yl)-6-(1-(methylsulfonyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine from the compound (CAS:1233339-68-8) and 4-indolylboronic acid were as follows: 1. suspend bis(triphenylphosphine)palladium chloride (1.692 g, 2.41 mmol), (R)-4-(2-chloro-6-(1-(methylsulfonyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine (8.00 g, 24.11 mmol), 1H-indol-4-ylboronic acid (4.27 g 26.52 mmol) and 2M aqueous sodium carbonate (36.2 mL, 72.33 mmol) were heated to 90 °C for overnight reaction. 2. After the reaction was completed, the DME was removed and the reaction mixture was diluted with EtOAc (100 mL). 3. The mixture was washed with water (2 x 100 mL), the organic phase was separated, filtered through a diatomaceous earth pad and concentrated in vacuum to give the crude product. 4. Purify the crude product by silica gel column chromatography with an elution gradient of 0 to 10% EtOAc in DCM solution. The grades containing the target product were combined and the solvent was evaporated. 5. The residue was purified again by silica gel column chromatography with an elution gradient of 0 to 25% EtOAc in DCM solution. The fractions containing the target product were combined and the solvent was evaporated. 6. The residue is dissolved and purified by reversed-phase C18 silica gel column (415g HP C18 column) using a mixture of water (containing 1% NH3) and MeCN as the eluent with decreasing polarity. The grades containing the target product were combined and the solvent was evaporated. 7. The residue was dissolved in anhydrous MeOH, dried over MgSO4, filtered and the solvent evaporated to give a gel. 8. The colloid was dissolved in DCM (500 mL), filtered and the solvent was removed under reduced pressure. 9. The residue was dissolved in MeOH (50 mL), stirred overnight at room temperature, and the resulting precipitate was collected by filtration to afford the target product (R)-4-(2-(1H-indol-4-yl)-6-(1-(methylsulfonyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine (5.10 g, 51% yield). Product characterization: 1H NMR (400 MHz, DMSO-d6) δ 1.29 (3H, d), 1.57-1.64 (2H, m), 1.68-1.78 (2H, m), 3.24-3.31 (1H, td), 3.29 (3H, s), 3.51 (1H, td), 3.67 (1H, dd), 3.80 (1H, d). d), 3.93-4.06 (1H, dd), 4.21 (1H, d), 4.61 (1H, bs), 6.85 (1H, s), 7.21 (1H, t), 7.32 (1H, t), 7.46 (1H, t), 7.56 (1H, d), 8.06 (1H, dd), 11.25 (1H, s); m/z (ESI+ ) MH+, 413.12. Chiral HPLC analysis (HPI 100 system on a 4,5 μm Chiralpak AS-H (250 mm × 4.6 mm) column, elution conditions: isohexane/EtOH/TEA 60/40/0.1) showed an Rf value of 8.815 and a purity of >99%.

in vivo

IC 50

ATR: 5 nM (IC₅₀); mTOR: 38 nM (IC₅₀); PI3Kα: 13000 nM (IC₅₀)

storage

Store at -20°C

References

[1] KEVIN M. FOOTE*. Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole (AZ20): A Potent and Selective Inhibitor of ATR Protein Kinase with Monotherapy in Vivo Antitumor Activity[J]. Journal of Medicinal Chemistry, 2013, 56 5: 2125-2138. DOI:10.1021/jm301859s
[2] SHUANG LIU. Inhibition of ATR potentiates the cytotoxic effect of gemcitabine on pancreatic cancer cells through enhancement of DNA damage and abrogation of ribonucleotide reductase induction by gemcitabine.[J]. Oncology reports, 2017: 3377-3386. DOI:10.3892/or.2017.5580

AZ20(1233339-22-4)Related Product Information

• NOTUMib-1
• Pomalidomide
• Dequalinium chloride
• Imiquimod
• MK-2206 2HCl
• WORTMANNIN
• VE-821
• KU-60019
• VE 822
• Olaparib