A.R. Genady / European Journal of Medicinal Chemistry 44 (2009) 409e416
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128.74 (Carom), 135.21 (CHarom), 167.11 (Carom), 180.02
(Carom); dB (33.083 MHz; d6-DMSO; SiMe4) ꢀ9.89 (1B),
ꢀ10.69 (2B), ꢀ11.17 (2B), ꢀ14.59 (1B), ꢀ22.71 (1B),
ꢀ32.96 (2B); (FABꢀ): m/z (%) ¼ 305 (87) [Mꢀ]; elemental
analysis calcd (%) for KC12H20B9N2O: C 41.81, H 5.85, N
8.13; Found: C 41.53, H 5.46, N 7.96.
CH3CO2H in 2:1 acetone/CHCl3) to yield colorless solid
substances.
Compound 12a. Yield: 78%, 0.35 g, Rf ¼ 0.24,
m.p. ¼ 263e264 ꢂC; IR nmax (KBr disc)/cmꢀ1: 2521s (BH),
1673s (C]O), 1619s (C]N), 1584m (C]C); dH
(100 MHz; d6-DMSO; SiMe4) ꢀ2.3 (br s, 2H, BH), 1.3 (br
s, 8H, BH), 1.8 (s, 3H, CH3), 3.35 (s, 2H, CH2), 7.29e7.58
(m, 6H, Harom), 7.71 (s, 1H, Harom), 8.56 (s, 1H, CH]N),
11.79 (br s, 1H, NH); dC (50 MHz; d6-DMSO; SiMe4) 14.83
(CH3), 30.72 (CH2), 58.21, 57.95 (Ccarborane), 105.15,
106.26, 109.95, 122.01, 126.97 (CHarom), 123.24, 141.27
(3Carom), 142.65 (CHarom), 147.12, 162.65 (2Carom), 168.11
(CH]N); dB (33.083 MHz; d6-DMSO; SiMe4) ꢀ9.91 (1B),
ꢀ10.57 (2B), ꢀ11.21 (2B), ꢀ14.65 (1B), ꢀ22.79 (1B),
ꢀ32.91 (2B); (FABꢀ): m/z (%) ¼ 408 (67) [Mꢀ]; elemental
analysis calcd (%) for KC19H25B9N3O: C 50.96, H 5.63, N
9.38; Found: C 50.64, H 5.14, N 9.02.
Compound 12b. Yield: 59%, 0.38 g, Rf ¼ 0.15,
m.p. ¼ 293e294 ꢂC; IR nmax (KBr disc)/cmꢀ1: 2525vs (BH),
1673s (C]O), 1619s (C]N), 1583m (C]C); dH
(100 MHz; d6-DMSO; SiMe4) ꢀ2.53 (br s, 2H, BH), 1.56
(br s, 8H, BH), 2.11 (s, 6H, 2CH3), 3.62 (s, 4H, 2CH2),
7.31e7.47 (m, 6H, Harom), 7.85 (s, 1H, Harom), 8.64 (s, 1H,
CH]N), 11.86 (br s, 1H, NH); dC (50 MHz; d6-DMSO;
SiMe4) 15.12 (2CH3), 31.65 (2CH2), 59.24, 58.89 (4Ccarborane),
105.16, 108.24, 109.34, 121.69, 123.47, 127.56 (6CHarom),
142.59 (Carom), 143.27 (CHarom), 147.83, 161.58 (2Carom),
166.92 (CH]N); dB (33.083 MHz; d6-DMSO; SiMe4)
ꢀ9.94 (2B), ꢀ10.71 (4B), ꢀ11.09 (4B), ꢀ14.64 (2B),
ꢀ22.86 (2B), ꢀ32.01 (4B); (FABꢀ) m/z (%) ¼ 568 (79)
[Mꢀ]; elemental analysis calcd (%) for K2C23H39B18N3O:
C 42.74, H 6.08, N 6.50; Found: C 42.65, H 5.89, N 6.19.
4.8. Synthesis of 6-[N-{3-(2-methyl-1,2-dicarba-closo-
dodecaboran(12)-1-yl)methyl}benzylidine
amino]quinazoline-4(3H )-one (11a), 6-[N-{3,5-di(2-
methyl-1,2-dicarba-closo-dodecaboran(12)-1-yl)
methyl}benzylidine amino]quinazoline-4(3H )-one (11b)
To a solution of 6-aminoquinazoline-4(3H )-one 9 (1.6 g,
10 mmol) in 20 ml methanol, carboranylbenzaldehyde 10a or
10b (11.0 mmol) and piperidine (1 ml) were added. The reac-
tion mixture was heated under reflux for 3 h. After cooling,
the deposited solid product was collected by filtration, washed
with methanol and purified by column chromatography using
acetone-chloroform 1:1 as eluent to give compound 11a or 11b.
Compound 11a. Yield: 84%, 3.5 g, Rf ¼ 0.35, m.p. ¼ 189e
191 ꢂC; IR nmax (KBr disc)/cmꢀ1: 2572s (BH), 1668s (C]O),
1628s (C]N), 1585m (C]C); dH (100 MHz; d6-DMSO;
SiMe4) 1.51e3.32 (br s, BH), 2.19 (s, 3H, CH3), 3.4 (s, 2H,
CH2), 7.25e7.56 (m, 6H, Harom), 7.73 (s, 1H, Harom), 8.53
(s, 1H, CH]N), 11.87 (br s, 1H, NH); dC (50 MHz;
d6-DMSO; SiMe4) 14.92 (CH3), 31.21 (CH2), 72.34, 73.91
(Ccarborane), 105.06, 107.14, 109.07, 121.13, 127.42 (CHarom),
123.61, 140.05 (3Carom), 142.43 (CHarom), 147.02, 162.73
(2Carom), 166.32 (CH]N); dB (33.083 MHz; d6-DMSO;
SiMe4) ꢀ2.91 (1B), ꢀ4.55 (1B), ꢀ9.24 (2B), ꢀ11.15 (2B),
ꢀ12.69 (4B); (FABþ): m/z (%) ¼ (92) 420 [M þ H]þ, 419
(79) [Mþ]; elemental analysis calcd (%) for C19H25B10N3O:
C 54.39, H 6.01, N 10.02; Found: C 54.16, H 6.41, N 10.38.
Compound 11b. Yield: 72%, 4.2 g, Rf ¼ 0.38, m.p. ¼ 205e
206 ꢂC; IR nmax (KBr disc)/cmꢀ1: 2575vs (BH), 1662s (C]O),
1632s (C]N), 1579m (C]C); dH (100 MHz; d6-DMSO;
SiMe4) 1.48e3.18 (br s, BH), 2.21 (s, 6H, 2CH3), 3.56 (s, 4H,
2CH2), 7.30e7.48 (m, 6H, Harom), 7.82 (s, 1H, Harom), 8.68 (s,
1H, CH]N), 11.91 (br s, 1H, NH); dC (50 MHz; d6-DMSO;
SiMe4) 15.02 (2CH3), 30.82 (2CH2), 72.51, 73.61 (4Ccarborane),
105.25, 108.19, 109.56, 121.74, 123.61, 127.32 (6CHarom),
142.51 (Carom), 143.21 (CHarom), 147.82, 161.98 (2Carom),
164.42 (CH]N); dB (33.083 MHz; d6-DMSO; SiMe4) ꢀ2.85
(2B), ꢀ4.55 (2B), ꢀ8.94 (4B), ꢀ11.06 (4B), ꢀ12.54 (8B);
(FABþ): m/z (%) ¼ 590 (95) ([M þ H]þ, 589 (81) [Mþ]; elemen-
tal analysis calcd (%) for C23H39B20N3O: C 46.84, H 6.66, N
7.12; Found: C 46.53, H 6.31, N 6.91.
4.10. Biological studies
All tests were repeated 2e3 times. For each compound
Petri dishes were seeded with B16 melanoma cells grown in
9.69 g lꢀ1 Eagle minimum essential medium (Biochrom KG)
supplemented (EMEM) 10 ml lꢀ1 PenicillineStreptomycin
(10,000 Ue10,000 mg mlꢀ1
,
Biochrom KG), 2.2 g lꢀ1
NaHCO3 and 10% FCS. Dishes were incubated overnight at
37 ꢂC in a humidified atmosphere containing 5% CO2. The
medium was replaced with medium containing varying con-
centrations of the boron compounds and incubated for an ad-
ditional 24 h at 37 ꢂC. The medium was removed from the
dishes. The cells were suspended by trypsinization, counted
and seeded out into new dishes at different dilutions. The num-
bers of colonies formed after one week were compared to the
numbers of colonies formed in the control without boron. The
medium was removed, washed with PBS, dyed with GIEMSA
for 10e15 min and washed again with ethanol.
4.9. Synthesis of 6-[N-{3-(2-methyl-nido-carborate-1-
yl)methyl}benzylidine amino]quinazoline-4(3H )-one
(12a), 6-[N-{3,5-di(2-methyl-nido-carborate-1-yl)
methyl}benzylidine amino]quinazoline-4(3H )-one (12b)
Acknowledgement
The conversion of compounds 11a and 11b to their nido-
forms 12a and 12b was performed as described for compounds 3.
Pure compounds were obtained after using TLC (0.1%
The author is grateful to Professor Doctor Detlef Gabel,
Department of Chemistry, University of Bremen, Germany,
for providing facilities for NMR and MS measurements.