747412-49-3

Basic information

• Product Name: 5-[2,4-Dihydroxy-5-isopropylphenyl]-N-ethyl-4-[4-(4-morpholinylmethyl)phenyl]-3-isoxazolecarboxamide
• Synonyms: 5-[2,4-Dihydroxy-5-isopropylphenyl]-N-ethyl-4-[4-(4-morpholinylmethyl)phenyl]-3-isoxazolecarboxamide;NVP-AUY922;AUY 922;AUY922 (NVP-AUY922);VER 52296;VER-52296;AUY922, VER-52296;LuMinespib
• CAS NO: 747412-49-3
• Molecular Formula: C₂₆H₃₁N₃O₅
• Molecular Weight: 465.547
• Product Categories: Potent and oral inhibitor of heat shock protein 90.;Aromatics;Heterocycles;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Inhibitor;Antineoplastic;API
• Mol File: 747412-49-3.mol
• Article Data: 2

Chemical Properties

• Boiling Point: 640.1°C at 760 mmHg
• Flash Point: 340.9°C
• Appearance: /
• Density: 1.234
• Vapor Pressure: 5.54E-17mmHg at 25°C
• Refractive Index: 1.597
• Storage Temp.: -20°C
• Solubility: Soluble in DMSO (>25 mg/ml)
• PKA: 8.47±0.48(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 2 months.
• CAS DataBase Reference: 5-[2,4-Dihydroxy-5-isopropylphenyl]-N-ethyl-4-[4-(4-morpholinylmethyl)phenyl]-3-isoxazolecarboxamide(CAS DataBase Reference)
• NIST Chemistry Reference: 5-[2,4-Dihydroxy-5-isopropylphenyl]-N-ethyl-4-[4-(4-morpholinylmethyl)phenyl]-3-isoxazolecarboxamide(747412-49-3)
• EPA Substance Registry System: 5-[2,4-Dihydroxy-5-isopropylphenyl]-N-ethyl-4-[4-(4-morpholinylmethyl)phenyl]-3-isoxazolecarboxamide(747412-49-3)

Safety Data

• Hazardous Substances Data: 747412-49-3(Hazardous Substances Data)

Usage

Description

5-[2,4-Dihydroxy-5-isopropylphenyl]-N-ethyl-4-[4-(4-morpholinylmethyl)phenyl]-3-isoxazolecarboxamide is a complex organic compound with a unique molecular structure. It is characterized by the presence of a 3-isoxazolecarboxamide core, a 2,4-dihydroxy-5-isopropylphenyl group, an N-ethyl substituent, and a 4-(4-morpholinylmethyl)phenyl group. 5-[2,4-Dihydroxy-5-isopropylphenyl]-N-ethyl-4-[4-(4-morpholinylmethyl)phenyl]-3-isoxazolecarboxamide has potential applications in various fields due to its distinct chemical properties and interactions with biological targets.

Uses

Used in Pharmaceutical Industry:
5-[2,4-Dihydroxy-5-isopropylphenyl]-N-ethyl-4-[4-(4-morpholinylmethyl)phenyl]-3-isoxazolecarboxamide is used as a pharmaceutical agent for the development of novel therapeutics. Its unique molecular structure allows it to modulate specific biological targets, making it a promising candidate for the treatment of various diseases.
Used in Cancer Therapy:
In the field of oncology, 5-[2,4-Dihydroxy-5-isopropylphenyl]-N-ethyl-4-[4-(4-morpholinylmethyl)phenyl]-3-isoxazolecarboxamide is used as an anticancer agent. It has the potential to inhibit the growth and proliferation of cancer cells by targeting specific molecular pathways involved in tumor development and progression.
Used in Drug Delivery Systems:
5-[2,4-Dihydroxy-5-isopropylphenyl]-N-ethyl-4-[4-(4-morpholinylmethyl)phenyl]-3-isoxazolecarboxamide can also be employed in the development of drug delivery systems. Its chemical properties allow for the design of innovative carriers and formulations that can improve the bioavailability, targeting, and therapeutic efficacy of various drugs.
Used in Chemical Research:
In the realm of chemical research, 5-[2,4-Dihydroxy-5-isopropylphenyl]-N-ethyl-4-[4-(4-morpholinylmethyl)phenyl]-3-isoxazolecarboxamide serves as a valuable compound for studying the structure-activity relationships of various biologically active molecules. Its unique features can provide insights into the design and synthesis of new compounds with improved pharmacological properties.
Used in Material Science:
5-[2,4-Dihydroxy-5-isopropylphenyl]-N-ethyl-4-[4-(4-morpholinylmethyl)phenyl]-3-isoxazolecarboxamide may also find applications in material science, where its chemical and physical properties can be harnessed for the development of novel materials with specific functions and properties. These materials could have potential uses in various industries, such as electronics, coatings, and sensors.

In vitro

NVP-AUY922 inhibits proliferation of various human cancer cell lines in vitro, with an average GI50 of 9 nM. The IC50 values of NVP-AUY922 fall in the range of 2 to 40 nM in these gastric cancer cell lines. IC50 value for the BEAS-2B cells is 28.49 nM. Treatment with NVP-AUY922 does not influence the expression of HSP90, but expression of HSP70 gets elevated by NVP-AUY922 treatment. NVP-AUY922 increases the binding of HSP70 to HSP90. NVP-AUY922 causes p23 dissociation from the HSP90 complex and can then recruit HSP70 to the HSP90 complex. After the treatment with NVP-AUY922, expression of receptor tyrosine kinases including VEGFR1, 2, 3 and PDGFRɑ is decreased. A decrease is also noticed in the expression of Akt and phospho-Akt. Meanwhile, treatment with NVP-AUY922 causes decreased expression of HER-2 in NCI-N87 cells. NVP-AUY922 treatment results in binding of HSP90 to client proteins and setting them up as targets for degradation by the proteasome. NVP-AUY922 can influence cell growth by affecting multiple signaling pathways. In addition, treatment with the proteasome inhibitor, MG132, restores expression of thymidylate synthase, which is decreased by NVP-AUY922. NVP-AUY922 increases the expression of cleaved caspase-3 leading to apoptosis in HSC-2 cells.

In vivo

Treatment with NVP-AUY922 causes a robust antitumor response and inhibits p-Akt and VEGF expression in an HSC-2 xenograft model. In BT474, NVP-AUY922 shows complete loss of ERBB2 and substantial depletion of ERα, in addition to reductions in CDK4 and phospho-ERK1/2.

References

Brough et al. (2008), 4,5-Diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer; Med. Chem. 51 196 Eccles et al. (2008), NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis; Cancer Res. 68 2850 Massey et al. (2010), Preclinical antitumor activity of the orally available heat shock protein 90 inhibitor; Cancer Ther. 5 1807 Song et al. (2020), HSP90A inhibition promotes anti-tumor immunity by reversing multi-modal resistance and stem-like property of immune-refractory tumors; Commun. 11 562 Schwab and Multhoff (2022), A Low Membrane Hsp70 Expression in Tumor Cells With Impaired Lactate Metabolism Mediates Radiosensitization by NVP-AUY922; Oncol. 12 861266 Djuzenova et al. (2012), Hsp90 inhibitor NVP-AUY922 enhances radiation sensitivity of tumor cells lines under hypoxia; Cancer Biol. Ther. 13 425 Schilling et al. (2015), Sensitizing tumor cells to radiation by targeting the heat shock response; Cancer Lett. 360 294

InChI:InChI=1/C26H31N3O5/c1-4-27-26(32)24-23(18-7-5-17(6-8-18)15-29-9-11-33-12-10-29)25(34-28-24)20-13-19(16(2)3)21(30)14-22(20)31/h5-8,13-14,16,30-31H,4,9-12,15H2,1-3H3,(H,27,32)

Synthetic route

5-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide → 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide (747412-49-3)

Conditions	Yield
With boron trichloride In dichloromethane at 20℃; for 1.5h;
With boron trichloride In dichloromethane at 0℃; for 0.5h;

5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide (747412-49-3) + methanesulfonic acid (75-75-2) → 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide mesylate

Conditions	Yield
In tert-butyl methyl ether; water; acetone at 0 - 45℃; for 26 - 26.5833h; Product distribution / selectivity;	85%

cholesteryl hemi-4-oxaglutarate + 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide (747412-49-3) → AUY922-diglycolate-cholesterol

Conditions	Yield
With dmap; diisopropyl-carbodiimide In dichloromethane at 19℃; for 4.25h; Inert atmosphere;	24%

5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide (747412-49-3) → 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide hydrochloride

Conditions	Yield
With hydrogenchloride In ethanol; water; ethyl acetate at 25℃;

5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide (747412-49-3) + di(succinimido) carbonate (74124-79-1) + N-ε-4-methyltrityl-L-lysine + S-trityl-2-mercaptopropionic acid (75286-49-6, 75368-95-5) + 2-hydroxyethanethiol (60-24-2) + 5-carboxy-2-(6-(dimethylamino)-3-(dimethyliminio)-3H-xanthen-9-yl)benzoate → C108H153N23O19S2 + C108H153N23O19S2

Conditions

Yield

Stage #1: N-ε-4-methyltrityl-L-lysine; S-trityl-2-mercaptopropionic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide Rink amide MBHA resin; Stage #2: With chlorotriisopropylsilane; trifluoroacetic acid In dichloromethane for 0.5h; Stage #3: 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; di(succinimido) carbonate; 2-hydroxyethanethiol; 5-carboxy-2-(6-(dimethylamino)-3-(dimethyliminio)-3H-xanthen-9-yl)benzoate Further stages;

5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide (747412-49-3) + di(succinimido) carbonate (74124-79-1) + C84H130N15O15PolS3 + S-trityl-2-mercaptopropionic acid (75286-49-6, 75368-95-5) + 2-hydroxyethanethiol (60-24-2) → C77H121N19O14S2 + C77H121N19O14S2

Conditions

Yield

Stage #1: C84H130N15O15PolS3; S-trityl-2-mercaptopropionic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide Rink amide MBHA resin; Stage #2: With chlorotriisopropylsilane; trifluoroacetic acid In water for 0.5h; Stage #3: 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; di(succinimido) carbonate; 2-hydroxyethanethiol Further stages;

Relevant articles and documents

4,5-Diarylisoxazole Hsp90 chaperone inhibitors: Potential therapeutic agents for the treatment of cancer

Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure - activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by ～50%.