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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
2,4-Dihydroxybenzaldehyde is an endogenous metabolite.
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Ashram, Muhammad ; Habashneh, Almeqdad Y. ; Bardaweel, Sanaa ; Taha, Mutasem O. ;
Abstract: A series of novel 1,2,3-triazole-benzoxazepine hybrid molecules were synthesized and evaluated for their anticancer properties against four cancer cell lines (Caco-2, PC3, MCF-7, and HL60). Most of the synthesized compounds exhibited moderate to good cytotoxicity against tested cancer cell lines. Three of the prepared compounds, namely, 2, 3, and 4, showed excellent anticancer properties with micromolar IC50 values ranging from 6 to 18 μM. In silico pharmacophore profiling followed by in-vitro enzyme assays showed 2, 3, and 4 to have micromolar inhibitory IC50 values against the oncogenic kinase FLT3. These compounds represent new inhibitory leads of novel chemotypes against FLT3.
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Keywords: Benzoxazepines ; 1, 2, 3-Triazoles ; Anticancer agents ; In vitro bioassay ; Docking study
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CAS No. : | 95-01-2 |
Formula : | C7H6O3 |
M.W : | 138.12 |
SMILES Code : | O=CC1=CC=C(O)C=C1O |
MDL No. : | MFCD00011686 |
InChI Key : | IUNJCFABHJZSKB-UHFFFAOYSA-N |
Pubchem ID : | 7213 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335-H412 |
Precautionary Statements: | P261-P273-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;Cooling with ice; | Combined 2,4-dihydroxybenzaldehyde (3.14 g, 22.75 mmol),triphenylphosphine (5.97 g, 22.75 mmol) and (2-methyl-[1,1?-biphenyl]-3-yl)methanol (4.1 g, 20.68 mmol) in dry tetrahydrofuran (50 mL) and cooled on an ice/water bath. Added diisopropyl azodicarboxylate (4.33 mL, 22.25 mmol) in tetrahydrofuran (50 mL) dropwise. The resulting yellow solution was allowed to slowly warm to room temperature with stirring overnight. Excess solvent was removed by rotary evaporator. The reaction mixture was chromatoghraphed with 0-20% ethyl acetate in hexanes on silica gel to give the desired product (4.2 g, 64%). 1H NMR (400 MHz, CHLOROFORM-d) delta 11.53 (s, 1H), 9.76 (s, 1H), 7.51-7.29 (m, 11H), 6.67 (dd, J=8.6, 2.2 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 5.17 (s, 2H), 2.26 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9%; 4%; 3% | With sodium hydrogencarbonate; at 65℃; for 24h;Inert atmosphere; | General procedure: A Kimax tube was charged with an equimolar quantity of benzoic acid 33-37 (1.3mmol, 1 equiv.), sodium bicarbonate (1.3mmol, 1 equiv), and the dibromoalkane (1.3mmol, 1 equiv.) in anhydrous acetonitrile or DMF (10mL). The tube was flushed with argon, stopped, and the reaction mixture was stirred at 65C or 90C for the time indicated in each case. The solvent was evaporated under vacuum to give a crude solid residue. The different products were isolated by silica chromatography (5g SI prepacked column) using hexane/EtOAc (100/0→50/50) as eluent. The structure of the obtained isomer (i.e. the benzoate product and not the 4-alkyloxy-substituted benzoic acid isomer) was checked by 1H-13C HMBC and NOESY experiments. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | In ethanol; for 6h;Reflux; | General procedure: A mixture of methyl 3,4-dimethoxybenzoate (1mmol) and corresponding benzaldehyde (1mmol) was refluxed in ethanol (7ml) for 6h. Reaction completion was checked by TLC. The mixture was cooled to room temperature and the resulted precipitate was collected and washed with diethyl ether to yield the final pure products. Moreover, in some cases, recrystallization in appropriate solvents was done in order to obtain the pure derivatives. 2.4.1 (E)-3,4-dimethoxy-N'-(4-nitrobenzylidene)benzohydrazide (D1) Yellow solid; yield: 82%; M.P: 208-210C. 1H NMR (300MHz, DMSO-d6): δ (ppm) 3.85 (s, 6H, OCH3), 7.09 (d, 1H, Ar-H-5, J=6.5Hz), 7.42-7.58 (m, 2H, Ar-H-2, 6), 7.96 (d, 2H, Ar-H-2′,6′), 8.28 (d, 2H, Ar-H-3′,5′), 8.55 (s, 1H, N=CH), 12.00 (s, 1H, NH). 13C NMR (75MHz, DMSO-d6): δ (ppm) 56.10 (OCH3), 56.14 (OCH3), 111.46, 121.66, 121.70, 124.52, 125.53, 128.32, 141.26, 145.06, 148.20, 148.86, 152.45, 163.24 (C=O). MS (EI, 70eV): m/z (%)=329 (M+, 10), 165 (100). Anal. Calcd for C16H15N3O5: C 58.36, H 4.59, N 12.76%, found: C 58.44, H 4.61, N 12.72%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium acetate; for 16h;Reflux; Inert atmosphere; | General procedure: Compounds were synthesized under anhydrous conditions, using a material previously dried at 60 C for at least 12 h and at 300 C for a few minutes immediately before use. A solution containing anhydrous CH3CO2K (2.94 mmol), the corresponding thiophenylacetic acid (1.67 mmol) and the corresponding hydroxysalicylaldehyde (1.67 mmol), in Ac2O (1.2 mL), was refluxed for 16 h. The reaction mixture was cooled, neutralized with 10% aqueous NaHCO3, and extracted with EtOAc (3 × 30 mL). The organic layers were combined, washed with water, dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The product was purified by recrystallization in EtOH and dried in vacuum to afford the desired compound [26,27]. |