Journal of Medicinal Chemistry
Article
(d, J = 8.4 Hz, 2H, H-3′, H-5′), 3.860 (s, 3H, OCH3-4′). ESI-MS m/z:
253.0 (M − 1)−; calcd for C16H14O3, 254.28.
H-α), 7.244−7.287 (m, 1H, H-6′), 6.544 (dd, J = 2.4 Hz, 8.4 Hz, 1H,
H-5), 6.483 (d, J = 1.8 Hz, 1H, H-3), 3.913 (s, 3H, OCH3-2), 3.865
(s, 3H, OCH3-4). ESI-MS m/z: 305.3 (M + 1)+; calcd for C17H14F2O3,
304.29.
(E)-2,4,4′,6-Tetramethoxychalcone (28). Yellow powder crystal,
45.3% yield, mp 142.5−144.6 °C. 1H NMR (CDCl3), δ: 8.232 (d, J =
15.6 Hz, 1H, H-β), 8.024 (d, J = 7.8 Hz, 2H, H-2′, H-6′), 7.885 (d, J =
9.6 Hz, 1H, H-α), 6.961 (d, J = 8.4 Hz, 2H, H-3′, H-5′), 6.141 (s, 2H,
H-3, H-5), 3.905 (s, 6H, OCH3-2, OCH3-6), 3.876 (s, 3H, OCH3-4′),
3.856 (s, 3H, OCH3-4). ESI-MS m/z: 329.0 (M + 1)+; calcd for
C19H20O5, 328.36.
(E)-2,3′,4,4′,5′-Pentamethoxychalcone (41). Yellow powder,
1
90.0% yield, mp 125.7−127.7 °C. H NMR (CDCl3), δ: 8.047 (d,
J = 15.6 Hz, 1H, H-β), 7.578 (d, J = 8.4 Hz, 1H, H-6), 7.475 (d, J =
16.2 Hz, 1H, H-α), 7.263 (s, 2H, H-2′, H-6′), 6.549 (dd, J = 1.8 Hz, 8.4
Hz, 1H, H-5), 6.487 (d, J = 2.4 Hz, 1H, H-3), 3.947 (s, 6H, OCH3-
3′,OCH3-5′), 3.933 (s, 3H, OCH3-2), 3.905 (s, 3H, OCH3-4′), 3.865
(s, 3H, OCH3-4). ESI-MS m/z: 359.0 (M + 1)+; calcd for C20H22O6,
358.39.
(E)-2,3-Dimethoxy-4′-methoxychalcone (30). White powder crys-
tal, 82.6% yield, mp 99.0−99.5 °C. 1H NMR (CDCl3), δ: 8.077 (d, J =
15.6 Hz, 1H, H-β), 8.040 (d, J = 8.4 Hz, 2H, H-2′, H-6′), 7.612 (d, J =
16.2 Hz,1H, H-α), 7.276 (d, J = 7.2 Hz, 1H, H-6), 7.094 (t, 1H, H-5),
6.982 (d, J = 8.4 Hz 2H, H-3′, H-5′), 6.964 (d,J = 7.2 Hz, 1H, H-4),
3.894 (s, 3H, OCH3-4′), 3.891 (s, 3H, OCH3-2), 3.886 (s, 3H, OCH3-
3). ESI-MS m/z: 299.2 (M + 1)+; calcd for C18H18O4, 298.33.
(E)-2-Trifluoromethyl-4′-aminochalcone (31). Light yellow pow-
(E)-2,4-Dichloro-3′,4′-dimethoxychalcone (42). White powder,
1
87.0% yield, mp 132.2−135.1 °C. H NMR (CDCl3), δ: 8.079 (d,
J = 15.6 Hz, 1H, H-β), 7.679 (d, J = 8.4 Hz, 1H, H-6′), 7.660 (d, J =
8.4 Hz, 1H, H-6), 7.613 (d, J = 0.6 Hz, 1H, H-3), 7.479 (d, J = 15.0 Hz,
1H, H-α), 7.471 (s, 1H, H-2′), 7.302 (dd, J = 1.2 Hz, 8.4 Hz, 1H, H-5)
6.932 (d, J = 8.4 Hz, 1H, H-5′), 3.943 (s, 6H, OCH3-3′, OCH3-4′).
ESI-MS m/z: 337.1, 339.1 (M + 1)+; calcd for C17H23Cl2O, 337.2.
(E)-4-Dimethylamino-3′,4′-dimethoxychalcone (44). Orange yel-
1
der, 70.8% yield, mp 50.6−50.8 °C. H NMR (CDCl3), δ: 8.105 (d,
J = 15.6 Hz, 1H, H-β), 8.024 (d, J = 8.4 Hz, 2H, H-2′, H-6′), 7.817 (d,
J = 7.8 Hz, 1H, H-3), 7.722 (d, J = 7.8 Hz, 1H, H-6), 7.597 (t, 1H, H-
5), 7.498 (t, 1H, H-4), 7.422 (d, J = 15.6 Hz, 1H, H-α), 6.984 (d, J = 9
Hz, 2H, H-3′, H-5′), 3.891 (s, 3H, OCH3-4′). ESI-MS m/z: 307.5
(M + 1)+; calcd for C17H13F3O2, 306.28.
1
low powder, 71.8% yield, mp 109.8−113.0 °C. H NMR (CDCl3), δ:
7.793 (d, J = 15.6 Hz, 1H, H-β), 7.672 (dd, J = 1.8 Hz, 8.4 Hz, 1H, H-
6′), 7.623 (d, J = 1.8 Hz, 1H, H-2′), 7.561 (d, J = 9.0 Hz, 2H, H-2, H-
6), 7.369 (d, J = 15.6 Hz, 1H, H-α), 6.924 (d, J = 8.4 Hz, 1H, H-5′),
6.733 (d, J = 7.2 Hz, 2H, H-3, H-5), 3.972 (s, 3H, OCH3-3′), 3.962
(s, 3H, OCH3-4′), 3.047 (s, 3H, N(CH3)2-4). ESI-MS m/z: 312.8
(M + 1)+; calcd for C19H21O3, 311.37.
(E)-2-Bromo-4′-methoxychalcone (32). White powder, 99.0%
1
yield, mp 42.9−43.8 °C. H NMR (CDCl3), δ: 8.109 (d, J = 15.6
Hz, 1H, H-β), 8.039 (d, J = 9.0 Hz, 2H, H-2′, H-6′), 7.729 (d, J = 7.8
Hz, 1H, H-6), 7.639 (d, J = 7.8 Hz, 1H, H-3), 7.437 (d, J = 15.6 Hz,
1H, H-α), 7.361 (t, 1H, H-5), 7.246 (t, 1H, H-4), 6.991 (d, J = 9 Hz,
2H, H-3′, H-5′), 3.898 (s, 3H, OCH3-4′). ESI-MS m/z: 319.7 (M +
1)+; calcd for C16H13BrO2, 317.18.
(E)-4-Methoxy-3′,4′-dimethoxychalcone (46). White powder,
1
81.1% yield, mp 83.3−85.2 °C. H NMR (CDCl3), δ: 7.778 (d, J =
15.6 Hz, 1H, H-β), 7.677 (dd, J = 1.2, 8.4 Hz, 1H, H-6′), 7.623 (d, J =
1.8 Hz, 1H, H-2′), 7.608 (d, J = 8.4 Hz, 2H, H-3, H-6), 7.446 (d, J =
15.0 Hz, 1H, H-α), 6.940 (d, J = 8.4 Hz, 2H, H-3, H-5), 6.929 (d, J =
7.8 Hz, 1H, H-5′), 3.971 (s, 6H, OCH3-3′, OCH3-4′), 3.858 (s, 3H,
OCH3-3). ESI-MS m/z: 299.5 (M + 1)+; calcd for C18H18O4, 298.33.
(E)-2,3′,4,4′-Tetramethoxychalcone (47). Yellow powder, 74.1%
(E)-3,4-Dichloro-4′-methoxychalcone (33). Light yellow powder,
68.1% yield, mp 126.0−127.4 °C. 1H NMR (CDCl3), δ: 8.035 (dd, J =
1.8 Hz, 7.2 Hz, 2H, H-2′, H-6′), 7.721 (d, J = 1.8 Hz, 1H, H-2), 7.678
(d, J = 15.6 Hz, 1H, H-β), 7.519 (d, J = 15.6 Hz, 1H, H-α), 7.486
(d, J = 7.8 Hz, 1H, H-5), 7.448 (dd, J = 1.8, 8.4 Hz, 1H, H-6), 6.992
(dd, J = 1.8, 7.2 Hz, 2H, H-3′, H-5′), 3.899 (s, 3H, OCH3-4′). ESI-MS
m/z: 307.3/309.3 (M + 1)+; calcd for C16H12Cl2O2, 307.17.
(E)-3,4-Dichloro-4′-methoxychalcone (34). White powder, 83.4%
yield, mp 132.5−134.7 °C. 1H NMR (CDCl3), δ: 8.032 (d, J = 8.4 Hz,
2H, H-2′, H-6′), 7.694 (d, J = 15.6 Hz, 1H, H-β), 7.468 (d, J = 8.4 Hz,
1H, H-6), 7.456 (d, 1H, H-α), 7.354 (brs, 1H, H-2), 7.183−7.227 (m,
1H, H-5), 6.991 (d, J = 8.4 Hz, 2H, H-3′, H-5′), 3.899 (s, 3H, OCH3-
4). ESI-MS m/z: 275.9 (M + 1)+; calcd for C16H12F2O2, 274.26.
(E)-2,4-Dichloro-2′-hydroxychalcone (35). Light yellow powder,
39.8% yield, mp 162.2−164.4 °C. 1H NMR (CDCl3), δ: 12.002 (s, 1H,
OH-2′), 8.224 (d, J = 15 Hz, 1H, H-β), 7.889 (d, J = 7.8 Hz, 1H, H-6′),
7.703 (d, J = 8.4 Hz, 1H, H-6), 7.624 (d, J = 15.6 Hz, 1H, H- α), 7.521
(t, 3H, H-4′), 7.493 (s, 1H, H-3), 7.330 (d, J = 6 Hz, 1H, H-5), 7.037
(t, 1H, H-3′), 6.952 (t, 1H, H-5′). ESI-MS m/z: 291.2 (M − 1)−; calcd
for C15H10Cl2O2, 293.14.
1
yield, mp 111.3−112.6 °C. H NMR (CDCl3), δ: 8.040 (d, J = 15.6
Hz, 1H, H-β), 7.666 (dd, J = 1.8 Hz, 8.4 Hz, 1H, H-6′), 7.6235 (d, J =
1.8 Hz, 1H, H-2′), 7.575 (d, J = 8.4 Hz, 1H, H-6), 7.563 (d, J = 15.6
Hz, 1H, H-α), 6.928 (d, J = 8.4 Hz, 1H, H-6), 6.539 (dd, J = 2.4 Hz,
8.4 Hz, 1H, H-5), 6.482 (d, J = 2.4 Hz, 1H, H-3), 3.970 (s, 3H, OCH3-
4′), 3.962 (s, 3H, OCH3-3′), 3.905 (s, 3H, OCH3-2), 3.858 (s, 3H,
OCH3-4). ESI-MS m/z: 329.1 (M + 1)+; calcd for C19H20O5, 328.36.
(E)-2-Methoxy-3′,5′-difluorochalcone (54). Light yellow powder,
1
74.1% yield, mp 94.5−96.7 °C. H NMR (CDCl3), δ: 8.163 (d, J =
16.2 Hz, 1H, H-β), 7.655 (dd, J = 1.8 Hz, 7.8 Hz, 2H, H-2′, H-6′),
7.543 (dd, J = 1.8, 7.8 Hz, 1H, H-6), 7.544 (d, J = 16.2 Hz, 1H, H-α),
7.439 (dt, J = 1.8, 8.4 Hz, 1H, H-4′), 7.048−7.066 (m, 1H, H-4),
7.034−7.048 (m, 1H, H-5), 6.990 (d, J = 8.4 Hz, 1H, H-3), 3.964
(s, 3H, OCH3-2). ESI-MS m/z: 274.5 (M + 1)+; calcd for C16H12F2O2,
274.26.
(E)-2,4,6-Trimethoxy-2′-hydroxychalcone (37). Yellow powder,
4.2. Animals. Male ICR mice and C57BL/6 (B6) mice weighing
18−22 g were obtained from the Animal Center of Wenzhou Medical
College (Wenzhou, China). Animals were housed at a constant room
temperature with a 12/12 h light−dark cycle and fed with a standard
rodent diet and water. The animals were acclimatized to the laboratory
for at least 7 days before used in experiments. Protocols involving the
use of animals were approved by the Wenzhou Medical College
Animal Policy and Welfare Committee (approval documents: 2009/
APWC/0031).
4.3. Reagents and Cells. Chemical reagents and lipopolysac-
charide (LPS) were purchased from Sigma (St. Louis, MO). Saline was
prepared as 0.9% NaCl solution. Mouse RAW 264.7 macrophages
were obtained from the American Type Culture Collection (ATCC,
U.S.). RAW 264.7 macrophages were incubated in DMEM medium
(Gibco, Eggenstein, Germany) supplemented with 10% FBS
(Hyclone, Logan, UT), 100 U/mL penicillin, and 100 mg/mL
streptomycin at 37 °C with 5% CO2. For peritoneal macrophage
preparation, ICR mice were stimulated by intraperitoneal (ip)
injection of 3 mL of thioglycollate solution (0.3 g of beef extract, 1
g of tryptone, 0.5 g of sodium chloride, and 6 g of soluble starch were
1
8.3% yield, mp 128.3−130.2 °C. H NMR (CDCl3), δ: 13.272 (s,
1H, OH-2′), 8.391 (d, J = 15.6 Hz, 1H, H-β), 8.022 (d, J = 15.6 Hz,
1H, H-α), 7.905 (dd, J = 8.1 Hz, 1H, H-6′), 7.436−7.464 (m, 1H, H-
4′), 6.998(dd, J = 8.7 Hz, 1H, H- 3′), 6.899−6.926(m, 1H, H-5′),
6.148(s, 2H, H-3, H-5), 3.937 (s, 6H, OCH3-2, OCH3-6), 3.872
(s, 3H, OCH3-4). ESI-MS m/z: 315.4 (M + 1)+; calcd for C18H18O5,
314.33.
(E)-2,4-Dimethoxy-2′-hydroxychalcone (38). Yellow powder,
1
54.3% yield, mp 88.3−89.6 °C. H NMR (CDCl3), δ: 8.171 (d, J =
15.6 Hz, 1H, H-β), 7.917 (d, J = 8.4 Hz, 1H, H-6′), 7.702 (d, J = 15.6
Hz, 1H, H-α), 7.590 (d, J = 9.0 Hz, 1H, H-6), 7.482 (m, 1H, H-4′),
7.013 (d, J = 8.4 Hz, 1H, H-3′), 6.927 (t, 1H, H-5′), 6.552 (d, J = 9.0
Hz, 1H, H-5), 6.495 (s, 1H, H-3), 3.917 (s, 3H, OCH3-2), 3.873 (s,
3H, OCH3-4). ESI-MS m/z: 285.5 (M + 1)+; calcd for C17H16O4,
284.31.
(E)-2,4-Dimethoxy-3′,4′-difluorochalcone (39). Yellow powder,
1
83.2% yield, mp 128.8−129.9 °C. H NMR (CDCl3), δ: 8.054 (d,
J = 15.6 Hz, 1H, H-β), 7.827−7.862 (m, 1H, H-5′), 7.775−7.797 (m,
1H, H-2′), 7.562 (d, J = 8.4 Hz, 1H, H-6), 7.466 (d, J = 15.6 Hz, 1H,
8120
dx.doi.org/10.1021/jm200946h|J. Med. Chem. 2011, 54, 8110−8123