N-(3-chlorophenyl)-6,7-dimethoxyquinazolin-4-amine

• ChemBase编号: 73224
• 分子式: C16H14ClN3O2
• 平均质量: 315.75426
• 单一同位素质量: 315.07745438
• SMILES: c1c2c(cc(c1OC)OC)c(ncn2)Nc1cc(ccc1)Cl
• Canonical SMILES: COc1cc2c(ncnc2cc1OC)Nc1cccc(c1)Cl
• InChI: InChI=1S/C16H14ClN3O2/c1-21-14-7-12-13(8-15(14)22-2)18-9-19-16(12)20-11-5-3-4-10(17)6-11/h3-9H,1-2H3,(H,18,19,20)
• InChIKey: GFNNBHLJANVSQV-UHFFFAOYSA-N

名称和登记号

名称

• IUPAC标准名: N-(3-chlorophenyl)-6,7-dimethoxyquinazolin-4-amine
• IUPAC传统名: N-(3-chlorophenyl)-6,7-dimethoxyquinazolin-4-amine
• 别名: Tyrphostin AG-1478; AG-1478 (Tyrphostin AG-1478); N-(3-Chlorophenyl)-6,7-dimethoxy-4-quinazolinamine; Tyrphostin AG 1478

登记号

• CAS号: 153436-53-4; 175178-82-2
• MDL号: MFCD00270914
• PubChem SID: 162038144; 24278735
• PubChem CID: 2051

理论计算性质

• 里宾斯基五规则: true
• Acid pKa: 15.959776
• 质子受体: 5
• 质子供体: 1
• LogD (pH = 5.5): 3.6949787
• LogD (pH = 7.4): 3.747435
• Log P: 3.748148
• 摩尔折射率: 85.3314 cm^3
• 极化性: 33.670418 Å^3
• 极化表面积: 56.27 Å^2
• 可自由旋转的化学键: 4

分子性质

安全信息

• 保存条件: -20°C
• 德国WGK号: 3
• 个人保护装置: Eyeshields, Gloves, type N95 (US), type P1 (EN143) respirator filter
• 保存温度: 2-8°C

药理学性质

• 作用靶点: EGFR(HER)
• 相关基因信息: human ... EGFR(1956)mouse ... Egfr(13649)

产品相关信息

• 纯度: ≥90%
• 成盐信息: Free Base

详细说明

Selleck Chemicals - S2728

Research Area

• Description: Cancer

Biological Activity

• Description: AG-1478 (Tyrphostin AG-1478) is a selective EGFR inhibitor with IC50 of 3 nM.
• Targets: EGFR
• IC50: 3 nM ^[1]
• In Vitro: AG-1478 is high selective over ErbB2 and PDGFR with IC50 of >100 μM. ^[1] AG-1478 preferentially inhibits U87MG cells expressing truncated EGFR with IC50 of 8.7 μM, compared to those expressing endogenous wt EGFR or overexpressing exogenous wt EGFR with IC50 of 34.6 μM and 48.4 μM, respectively, and inhibits the DNA synthesis with IC50 of 4.6 μM, 19.67 μM, and 35.2 μM, respectively. AG-1478 also preferentially inhibits the tyrosine kinase activity and autophosphorylation of the ΔEGFR compared to endogenous or overexpressed exogenous wt EGFR. ^[2] AG-1478 (0.25 μM) abolishes the MAPK activation induced by Ang II, a Ca2+ ionophore as well as EGF but not by a phorbol ester or platelet-derived growth factor-BB in the VSMC. ^[3] AG-1478 inhibits EGF-induced mitogenesis of the BaF/ERX and LIM1215 cells with IC50 of 0.07 μM and 0.2 μM, respectively. ^[6] AG1478 is able to inhibit the function of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCG2, with a more pronounced effect on ABCG2. ^[7]
• In Vivo: Administration of AG-1478 blocks phosphorylation of the EGFR at the tumor site and inhibits the growth of A431 xenografts that overexpress the WT EGFR and glioma xenografts expressing the de2-7 EGFR. Even subtherapeutic doses of AG-1478 significantly enhance the efficacy of cytotoxic drugs, with the combination of AG-1478 and temozolomide displaying synergistic antitumor activity against human glioma xenografts. The combination of AG-1478 and an anti-EGFR antibody (mAb 806) displays additive and in some cases synergistic, antitumor activity against tumor xenografts overexpressing the EGFR. ^[4] The combination of AG-1478 (0.4 mg) with a single dose of 25 μCi ^90Y-CHX-A''-DTPA-hu3S193 results in a significant enhancement of efficacy compared with either agent alone. ^[5]

Combination Therapy

• Description: AG-1478 in combination with cisplatin displays significantly higher antitumor activity against established U87MG.Δ2-7 and A431 xenografts than either agent used alone. ^[4] Similar to erlotinib, AG-1478 potently sensitizes drug-resistant cells overexpressing either wild-type or mutated ABCG2 to the ABCG2 substrate anti-cancer drugs flavopiridol and mitoxantrone. Furthermore, AG-1478 is able to significantly enhance the intracellular accumulation of mitoxantrone in cells expressing either wildtype or mutated ABCG2. ^[8] AG-1478 in combination with cisplatin or paclitaxel has a synergistic effect against endometrial and ovarian cancer cells. ^[9]

Protocol

• Protocol: Cell Assay ^[2]
• Cell Lines: U87MG
• Concentrations: Dissolved in DMSO, final concentrations ~100 μM
• Incubation Time: 72 hours
• Methods: Cells are exposed to different concentrations of AG-1478 for 72 hours in 96-well plates. The effects of AG-1478 on cell growth are examined using an Alamar Blue assay. A 20-μL aliquot of Alamar Blue is added to each well, and its absorbance is determined using a Spectromax Scanning Micro plate Reader. The effects of AG-1478 are expressed as percentage of growth inhibition using untreated cells as the control (0% inhibition). Cellular DNA synthesis is determined using a [^3H]thymidine incorporation assay.
• Protocol: Animal Study ^[4]
• Animal Models: Female BALB/c nu/nu mice inoculated s.c. with A431 or U87MG.Δ2-7 tumor cells
• Formulation: Dissolved in 100 mM Captisol
• Doses: ~1 mg/kg
• Administration: Injection i.p. three times per week

References

• References: [1] Levitzki A, et al. Science, 1995, 267(5205), 1782-1788.
• References: [2] Han Y, et al. Cancer Res, 1996, 56(17), 3859-3861.
• References: [3] Eguchi S, et al. J Biol Chem, 1998, 273(15), 8890-8896.
• References: [4] Johns TG, et al. Proc Natl Acad Sci U S A, 2003, 100(26), 15871-15876.
• References: [5] Lee FT, et al. Clin Cancer Res, 2005, 11(19 Pt 2), 7080s-7086s.
• References: [6] Ellis AG, et al. Biochem Pharmacol, 2006, 71(10), 1422-1434.

Sigma Aldrich - T4182

Biochem/physiol Actions
Selective inhibitor of epidermal growth factor receptor protein

参考文献

• Levitzki A, et al. Science, 1995, 267(5205), 1782-1788.
• Han Y, et al. Cancer Res, 1996, 56(17), 3859-3861.
• Eguchi S, et al. J Biol Chem, 1998, 273(15), 8890-8896.
• Johns TG, et al. Proc Natl Acad Sci U S A, 2003, 100(26), 15871-15876.
• Lee FT, et al. Clin Cancer Res, 2005, 11(19 Pt 2), 7080s-7086s.
• Ellis AG, et al. Biochem Pharmacol, 2006, 71(10), 1422-1434.