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Synthesis, Biological Evaluation of SPF-32629A-Based 2- and 4-Pyridone Analogs as Chymase Inhibitors
Synthesis, Biological Evaluation of SPF-32629A-Based 2- and 4-Pyridone Analogs as Chymase Inhibitors
Bulletin of the Korean Chemical Society. 2014. Aug, 35(8): 2547-2550
Copyright © 2014, Korea Chemical Society
  • Received : March 24, 2014
  • Accepted : April 08, 2014
  • Published : August 20, 2014
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About the Authors
Xiang Fei
Yue Yuan
Young-Mi Lee
Department of Oriental Pharmacy, College of Pharmacy, Wonkwang University, Iksan 570-749, Korea
Kwang Won Jeong
Seung-Yong Seo

Abstract
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Experimental
General Procedures for Synthesis of 3a-e. To a solution of 6-methoxy-2-pyridinecarboxaldehyde (1.0 eq) in THF (0.05 M) was added dropwise ArMgBr (1.0 M in Et 2 O, 1.2 eq) at –78 °C. After stirring at –78 °C for 1 h, the reaction mixture was quenched by 1 N HCl and extracted with EtOAc. A combined organic layer was washed with brine, dried over MgSO 4 and concentrated in vacuo . The residue was purified by flash column chromatography (EtOAc/hexanes).
(6-Methoxypyridin-2-yl)(phenyl)methanol (3a): 1 HNMR (600 MHz, CDCl 3 ) δ 7.48 (m, 1H), 7.44 (d, 2H, J = 7.2 Hz), 7.35 (m, 2H), 7.29 (m, 1H), 6.73 (d, 1H, J = 7.2 Hz), 6.63 (d, 1H, J = 7.8 Hz), 5.72 (s, 1H), 5.09 (s, 1H), 3.98 (s, 3H); 13 C-NMR (150 MHz, CDCl 3 ) δ 163.2, 158.9, 143.2, 139.5, 128.5, 127.8, 127.0, 113.7, 109.2, 74.8, 53.4. LRMS (ESI + ) m/z 216.0 (M+H + ).
(4-Fluorophenyl)(6-methoxypyridin-2-yl)methanol (3b): Yield 73%. 1 H-NMR (600 MHz, CDCl 3 ) δ 7.42 (t, 1H, J = 7.8 Hz), 7.36-7.34 (m, 2H), 6.98-6.96 (m, 2H), 6.7 (d, 1H, J = 7.2 Hz), 6.58 (d, 1H, J =8.4 Hz), 5.64 (d, 1H, J = 4.8 Hz), 5.08 (d, 1H, J = 4.8 Hz), 4.00 (s, 3H); 13 C-NMR (150 MHz, CDCl 3 ) δ 163.2, 161.4, 158.9, 139.5, 139.1, 128.6, 115.2, 113.4, 109.2, 74.3, 53.3; LRMS (ESI + ) m/z 233.2 (M+H + ).
(4-Chlorophenyl)(6-methoxypyridin-2-yl)methanol (3c): Yield 80%. 1 H-NMR (600 MHz, CDCl 3 ) δ 7.45 (d, 1H, J = 4.8 Hz), 7.30 (d, 2H, J = 8.4 Hz), 7.06 (d, 2H, J =8.4 Hz), 6.67 (d, 1H, J = 7.2 Hz), 6.60 (s, 1H), 5.62 (s, 1H), 5.03 (s, 1H), 3.92 (s, 3H); 13 C-NMR (150 MHz, CDCl 3 ) δ 163.2, 158.4, 141.7, 139.6, 133.4, 128.5, 128.3, 116.7, 113.4, 119.4, 74.2, 60.5, 53.4, 21.0, 14.1; LRMS (ESI + ) m/z 250.0 (M+H + ).
(6-Methoxypyridin-2-yl)(p-tolyl)methanol (3d): Yield 80%. 1 H-NMR (600 MHz, CDCl 3 ) δ 7.48 (t, 1H, J = 7.8 Hz), 7.32 (d, 2H, J = 7.8 Hz), 7.17 (d, 2H, J = 7.8 Hz), 6.73 (d, 1H, J = 7.2 Hz), 6.63 (d, 1H, J =7.8 Hz), 5.68 (d, 1H, J = 3.6 Hz), 4.98 (d, 1H, J = 4.2 Hz), 4.00 (s, 3H), 2.35 (s, 3H); 13 CNMR (150 MHz, CDCl 3 ) δ 163.2, 159.2, 140.4, 139.5, 137.3, 129.2, 126.9, 113.6, 109.1, 74.7, 53.4, 21.1. LRMS (ESI + ) m/z 230.1 (M+H + ).
General Procedures for Synthesis of 4a-e. To a CHCl 3 solution of the 3 (1.0 eq) iodotrimethylsilane (3.0 eq) was added at 60 °C. After stirring for 1 h, the reaction mixture was quenched with aq NaHSO 3 , and extracted with CH 2 Cl 2 . The organic phase was washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by column chromatography (CH 2 Cl 2 /MeOH).
6-(Hydroxy(phenyl)methyl)pyridin-2(1H)-one (4a): Yield 76%. 1 H-NMR (600 MHz, CD 3 OD) δ 7.52 (dd, 1H, J = 7.2 9.0 Hz), 7.41-7.40 (m, 2H), 7.36-7.33 (m, 2H), 7.30-7.29 (m, 1H), 6.39 (dd, 1H, J = 9.0, 0.6 Hz), 6.32 (d, 1H, J = 7.2 Hz), 5.62 (s, 1H); 13 C-NMR (150 MHz, CD 3 OD) δ 164.5, 151.0, 142.2, 141.2, 128.2, 127.9, 126.4, 117.3, 104.3, 71.7; LRMS (ESI + ) m/z 202.1 (M+H + ).
6-((4-Fluorophenyl)(hydroxy)methyl)pyridin-2(1H)-one (4b): Yield 74%. 1 H-NMR (600 MHz, CD 3 OD) δ 7.50 (dd, 1H, J = 9.0, 7.2 Hz), 7.44-7.41 (m, 2H), 7.05 (t, 2H, J = 8.7 Hz), 6.41 (d, 1H, J = 9.0 Hz), 6.32 (d, 1H, J = 7.2 Hz), 5.68 (s, 1H); 13 C-NMR (150 MHz, CD 3 OD) δ 164.4, 150.9, 142.3, 137.3, 128.6, 128.5, 117.4, 104.6, 71.0. LRMS (ESI + ) m/z 220.1 (M+H + ).
6-((4-Chlorophenyl)(hydroxy)methyl)pyridin-2(1H)-one (4c): Yield 70%. 1 H-NMR (600 MHz, CD 3 OD) δ 7.52 (dd, 1H, J = 7.2, 9.0 Hz), 7.41-7.39 (m, 2H), 7.36-7.34 (m, 2H), 6.40 (d, 1H, J = 9.0 Hz), 6.33 (d, 1H, J = 7.2 Hz), 5.62 (s, 1H); 13 C-NMR (150 MHz, CD 3 OD) δ 164.5, 150.6, 142.2, 140.0, 133.6, 128.3, 128.0, 117.5, 104.4, 70.9; LRMS (ESI + ) m/z 216.2 (M+H + ).
6-(Hydroxy(p-tolyl)methyl)pyridin-2(1H)-one (4d): Yield 77%. 1 H-NMR (600 MHz, CD 3 OD) δ 7.52 (t, 1H, J = 7.2, 9.0 Hz), 7.27 (d, 2H, J = 7.8 Hz), 7.17 (d, 2H, J = 7.8 Hz), 6.38 (d, 1H, J = 9.0 Hz), 6.31 (d, 1H, J = 7.2 Hz), 5.58 (s, 1H), 2.31 (s, 3H); 13 C-NMR (150 MHz, CD 3 OD) δ 164.4, 151.1, 142.2, 138.2, 137.8, 128.8, 126.4, 117.1, 104.2, 71.5, 19.75. LRMS (ESI + ) m/z 216.2 (M+H + ).
General Procedures for Synthesis of 5a-e and 6a-e . To a solution of the 2-pyridone 4 (1.0 eq) in CH2Cl2 was added EDCI (1.2 eq), DMAP (0.3 eq) and isovaleric acid (1.2 eq) at 0 °C. After stirring at ambient temperature for 1 h, the reaction mixture was washed with saturated aq. NaHCO 3 and extracted with EtOAc. A combined organic layer was washed with brine, dried over MgSO 4 and concentrated in vacuo . The residue was purified by column chromatography (CH 2 Cl 2/ MeOH) to afford the monoester 5 and diester 6.
(6-Oxo-1,6-dihydropyridin-2-yl)(phenyl)methyl isovaleroate (5a) : 1 H-NMR (600 MHz, CDCl 3 ) δ 11.85 (br s, 1H), 7.43-7.45 (m, 2H), 7.31-7.37 (m, 4H), 6.64 (s, 1H), 6.45 (dd, 1H, J = 0.6, 9 Hz), 6.09 (dt, 1H, J = 1.2, 6 Hz), 2.33 (d, 2H, J = 7.2 Hz), 2.13 (m, 1H), 0.91 (d, 6H, 6.6 Hz); 13 CNMR (150 MHz, CDCl 3 ) δ 171.6, 164.4, 146.4, 140.9, 136.7, 128.9, 128.8, 127.2, 119.8, 104.4, 73.1, 43.2, 25.6, 22.4, 22.3; LRMS (ESI + ) m/z 286.0 (M+H + ).
(4-Fluorophenyl)(6-oxo-1,6-dihydropyridin-2-yl)methyl isovaleroate (5b): Yield 22%. 1 H-NMR (600 MHz, CDCl 3 ) δ 12.96 (s, 1H), 7.47-7.45 (m, 2H), 7.35 (dd, 1H, J = 7.2, 9 Hz), 7.01 (t, 2H, J = 8.4 Hz), 6.62 (s, 1H), 6.11 (d, 2H, J = 6.6 Hz), 6.44 (d, 1H, J = 8.4 Hz), 6.11 (d, 1H, J = 6.6 Hz), 2.32 (dd, 2H, J = 1.8, 7.8 Hz), 2.13-2.09 (m, 1H), 0.89 (d, 1H, J = 6.6); 13 C-NMR (150 MHz, CDCl 3 ) 171.6, 165.0, 163.6, 162.0, 146.9, 141.0, 132.9, 132.9, 129.4, 129.4, 119.6, 115.8, 115.6, 104.0, 77.3, 77.1, 76.9, 72.6, 43.2, 25.6, 22.4, 22.4; LRMS (ESI + ) m/z 304.1 (M+H + ).
(6-Oxo-1,6-dihydropyridin-2-yl)(p-tolyl)methyl isovaleroate (5d): 1 H-NMR (600 MHz, CDCl 3 ) δ 11.52 (br s, 1H), 7.30-7.34 (m, 3H), 7.16 (d, 2H, J = 7.8 Hz), 6.61 (s, 1H), 6.43 (d, 1H, 9 Hz), 6.08 (d, 1H, J = 7.2 Hz), 2.31 (dd, 5H, J = 1.2, 1.8 Hz), 2.09-2.16 (m, 1H), 0.91 (d, 6H, J = 6.6 Hz); 13 C-NMR (150 MHz, CDCl 3 ) δ 171.6, 164.4, 146.4, 140.9, 138.8, 133.6, 129.5, 127.2, 119.8, 104.2, 73.0, 43.2, 30.3, 25.6, 22.4, 22.3, 21.2; LRMS (ESI + ) m/z 300.1 (M+H + ).
6-((4-Fluorophenyl)(isovaleryloxy)methyl)pyridin-2-yl isovaleroate (6b): Yield 17%. 1 H-NMR (600 MHz, CDCl 3 ) δ 7.75 (t, 1H, J = 7.8 Hz), 7.38-7.36 (m, 2H), 7.31 (d, 1H J = 7.8), 7.0-6.97 (m, 3H), 5.44 (d, 2H, J = 7.2 Hz), 2.31 (d, 2H, J = 7.2 Hz), 2.25-2.18 (m, 1H), 2.17-2.10 (m, 1H), 1.03 (d, 6H, J = 7.2 Hz), 0.93 (d, 6H, J = 7.2 Hz); LRMS (ESI + ) m/z 388.1 (M+H + ).
General Procedures for Synthesis of 9a-d. To a THF solution of 4-(benzyloxy)picolinonitrile 8 (1.0 eq) was added ArMgBr (1.0 M in Et2O, 1.0 eq) at –78 °C. After stirring for 1 h, the reaction mixture was quenched with 6 N HCl, and stirred for 12 h. The organic phase was washed with brine, dried over MgSO 4 and concentrated i n vacuo. The residue was purified by column chromatography (EtOAc/hexanes) to afford the ketone 9 .
(4-(Benzyloxy)pyridin-2-yl)(phenyl)methanone (9a): Yield 80%. 1 H-NMR (600 MHz, CDCl 3 ) δ 8.53 (d, 1H, J = 5.4Hz), 8.07 (dd, 2H J = 1.2, 8.4 Hz), 7.65 (d, 1H, J = 2.4 Hz), 7.59-7.56 (m, 1H), 7.49-7.45 (m, 2H), 7.45-7.40 (m, 4H), 7.34-7.35 (m, 1H), 7.05 (dd, 1H, J = 2.4, 6.0 Hz), 5.17 (s, 2H); 13 C-NMR (150 MHz, CDCl 3 ) δ 193.7, 165.6, 156.8, 149.9, 136.3, 135.3, 132.9, 131.0, 128.8, 128.5, 128.1, 127.6, 113.3, 110.8, 70.2; LRMS (ESI + ) m/z 290.1 (M+H + ).
General Procedures for Synthesis of 10a-d. To a solution of 9 in MeOH was added NaBH 4 (1.0 eq) at –78 °C. After stirring for 30 min, the reaction mixture was quenched with MeOH and concentrated in vacuo . The residue was purified by column chromatography (EtOAc/hexanes) to afford 10 .
2-(Hydroxyphenylmethyl)-4(1H)-pyridone (10a): Yield 71%. 1 H-NMR (600 MHz, CD 3 OD) δ 7.74 (d, 1H J = 9.0 Hz), 7.45 (t, 2H, J = 1.2, 9.0 Hz), 7.39 (t, 2H, J = 9.6 Hz), 7.35-7.31 (m, 1H), 6.42-6.38 (m, 2H), 5.70 (s, 1H); 13 CNMR (125 MHz, CD 3 OD) δ 180.3, 155.0, 141.3, 138.2, 128.4, 128.0, 126.4, 115.4, 113.4, 72.0; LRMS (ESI + ) m/z 202.1 (M+H + ).
General Procedures for Synthesis of 11a-d. A solution of the alcohol 10 in MeOH was treated with 10% Pd/C and hydrogenated for 1 h. The reaction mixture was filtered through Celite ® and the solvent was removed in vacuo . The residue was purified by flash column chromatography (CH 2 Cl 2 /MeOH) to afford the 4-pyridone 11.
(4-(Benzyloxy)pyridin-2-yl)(phenyl)methanone (11a): Yield 80%. 1 H-NMR (600 MHz, CDCl 3 ) δ 8.53 (d, 1H, J = 5.4 Hz), 8.08 (dd, 2H, J = 1.2, 8.4 Hz), 7.65 (d, 1H, J = 2.4 Hz), 7.59-7.56 (m, 1H), 7.49-7.45 (m, 2H), 7.45-7.40 (m, 4H), 7.34-7.35 (m, 1H), 7.05 (dd, 1H, J = 2.4, 6.0 Hz), 5.18 (s, 2H); 13 C-NMR (150 MHz, CDCl 3 ) δ 193.7, 165.6, 156.8, 149.9, 136.3, 135.3, 132.9, 131.0, 128.8, 128.5, 128.1, 127.6, 113.3, 110.8, 70.2; LRMS (ESI + ) m/z 290.1 (M+H + ).
2-((4-Fluorophenyl)(hydroxy)methyl)pyridin-4(1H)-one (11b): Yield 95%. 1 H-NMR (600 MHz, CD 3 OD) δ 7.74 (d, 1H, J = 8.4 Hz), 7.49-7.46 (m, 2H), 7.14-7.11 (m, 2H), 6.40 (t, 2H, J = 3.0, 8.4 Hz), 5.71 (s, 1H); 13 C-NMR (150 MHz, CD 3 OD) δ 163.6, 161.7, 137.4, 128.4, 115.4, 113.4, 71.2; LRMS (ESI + ) m/z 220.0 (M+H + ).
2-(Hydroxy(p-tolyl)methyl)pyridin-4(1H)-one (11d): Yield 93%. 1 H-NMR (600 MHz, CD 3 OD) δ 7.73 (d, 1H, J = 9.0 Hz), 7.32 (d, 2H, J = 9.6 Hz), 7.21 (d, 1H, J = 9.6 Hz), 6.39 (t, 2H, J = 7.2, 3 Hz), 5.65 (s, 1H), 2.34 (s, 3H); 13 CNMR (150 MHz, CD 3 OD) δ 138.3, 138.0, 128.9, 126.4, 115.3, 113.3, 71.8, 19.8; LRMS (ESI + ) m/z 216.1 (M+H + ).
General Procedures for Synthesis of 12a-e and 13a-e. To a solution of 11 in CH 2 Cl 2 was added EDCI (1.1 eq), DMAP (0.5 eq) and isovaleric acid (1.0 eq) at 0 °C. The reaction mixture was stirred at ambient temperature for 1 h. After the completion of the reaction, saturated aq. NaHCO 3 was added for quenching. The mixture was extracted with EtOAc. A combined organic layer was washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by column chromatography (CH 2 Cl 2 /MeOH) to afford 12 and 13 .
(4-Oxo-1,4-dihydropyridin-2-yl)(phenyl)methyl isovaleroate (12a): Yield 70%. 1 H-NMR (600 MHz, CDCl 3 ) δ 7.55 (d, 1H, J = 7.8 Hz), 7.54-7.36 (m, 2H), 7.31-7.29 (m, 3H), 6.71 (s, 1H), 6.60 (s, 1H), 6.37 (dd, 1H, J = 2.4, 8.4 Hz), 5.31 (s, 1H), 3.47 (s, 1H), 2.28 (d, 2H, J = 8.4 Hz), 0.90 (dd, 6H, J = 3.6, 7.8 Hz); 13 C-NMR (150 MHz, CDCl 3 ) δ 177.5, 171.7, 152.5, 140.4, 137.1, 128.9, 128.8, 127.4, 115.39, 113.8, 73.9, 53.4, 50.5, 43.1, 29.7, 25.6, 22.3; LRMS (ESI + ) m/z 286.1 (M+H + ).
(4-Fluorophenyl)(4-oxo-1,4-dihydropyridin-2-yl)methyl isovaleroate (12b): Yield 28%. 1 H-NMR (600 MHz, CDCl 3 ) δ 7.61 (d, 1H, J = 7.8 Hz), 7.37 (dd, 2H, J = 6.6, 10.2 Hz), 6.98 (t, 2H, J = 10.2 Hz), 6.72 (s, 1H), 6.61 (d, 1H, J = 3 Hz), 6.41-6.40 (m, 1H), 5.29 (s, 1H), 2.27 (d, 2H, J = 9 Hz), 0.97 (d, 1H, J = 7.8), 0.89 (dd, 6H, J = 3.6, 8.4 Hz); 13 CNMR (125 MHz, CDCl 3 ) δ 177.8, 177.1, 171..5, 163.8, 161.8, 152.5, 140.4, 133, 132.9, 129.4, 129.3, 115.9, 115.7, 115.4, 113.5, 72.9, 53.4, 44.2, 43.1, 25.7, 25.6, 22.5, 22.3; LRMS (ESI + ) m/z 301.2 (M+H + ).
(4-Oxo-1,4-dihydropyridin-2-yl)(p-tolyl)methyl isovaleroate (12d): Yield 21%. 1 H-NMR (600 MHz, CDCl 3 ) δ 7.56 (d, 1H, J = 8.4 Hz), 7.28 (d, 1H, J = 12 Hz), 7.11 (d, 1H, J = 9.6 Hz), 6.69 (s, 1H), 6.61 (d, 1H, J = 3 Hz), 6.39 (dd, 1H, J = 3, 8.4 Hz), 5.31 (s, 1H), 2.31 (s, 3H), 2.27 (d, 2H, J = 8.4 Hz), 0.99 (d, 1H, J = 7.8 Hz), 0.90 (dd, 6H, J = 3, 8.4 Hz); 13 C-NMR (125 MHz, CDCl 3 ) δ 177.9, 171.6, 152.5, 140.1, 138.8 134.0, 129.5, 127.4, 115.4, 113.7, 73.6, 43.1, 25.7, 25.6, 22.5, 22.4, 22.3, 21.1; LRMS (ESI + ) m/z 300.2 (M+H + ).
2-((4-Fluorophenyl)(isovaleryloxy)methyl)pyridin-4-yl isovaleroate (13b): 1 H-NMR (600 MHz, CDCl 3 ) δ 8.60 (d, 1H, J = 6.6 Hz), 7.42 (dd, 2H, J = 6.6, 10.2 Hz), 7.28 (d, 1H, J = 2.4 Hz), 7.07-7.01 (m, 3H), 6.90 (s, 1H), 2.47 (d, 1H, J = 8.4 Hz), 2.47 (d, 1H, J = 8.4 Hz), 2.36 (d, 2H, J = 8.4 Hz), 1.07 (d, 6H, J = 7.8 Hz), 1.00 (d, 4H, J = 7.8 Hz), 0.96 (d, 6H, J = 7.8 Hz); LRMS (ESI + ) m/z 388.1 (M+H + ).
2-((Isovaleryloxy)(p-tolyl)methyl)pyridin-4-yl isovaleroate (13d): Yield 90%. 1 H-NMR (600 MHz, CDCl 3 ) δ 8.56 (d, 1H, J = 6.6 Hz), 7.35 (d, 2H, J = 9.6 Hz), 7.28 (d, 1H, J = 3 Hz), 7.17 (d, 2H, J = 9.6 Hz), 7.04 (dd, 1H, J = 2.4, 6.6 Hz), 6.91 (s, 1H), 2.48 (d, 2H, J = 8.4 Hz), 2.36 (t, 2H, J = 8.4, 14.4 Hz), 1.09 (d, 6H, J = 7.8 Hz), 0.98 (dd, 6H, J = 1.2, 7.8 Hz); LRMS (ESI + ) m/z 384.2 (M+H + ).
Chymase Inhibition Assay. Chymase assay was performed with Chymase Activity Assay kit (Sigma-Aldrich) according to the manufacturer’s protocol. Briefly, test compounds dissolved in DMSO were incubated with 0.3 mg of chymase (Cat. Number C8118) in assay buffer (Cat. number A9606). The reaction was initiated by addition of substrate A (Nsuccinyl- Ala-Ala-Pro-Phe p-nitroanilide, Cat. Number S0448), and enzymatic activity was monitored by measuring absorbance at 405 nm for 20 min using Victor X3 (Perkin- Elmer) microplate reader. Percent inhibition and IC 50 of each sample were calculated by Prism (GraphPad). Chymostatin was used as positive control.
α-Chymotrypsin Inhibition Assay. α-Chymotrypsin assay was performed in 38 mM Tris–HCl buffer (pH 7.8) with 53 mM CaCl 2 . α-Chymotrypsin (2-5 units/mL prepared in buffer mentioned above) with various concentrations (1, 10, 100 μM) of test compounds prepared in DW was incubated at 30 °C or 10 min. The reaction was started by the addition of the substrate, p -NA. All the reactions were performed in triplicate in a final volume of 180 μL, by using a plate reader. The plate reader absorbance wavelength was settled at 405 nm. Aprotinin was used as positive control.
Supporting Information. The 1 H- and 13 C-NMR spectral data of synthesized analogs are available as Supporting Information.
Acknowledgements
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2010-0004496 and NRF-2013R1A1A2007151).
References
Maryanoff B. E. 2004 J. Med. Chem. 47 769 - 787    DOI : 10.1021/jm030493t
Hollenberg N. K. , Fisher N. D. , Price D. A. 1998 Hypertension 32 387 - 392    DOI : 10.1161/01.HYP.32.3.387
Caughey G. H. 2007 Immunological Rev. 217 141 - 154    DOI : 10.1111/j.1600-065X.2007.00509.x
Taylor S. J. , Padyana A. K. , Abeywardane A. , Liang S. , Hao M.-H. , Lombaert S. D. , Proudfoot J. , Farmer B. S. , Li X. , Collins B. , Martin L. , Albaugh D. R. , Hill-Drzewi M. , Pullen S. S. , Takahashi H. 2013 J. Med. Chem. 56 4465 - 4481    DOI : 10.1021/jm400138z
Shimatani T. , Hosotani N. , Ohnishi M. , Kumagai K. , Saji I. 2006 J. Antibiot. 59 29 - 34