M. Di Yang, et al.
Biomedicine&Pharmacotherapy113(2019)108747
Table 1
7.52 (d, J = 8.5, 2 H), 7.18-7.13 (m, 2 H), 7.04 (s, 1 H), 6.04 (dd,
J = 6.7, 5.1, 1 H), 5.10 (t, J = 7.2, 1 H), 2.86-2.82 (m, 2 H), 2.71-2.67
(m, 2 H), 2.64-2.58 (m, 1 H), 2.53-2.45 (m, 1 H), 1.65 (s, 3 H), 1.55 (s,
3 H). 13C NMR (151 MHz, CDCl3) δ 177.27, 175.74, 172.03, 169.57,
168.26, 167.73, 147.39, 140.69, 136.33, 133.18, 132.94, 131.49,
126.22, 126.19, 124.89, 123.09, 119.13, 117.39, 111.76, 111.53,
70.19, 32.78, 32.06, 29.33, 25.72, 17.94.
Representative dihydroxy-naphthalene-1,4-dione derivatives through virtual
screening.
Compounds
PIK-39
-CDOCKER INTERACTION ENERGY (kcal/mol)
53.0399
59.9951
4c: (S)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-
methylpent-3-enyl 4-(4-bromobenzylamino)-4-oxobutanoate
Red solid. Yield: 69.4%. m.p.121.0 °C. 1H NMR (600 MHz, CDCl3)
δ = 12.58 (s, 1 H), 12.40 (s, 1 H), 7.39 (d, J = 8.3, 2 H), 7.17 (s, 2 H),
7.10 (d, J = 8.3, 2 H), 7.00 (s, 1 H), 6.01 (dd, J = 6.4, 5.0, 1 H), 5.91
(br, 1 H), 5.10 (t, J = 7.3, 1 H), 4.37 (t, J = 6.2, 2 H), 2.79 (t, J = 6.7,
2 H), 2.63-2.57 (m, 1 H), 2.52 (t, J = 6.7, 2 H), 2.47-2.44 (m, 1 H), 1.67
(s, 3 H), 1.56 (s, 3 H). 13C NMR (151 MHz, CDCl3) δ 177.66, 176.16,
171.88, 170.95, 167.90, 167.36, 147.71, 137.14, 136.21, 133.05,
132.82, 131.69, 131.50, 129.30, 121.32, 117.51, 111.77, 111.52,
69.94, 42.97, 32.79, 30.83, 29.46, 25.76, 17.95.
64.7394
61.0376
57.2896
4d: (S)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-
methylpent-3-enyl 4-(3-methoxybenzylamino)-4-oxobutanoate
Red solid. Yield: 57.3%. m.p.87.0 °C. 1H NMR (600 MHz, CDCl3)
δ = 12.57 (s, 1 H), 12.40 (s, 1 H), 7.20 (t, J = 7.8, 1 H), 7.17 (s, 2 H),
7.00 (s, 1 H), 6.81 (d, J = 7.5, 1 H), 6.79-6.74 (m, 2 H), 6.01 (dd,
J = 6.4, 5.2, 1 H), 5.86 (br, 1 H), 5.10 (t, J = 7.3, 1 H), 4.40 (d, J = 5.7,
2 H), 3.76 (s, 3 H), 2.81-2.77 (m, 2 H), 2.63-2.57 (m, 1 H), 2.52 (t,
J = 6.7, 2 H), 2.50-2.41 (m, 1 H), 1.67 (s, 3 H), 1.56 (s, 3 H). 13C NMR
(151 MHz, CDCl3) δ 177.90, 176.43, 171.85, 170.80, 167.64, 167.10,
159.83, 147.79, 139.60, 136.17, 132.93, 132.68, 131.57, 129.67,
119.83, 117.54, 113.09, 113.01, 111.80, 111.55, 69.88, 55.18, 43.62,
32.80, 30.87, 29.50, 25.75, 17.94.
54.1587
40.0391
Shikonin
then proposed in an effort to verify the biological activity [35].
2. Material and methods
4e: (S)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-
methylpent-3-enyl 4-(4-methoxybenzylamino)-4-oxobutanoate
Red solid. Yield: 42.1%. m.p.107.0 °C. 1H NMR (600 MHz, CDCl3)
δ = 12.57 (s, 1 H), 12.41 (s, 1 H), 7.17 (s, 3 H), 7.15 (s, 1 H), 7.01 (s,
1 H), 6.82 (d, J = 8.6, 2 H), 6.01 (dd, J = 6.3, 5.3, 1 H), 5.79 (br, 1 H),
5.10 (t, J = 7.3, 1 H), 4.35 (d, J = 5.6, 2 H), 3.77 (s, 3 H), 2.80-2.76 (m,
2 H), 2.63-2.57 (m, 1 H), 2.51-2.45 (m, 3 H), 1.67 (s, 3 H), 1.56 (s, 3 H).
13C NMR (151 MHz, CDCl3) δ 177.96, 176.48, 171.83, 170.67, 167.60,
167.07, 158.97, 147.83, 136.17, 132.92, 132.68, 131.60, 130.10,
129.07, 117.54, 114.02, 111.79, 111.54, 69.84, 55.24, 43.18, 32.80,
30.86, 29.52, 25.76, 17.95.
2.1. Chemistry
All chemical procedures were screened by Thin-Layer
Chromatography (TLC). Melting points recorded by XT4MP device
without correction (Taike Corporation, Beijing). Spectra of nuclear
magnetic resonance were detected through Brucker AM500. Reagents
were commercial available.
2.2. General procedure for the synthesis of title compounds 4a˜4k
A solution of carboxylic acid, dicyclohexylcarbodiimide and 4-di-
methylaminopyridine (DMAP) in dichloromethane (DCM) was stirred
in ice bath for 15 min. Then was added shikonin, the solution was
stirred in ice bath and stirred for 6 h slowly to room temperature. After
TLC shows the reaction was completed, the solution was concentrated
and cooled to 0 °C and filtered to removal all the dicyclohexylurea
(DCU), the filtrate was evaporated, the resulting product was purified
through prepared layer chromatography. Compound 4 is light red solid
4f: (S)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-
methylpent-3-enyl 4-(furan-2-ylmethylamino)-4-oxobutanoate
Red solid. Yield: 66.2%. m.p.115.0 °C. 1H NMR (600 MHz, CDCl3)
δ = 12.57 (s, 1 H), 12.42 (s, 1 H), 7.32 (s, 1 H), 7.19-7.15 (m, 2 H), 7.00
(s, 1 H), 6.28 (dd, J = 2.9, 1.9, 1 H), 6.20 (d, J = 2.6, 1 H), 6.03-5.98
(m, 1 H), 5.89 (s, 1 H), 5.10 (t, J = 7.2, 1 H), 4.42 (d, J = 5.5, 2 H),
2.81-2.73 (m, 2 H), 2.63-2.57 (m, 1 H), 2.51-2.44 (m, 3 H), 1.67 (s,
3 H), 1.56 (s, 3 H). 13C NMR (151 MHz, CDCl3) δ 178.02, 176.52,
171.77, 170.68, 167.56, 167.03, 151.03, 147.84, 142.17, 136.17,
132.91, 132.68, 131.61, 117.53, 111.79, 111.56, 110.42, 107.46,
69.85, 36.60, 32.79, 30.71, 29.41, 25.75, 17.94.
4a: (R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-
methylpent-3-enyl 4-(2-chloro-5-(trifluoromethyl)phenylamino)-4-ox-
obutanoate
4 g: (S)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-
methylpent-3-enyl 4-(isopropylamino)-4-oxobutanoate
Red solid. Yield: 75.2%. m.p.68.0 °C. 1H NMR (600 MHz, CDCl3)
δ = 12.57 (s, 1 H), 12.39 (s, 1 H), 8.74 (s, 1 H), 7.88 (s, 1 H), 7.44 (d,
J = 8.4, 1 H), 7.29-7.26 (m, 1 H), 7.18-7.13 (m, 2 H), 7.06 (d, J = 0.8,
1 H), 6.05 (dd, J = 6.7, 5.0, 1 H), 5.11 (t, J = 7.3, 1 H), 2.84 (t, J = 6.2,
2 H), 2.80-2.75 (m, 2 H), 2.66-2.60 (m, 1 H), 2.53-2.46 (m, 1 H), 1.66
(s, 3 H), 1.56 (s, 3 H). 13C NMR (151 MHz, CDCl3) δ 177.44, 175.98,
171.64, 169.57, 168.06, 167.53, 147.44, 136.26, 134.99, 133.09,
132.83, 131.57, 130.11, 129.36, 128.81, 124.33, 122.52, 121.03,
117.46, 111.79, 111.53, 70.20, 32.77, 29.14, 25.70, 25.58, 17.94.
4b: (R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-
methylpent-3-enyl 4-oxo-4-(4-(trifluoromethyl)phenylamino)butanoate
Red solid. Yield: 74.8%. m.p.125.0 °C. 1H NMR (600 MHz, CDCl3)
δ = 12.56 (s, 1 H), 12.40 (s, 1 H), 7.65 (br, 1 H), 7.59 (d, J = 8.3, 2 H),
Red solid. Yield: 67.4%. m.p.87.0 °C. 1H NMR (600 MHz, CDCl3)
δ = 12.57 (s, 1 H), 12.42 (s, 1 H), 7.19-7.14 (m, 2 H), 7.00 (s, 1 H), 6.01
(dd, J = 6.4, 5.1, 1 H), 5.39 (d, J = 6.7, 1 H), 5.10 (t, J = 7.3, 1 H),
4.09-4.01 (m, 1 H), 2.78-2.69 (m, 2 H), 2.61-2.56 (m, 1 H), 2.50-2.46
(m, 1 H), 2.43 (t, J = 6.9, 2 H), 1.67 (s, 3 H), 1.56 (s, 3 H), 1.11 (dd,
J = 13.8, 6.6, 6 H). 13C NMR (151 MHz, CDCl3) δ 178.05, 176.55,
171.88, 169.98, 167.53, 167.01, 147.91, 136.15, 132.90, 132.67,
131.58, 117.54, 111.79, 111.54, 69.77, 41.50, 32.80, 31.00, 29.55,
25.75, 22.72, 22.69, 17.94.
4h: (S)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-
methylpent-3-enyl 4-(tert-butylamino)-4-oxobutanoate
Red solid. Yield: 79.1%. m.p.76.8 °C. 1H NMR (600 MHz, CDCl3)
2