M. Güney et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
5
Table 1
d 182.70, 150.63, 142.01, 137.15, 136.22, 134.79, 134.34, 133.87,
133.64, 131.61, 120.61, 117.39. IR (KBr, cmꢀ1): 3436, 2220, 1632,
1591, 1553, 1402, 1341, 1305, 1212, 1092, 882. Anal. Calcd for
Human carbonic anhydrase isoenzymes (hCA I and hCA II) inhibition value of some
new benzotropone derivatives by an esterase bioassay with NPA as substrate
Compounds
IC50
hCA I
(l
M)
Ki (lM)
C12H7NO: C, 79.55; H, 3.89. Found: C, 79.57; H, 3.98.
hCA II
hCA I
hCA II
3.3. Oxidation of 5H-benzocycloheptene-7-carbonitrile (7) with
CrO3
7
4.52
5.77
5.96
7.07
5.25
5.13
4.38
4.07
3.82
3.64
3.22
3.74
4.06 0.61
2.88 0.86
3.93 0.81
4.01 0.62
3.66 0.61
3.62 0.95
3.23 0.23
3.06 0.15
3.91 0.74
2.68 0.38
3.31 0.72
2.51 0.34
11
12
13
14
15
The reaction was carried out according to the above-mentioned
procedure using 4.86 g (48.6 mmol) CrO3, 1.25 g (7.5 mmol) of 7
and pyridine/CH2Cl2 1:1 (36 ml). The product was purified by a
column on silica gel (30 g) with ethylacetate/n-hexane (5:95).
5-Oxo-5H-benzocycloheptene-7-carbonitrile (15) was obtained as a
sole product (500 mg, 37%). Yellowish crystals from CH2Cl2/n-hexane
(2:1), mp: 92–93 °C. 1H NMR (200 MHz, CDCl3): d 8.39 (m, 1H),
7,74 (m, 3H), 7.39 (d, A part of AB system, J8,9 = 12.0 Hz), 7.27 (m,
1H), 6.68 (dd, B part of AB system, J8,9 = 12.0, J6,8 = 1.6 Hz, 1H).
13C NMR (50 MHz, CDCl3): d 188.07, 144.27, 142.79, 141.06,
136.59, 136.39, 135.49, 134.05, 133.00, 126.41, 122.54, 120.56. IR
(KBr, cmꢀ1): 2919, 2217, 1726, 1639, 1586, 1450, 1333, 1195,
844, 772. Anal. Calcd for C12H7NO: C, 79.55; H, 3.89. Found: C,
79.42; H, 3.75.
1597, 1556, 1445, 1324, 1206, 1133, 1010, 902. Anal. Calcd for
C12H9N: C, 86.20; H, 5.43. Found: C, 86.10; H, 5.61.
3.2. Oxidation of 9H-benzocycloheptene-6-carbonitrile (11)
with CrO3
A solution of 2.06 g (20.6 mmol) CrO3 in pyridine/CH2Cl2 1:1
(48 ml) was cooled to 0 °C. Then 575 mg (3.44 mmol) 9H-benzocy-
cloheptene-6-carbonitrile (11) in CH2Cl2 (15 ml) was added drop-
wise. The mixture was stirred at 0 °C for 2 h and rt for 24 h, and
the solvent was evaporated. The residue was filtered over silica
gel (50 g) with ethylacetate/n-hexane (5:95 and 50:50). The firs
fraction was 9-oxo-9H-benzocycloheptene-6-carbonitrile (12)
(100 mg, 16%). White crystals from CH2Cl2/n-hexane (2:1), mp:
175–176 °C. 1H NMR (400 MHz, CDCl3): d 8.49–8.46 (m, 1H, Haryl),
7.85–7.73 (m, 4H, Haryl and H5), 7.05 (dd, A part of AB system,
J7,8 = 12.4 Hz, J5,7: 1.1 Hz, 1H, H7), 6.96 (d, B part of AB system,
J7,8 = 12.4 Hz, 1H, H8). 13C NMR (100 MHz, CDCl3): d 186.81,
148.43, 140.03, 137.33, 135.34, 133.83, 133.39, 133.19, 132.61,
131.60, 119.56, 111.94, 96.35. IR (KBr, cmꢀ1): 3436, 2215, 1639,
1616, 1584, 1549, 1450, 1402, 1332, 1246, 1195, 1092, 933. Anal.
Calcd for C12H7NO: C, 79.55; H, 3.89. Found: C, 79.78; H, 3.92. In
the second fraction, 5-oxo-5H-benzocycloheptene-6-carbonitrile
(13) and 9-oxo-9H-benzocycloheptene-6-carbonitrile (12) (in a
90:10 ratio) were obtained as a mixture (100 mg, 16%). Compound
13 was not isolated as pure state, although NMR signals were
chosen from the mixture. 1H NMR (400 MHz, CDCl3): d 8.58–8.55
(m, 1H), 7.84–7.59 (m, 5H), 6.81–6.75 (m, 1H). 13C NMR
3.4. Photooxygenation of 15
Tropone derivative 15 0.88 g (4.84 mmol) and tetraphenylpor-
phyrin (5 mg, 0.008 mmol) were dissolved in 40 mL of CCl4. The
solution was then irradiated with a projection lamp (500 W) while
a slow stream of dry oxygen was passed through the solution at rt.
After 20 h, the solvent was evaporated at 20 °C and the crude
product was crystallized from CH2Cl2/n-hexane (3:1) to give endo-
peroxide 16 (125 mg, 14%). Yellow crystals from CH2Cl2/n-hexane
(2:1), mp 130–131 °C. 1H NMR (200 MHz, CDCl3): d 8.15 (d, J =
7.2 Hz, 1H, Haryl), 7.84 (d, J = 7.3, A part of AX system), 7.65–7.58
(m, 2H), 7.36 (d, J = 7.2 Hz, 1H), 5.66 (d, J = 7.3 Hz, X part of AX
system), 5.34 (s, 1H). 13C NMR (50 MHz, CDCl3): d 189.70, 151.32,
137.60, 134.88, 131.55, 131.37, 131.13, 128.98, 114.01, 110.78,
84.85, 81.99. IR (KBr, cmꢀ1): 3409, 2938, 2248, 1769, 1465, 1359,
1295, 1267, 1213, 1141, 991, 939. Anal. Calcd for C12H7NO3: C,
67.61; H, 3.31. Found: C, 68.15; H, 3.39. Afterwards, the residue
chromographed on silica gel (30 g) using EtOAc/n-hexane (97:3).
Pure 8-oxo-12,13-dioxa-tricyclo[7.3.1.02,7]trideca-2,4,6,10-tetrae-
ne-10-carbonitrile (17) (125 mg, 14%) which was crystallized
from CH2Cl2/n-hexane (1:1) was obtained. White crystals mp
164–165 °C. 1H NMR (400 MHz, CDCl3): d 8.12 (d, J = 7.7, 1H),
7.74 (m, 1H), 7.62 (m, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.22 (s, 1H),
6.43 (s, 1H), 4.89 (s, 1H). 13C NMR (100 MHz, CDCl3): d 189.00,
154.35, 135.73, 135.56, 131.35, 127.13, 126.88, 126.11, 114.53,
(100 MHz, CDCl3):
d 183.56, 148.49, 145.70, 144.38, 135.38,
135.13, 133.87, 133.43, 132.78, 131.85, 124.70, 117.71. The third
fraction was 7-oxo-7H-benzocycloheptene-6-carbonitrile (14)
(120 mg, 19%). White crystals from CH2Cl2/n-hexane (2:1), mp:
213–214 °C. 1H NMR (400 MHz, CDCl3): d 8.11 (s, 1H), 7.81–7.69
(m, 4H), 7.52 (d, A part of AB system, J8,9 = 12.4 Hz, 1H), 6.89 (d,
B part of AB system, J8,9 = 12.4 Hz, 1H). 13C NMR (100 MHz, CDCl3):
O
H
C
N
N
Thr199
H
O
Zn+2
H
O
H
His119
His96
His94
Figure 2. The purposed interaction between new benzotropone derivative (15) and active site region in the hCA II.