3824
H. W. Fang et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3822–3824
30 min, compound 3 was added slowly and the reaction mixture was stirred for
Table 4
2 h under À78 °C. The reaction was monitored by TLC. Water and ammonium
chloride solution was added to stop the reaction. After the reaction mixture
returned to room temperature, it was partitioned with EA, washed with brine
and dried over MgSO4. The crude product was purified with silica gel column
chromatography (n-hexane/EA = 6:1–4:1) to afford the desired compound.
Yield: 64%. Yellow powder. Mp 139.4–141.9 °C. 1H NMR (400 MHz, CDCl3) d
10.21 (s, 1H), 8.53 (d, J = 5.2 Hz, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.15 (d, J = 8.0 Hz,
1H), 7.62 (td, J = 8.0, 1.2 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.34 (td, J = 8.0, 1.2 Hz,
1H), 4.39 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3) d 197.0, 168.2, 141.3, 137.9, 135.6, 134.2, 132.0, 129.6, 121.9,
121.0, 120.4, 119.4, 112.0, 61.2, 44.9, 14.1. HR-ESI-MS: m/z calcd for C16H15N2O3
283.1083, found [M]+ 283.1084.
Effects of compounds 1, 3, 4, (5a+5b) on superoxide anion generation and elastase
release in FMLP/CB-induced human neutrophils
Compound
Superoxide anion
g/mL) Inhibition (%)
Elastase release
(lg/mL) Inhibition (%)
IC50
>10
(l
IC50
>10
1
3
4
29.50 2.72
93.92 6.25
10.48 3.94
49.53 0.92
8.20 2.60
70.75 3.48
3.06 1.15
26.99 3.71
4.87 0.59
>10
6.29 0.22
>10
5a+5b
>10
>10
6. (E,Z)-Ethyl 3-methoxy-3-(9H-pyrido[3,4-b]indol-1-yl)acrylate (5). To compound
4 (75 mg, 0.265 mmol) in DMF (10 mL), Cs2CO3 (129 mg, 0.397 mmol) and
methyl methanesulfonate (MeOMs, 0.044 ml, 0.397 mmol) were added under
inert atmosphere. The reaction mixture was stirred at ambient temperature for
6 h until starting material disappeared. After DMF was removed in vacuo, water
was added and EA was used for partitioning. The organic layer was washed with
brine and dried over MgSO4. The crude product underwent silica gel column
chromatography (n-hexane/EA = 4:1–3:1) to afford the desired compound.
compounds, compound 3 showed the best activity with inhibitory
IC50 values of 4.87 and 6.29 g/mL in the superoxide anion gener-
ation and elastase release assays, respectively.
In this study, cordatanine was totally synthesized in four steps
via a Pictet–Spengler reaction using tryptamine and methyl gly-
oxylate with a total yield of 8%. The NMR spectra of synthesized
cordatanine were compared with those of drymaritin isolated by
Hsieh et al. and the mistaken structural assignment was confirmed.
In addition, the synthetic intermediate, kumujian A, showed signif-
icant anti-inflammatory effects with IC50 values against superoxide
l
Yield: 51%. Yellow oil. 1H NMR (300 MHz, CDCl3)
d 9.22 (s, 1H), 8.44 (d,
J = 4.8 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 4.8 Hz, 1H), 7.52 (t, J = 7.8 Hz,
1H), 7.46 (d, J = 7.8 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 6.67 (s, 1H), 4.25 (q, J = 7.2 Hz,
2H), 4.13 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 166.0, 165.4,
140.2, 138.8, 133.8, 130.9, 128.9, 121.5, 120.7, 120.2, 116.0, 111.5, 101.5, 61.6,
59.9, 14.2. HR-ESI-MS: m/z calcd for C17H17N2O3 297.1239, found [M]+ 297.1240.
7. 4-Methoxy-6H-indole[3,2,1-ij][1,5]naphthyridin-6-one
(1).
Under
inert
anion generation and elastase release of 4.87 and 6.29
respectively.
lg/mL,
atmosphere, NaH (60%, 10.8 mg, 0.270 mmol) was washed with n-hexane and
then anhydrous THF (30 mL) was added. The mixture of compounds 5a+5b
(40 mg, 0.135 mmol) was added and stirring continued for 16 h. Water was
added to stop the reaction and THF was removed in vacuo. CHCl3 and EA were
used for partitioning. The organic layer was washed with brine and dried over
MgSO4. The crude product was purified by using Al2O3 column chromatography
(benzene/CHCl3 = 13:1–5:1) to afford cordatanine. Yield: 61%. Yellow powder.
1H NMR (500 MHz, CDCl3) d 8.86 (d, J = 5.0 Hz, 1H), 8.67 (d, J = 7.8 Hz, 1H), 8.13
(d, J = 7.8 Hz, 1H), 8.03 (d, J = 5.0 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.53 (t,
J = 7.8 Hz, 1H), 6.22 (s, 1H), 4.15 (s, 3H). 13C NMR (125 MHz, CDCl3) d 164.2,
161.0, 145.1, 139.4, 132.2, 132.1, 131.0, 130.7, 125.1, 124.5, 122.7, 117.0, 117.0,
References and notes
5. Ethyl 3-oxo-3-(9H-pyrido[3,4-b]indol-1-yl)propanoate (4). Under nitrogen,
ethyl acetate (EA) (0.223 mL, 2.095 mmol) in anhydrous THF (15 mL) was
cooled to À78 °C and NaHMDA (2.93 mL, 2.93 mmol) was added slowly. After
101.9, 56.9. HR-ESI-MS: m/z calcd for
C
15H11N2O2 251.0820, found [M]+
251.0821.