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Synthesis and Bioevaluation of 4,5,6,7-Tetrahydrobenzo[d]isoxazole Derivatives as Melanogenesis Inhibitors
Synthesis and Bioevaluation of 4,5,6,7-Tetrahydrobenzo[d]isoxazole Derivatives as Melanogenesis Inhibitors
Bulletin of the Korean Chemical Society. 2014. Feb, 35(2): 666-668
Copyright © 2014, Korea Chemical Society
  • Received : November 21, 2013
  • Accepted : November 27, 2013
  • Published : February 20, 2014
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About the Authors
Jiho Song
Kiho Lee
College of Pharmacy, Korea University, Sejong 339-700, Korea
Doran Kim
Jongmin Kim
Seul Lee
Jun Seob Shin
College of Medicine, Chung-Ang University, Seoul 156-756, Korea.
Dong-Seok Kim
College of Medicine, Chung-Ang University, Seoul 156-756, Korea.
Kyung Hoon Min

Abstract
Keywords
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Experimental
General Procedure for Synthesis of 3a-b . To a solution of 4,5,6,7-tetrahydrobenzo[ d ] isoxazole-3-carboxylic acids 2a-b (1.0 equiv.), oxalyl chloride (3.0 equiv.) in dichloromethane, was added DMF (0.01 equiv.). The mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated in rotary evaporator, dried in vacuo . The crude product was used next step without further purification
General Procedure for Synthesis of 4a-j . To a solution of acid chloride 3a-b (1.0 equiv.), triethylamine (3.0 equiv.) in dry THF, was added arylpiperazines (1.2 equiv.) in dry THF dropwise. The mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous MgSO 4 , and concentrated in vacuo . The crude product was purified by flash column chromatography on silica gel (EtOAC: hexanes = 1:1-1:5) to yield the desired products ( 4a-j ).
Compound 4a : 1 H NMR (300 MHz, CDCl 3 ) δ 6.82 (m, 4H), 3.90 (m, 4H), 3.11 (s, 4H), 3.02 (m, 2H), 2.59 (m, 1H), 2.35 (m, 1H), 2.11 (m, 1H), 1.34 (m, 2H), 0.95 (s, 9H).
Compound 4b : 1 H NMR (600 MHz, CDCl 3 ) δ 6.90-6.93 (m, 2H), 6.84-6.87 (m, 2H), 3.87-4.01 (m, 4H), 3.77 (s, 3H), 3.10-3.18 (m, 4H), 2.96-3.06 (m, 2H), 2.53-2.61 (m, 1H), 2.30-2.37 (m, 1H), 2.00-2.13 (m, 1H), 1.28-1.42 (m, 2H), 0.96 (s, 9H).
Compound 4c : 1 H NMR (600 MHz, CDCl 3 ) δ 7.01-7.06 (m, 1H), 6.87-6.94 (m, 3H), 3.91-4.02 (m, 4H), 3.89 (s, 3H), 3.09-3.17 (m, 4H), 2.96-3.06 (m, 2H), 2.53-2.61 (m, 1H), 2.31-2.38 (m, 1H), 2.06-2.13 (m, 1H), 1.27-1.42 (m, 2H), 0.96 (s, 9H).
Compound 4d : 1 H NMR (300 MHz, CDCl 3 ) δ 7.52 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.6 Hz, 2H), 3.92 (m, 4H), 3.37 (s, 4H), 3.03 (m, 2H), 2.56 (m, 1H), 2.35 (m, 1H), 2.13 (m, 1H), 1.34 (m, 2H), 0.96 (s, 9H).
Compound 4e : 1 H NMR (300 MHz, CDCl 3 ) δ 6.94 (m, 4H), 3.93 (m, 4H), 3.17 (s, 4H), 3.02 (m, 2H), 2.59 (m, 1H), 2.35 (m, 1H), 2.11 (m, 1H), 1.37 (m, 2H), 0.97 (s, 9H).
Compound 4f : 1 H NMR (600 MHz, CDCl 3 ) δ 6.80-6.84 (m, 2H), 6.73-6.76 (m, 2H), 3.82-3.92 (m, 4H), 3.07 (s, 4H), 2.68-2.77 (m, 4H), 2.17 (s, 1H), 1.69-1.82 (m, 4H).
Compound 4g : 1 H NMR (300 MHz, CDCl 3 ) δ 6.81-6.95 (m, 4H), 3.92 (s, 4H), 3.78 (s, 3H), 3.18 (s, 4H), 2.69-2.84 (m, 4H), 1.69-1.87 (m, 4H).
Compound 4h : 1 H-NMR (300 MHz, CDCl 3 )δ 7.00-7.09 (m, 1H), 6.86-6.95 (m, 3H), 3.86-4.02 (m, 4H), 3.89 (s, 3H), 3.13 (s, 4H), 2.71-2.83 (m, 4H), 1.69-1.88 (m, 4H).
Compound 4i : 1 H NMR (300 MHz, CDCl 3 ) δ 7.52 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 3.95 (m, 4H), 3.37 (m, 4H), 2.79 (m, 4H), 1.80 (m, 4H).
Compound 4j : 1 H NMR (300 MHz, CDCl 3 ) δ 6.99 (m, 2H), 6.90 (m, 2H), 3.93 (m, 4H), 3.17 (m, 4H), 1.06 (m, 4H), 1.79 (m, 4H).
Compound 5 : A mixture of 4f (20 mg, 0.061 mmol), EtI (19 mg, 0.122 mmol) and K 2 CO 3 (84 mg, 0.61 mmol) in DMF (1 mL) was stirred overnight at 80 °C. the solids were filtered off and the filtrate was evaporated to give a residue. The residue was purified by flash column chromatography on silica gel (EtOAc:hexanes = 1:3) to afford 16 mg of compound 5 (75%) as a yellowish solid. 1 H NMR (300 MHz, CDCl 3 ) δ 6.87 (m, 4H), 3.98 (m, 6H), 3.13 (s, 4H), 2.77 (m, 4H), 1.79 (m, 4H), 1.39 (t, J = 7.0 Hz, 3H).
Measurement of Melanin Content . Extracellular melanin release was measured as described previously. 10 Briefly, melanin biosynthesis inhibitory activity of synthesized compounds was evaluated for α-melanocyte-stimulating hormone (α-MSH) induced melanogenesis in mouse melanoma cell line B16F10. The melanoma cells were treated with compounds (1 µM, 10 µM) in the presence of α-MSH (1 µM) and incubated for 3 days. Absorbance was measured at 400 nm to quantify the melanin content in culture media and was normalized by the number of viable cells. The cells were then counted using a hemocytometer. Melanin production was expressed as the percentage of α-MSH-treated controls.
Acknowledgements
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Korean Government (2011-0007305), and partially by the Chung-Ang University Excellent Student Scholarship in 2013.
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