RhIII-Pyridocarbazole Complexes as Protein Kinase Inhibitors
(6 mL) and dried in vacuo to obtain the compounds 4a–g as red
nitrate salts. Yields: 4a (41%), 4b (50%), 4c (27%), 4d (20%), 4e
(38%), 4f (39%), 4g (37%).
4a: 1H NMR (250 MHz, [D6]DMSO): δ = 9.35 (d, J = 8.5 Hz, 1
H), 9.18 (d, J = 4.8 Hz, 1 H), 8.82 (d, J = 7.8 Hz, 1 H), 8.04 (dd,
J = 8.3, 5.5 Hz, 1 H), 7.77 (d, J = 8.1 Hz, 1 H), 7.65 (t, J = 7.1 Hz,
1 H), 7.48–7.23 (m, 6 H), 4.90 (s, 2 H), 3.95–3.23 (m, 11 H), 3.03–
2.86 (m, 1 H) ppm. 13C NMR (63 MHz, [D6]DMSO): δ = 168.8,
168.5, 152.0, 151.9, 149.91, 148.88, 141.2, 137.1, 135.9, 130.1,
128.6, 127.44, 127.36, 125.3, 124.9, 123.6, 121.7, 120.3, 115.6,
1493, 1448, 1410, 1336, 1261, 1223, 1175, 1134, 1079, 1008, 946,
911, 875, 824, 795, 743, 706, 635, 487, 434 cm–1. HRMS (ESI):
calcd. for C23H20ClN3O2RhS3 (M – NO3)+ 603.9467; found
603.9454.
1
4f: H NMR (500 MHz, [D6]DMSO): δ = 11.21 (s, 1 H), 9.27 (d,
J = 8.3 Hz, 1 H), 9.24 (d, J = 5.1 Hz, 1 H), 8.79 (d, J = 7.8 Hz, 1
H), 8.77 (br. s, 1 H), 8.57 (br. s, 1 H), 8.04 (dd, J = 8.3, 5.2 Hz, 1
H), 7.96 (d, J = 8.4 Hz, 1 H), 7.61 (ddd, J = 8.2, 7.1, 1.1 Hz, 1 H),
7.43–7.37 (m, 2 H), 3.74–3.64 (m, 2 H), 3.64–3.55 (m, 1 H), 3.52–
3.42 (m, 1 H), 3.30–3.25 (m, 1 H), 3.20–3.07 (m, 3 H), 2.92–2.81
(m, 4 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 170.7, 170.4,
153.1, 151.0, 148.7, 142.8, 134.8, 130.8, 126.2, 124.5, 123.8, 123.6,
121.0, 119.6, 114.9, 114.8, 113.6, 52.4, 52.1, 51.7, 51.4, 50.5,
113.9, 113.8, 40.9, 37.0, 36.3, 32.4 ppm. IR (film): ν = 3425, 2934,
˜
1751, 1692, 1624, 1583, 1521, 1493, 1384, 1334, 1225, 1178, 1141,
1107, 1077, 1030, 940, 905, 823, 798, 736, 697, 657, 628, 496,
429 cm–1. HRMS (ESI): calcd. for C30H26ClN3O2RhS3 (M –
NO3)+ 693.9925; found 693.9922.
49.6 ppm. IR (film): ν = 3154, 2923, 2854, 1744, 1699, 1584, 1494,
˜
1345, 1288, 1227, 1150, 1020, 808, 744, 705, 639, 559, 483,
423 cm–1. HRMS (ESI): calcd. for C23H23ClN6O2Rh (M – NO3)+
553.0621; found 553.0620.
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4b: H NMR: (500 MHz, [D6]DMSO): δ = 9.28 (d, J = 8.6 Hz, 1
H), 9.26 (d, J = 5.5 Hz, 1 H), 8.80 (d, J = 8.0 Hz, 1 H), 8.79 (br.
s, 1 H), 8.59 (br. s, 1 H), 8.06 (dd, J = 8.3, 5.2 Hz, 1 H), 7.98 (d, J
= 8.4 Hz, 1 H), 7.63 (ddd, J = 8.2, 7.2, 1.2 Hz, 1 H), 7.44–7.33 (m,
6 H), 7.27 (t, J = 7.2 Hz, 1 H), 4.93 (s, 2 H), 3.74–3.65 (m, 2 H),
3.64–356 (m, 1 H), 3.52–3.43 (m, 1 H), 3.31–3.24 (m, 1 H), 3.22–
3.09 (m, 3 H), 2.93–2.80 (m, 4 H) ppm. 13C NMR: (125 MHz, [D6]-
DMSO): δ = 169.0, 168.8, 153.4, 151.2, 148.82, 148.80, 142.7,
137.2, 134.7, 129.8, 128.6, 127.3, 127.1, 126.5, 124.4, 124.1, 123.5,
121.0, 119.8, 115.1, 112.2, 52.4, 52.1, 51.8, 51.4, 50.5, 49.7,
1
4g: H NMR (300 MHz, [D6]DMSO): δ = 11.29 (s, 1 H), 9.45 (d,
J = 5.5 Hz, 1 H), 9.40 (d, J = 8.2 Hz, 1 H), 8.98 (d, J = 7.9 Hz, 1
H), 8.09–7.99 (m, 2 H), 7.62 (t, J = 7.5 Hz, 1 H), 7.43 (t, J =
7.5 Hz, 1 H), 4.34–4.22 (m, 1 H), 3.96–3.80 (m, 2 H), 3.72–3.33 (m,
10 H), 3.32–3.13 (m, 5 H), 2.05 (s, 3 H) ppm. 13C NMR (125 MHz,
[D6]DMSO): δ = 170.5, 170.2, 152.7, 150.5, 146.9, 142.9, 135.8,
130.1, 126.4, 125.3, 124.5, 123.6, 121.5, 119.6, 116.3, 115.6, 114.8,
64.2, 63.6, 62.5, 61.6, 61.2, 60.5, 55.5, 52.3, 51.7 ppm. IR (film): ν
˜
40.7 ppm. IR (film): ν = 3420, 3192, 3115, 2924, 1746, 1685, 1625,
˜
= 3244, 2958, 2923, 2853, 1748, 1708, 1583, 1530, 1461, 1414, 1378,
1342, 1259, 1229, 1090, 1018, 867, 799, 749, 701, 641, 491 cm–1.
HRMS (ESI): calcd. for C26H29ClN6O2Rh (M – NO3)+ 595.1090;
found 595.1095.
1583, 1526, 1495, 1416, 1384, 1324, 1293, 1226, 1147, 1109, 1052,
1023, 980, 935, 898, 819, 739, 696, 659, 628, 560, 498, 481,
428 cm–1. HRMS (ESI): calcd. for C30H29ClN6O2Rh (M – NO3)+
643.1090; found 643.1087.
Compound 4h: A solution of compound 4a (13.0 mg, 17 μmol) and
NaI (25.8 mg, 172 μmol) was dissolved in freshly distilled DMF
(2 mL) and stirred at 120 °C for 16 h. The solvent was removed
and the red residue was purified by silica gel chromatography with
MeCN/H2O/KNO3(satd.) 50:3:1. The solvent of the combined
product eluents were removed and the residue dissolved in a mini-
muml amount of acetonitrile/water and subsequently precipitated
with an excess of water. The product was isolated by centrifugation,
washed four times with water and dried in vacuo to obtain 4h as a
4c: 1H NMR (300 MHz, [D6]DMSO): δ = 9.47 (d, J = 5.4 Hz, 1
H), 9.40 (d, J = 8.3 Hz, 1 H), 8.99 (d, J = 7.9 Hz, 1 H), 8.12–8.01
(m, 2 H), 7.64 (t, J = 7.5 Hz, 1 H), 7.48–7.24 (m, 6 H), 4.90 (s, 2
H), 4.34–4.25 (m, 1 H), 3.97–3.80 (m, 2 H), 3.72–3.33 (m, 10 H),
3.32–3.14 (m, 5 H), 2.05 (s, 3 H) ppm. 13C NMR (63 MHz, [D6]-
DMSO): δ = 168.8, 168.6, 152.9, 150.7, 147.04, 147.01, 142.7,
137.1, 135.7, 129.1, 128.6, 127.4, 126.6, 125.2, 124.4, 123.8, 121.6,
119.9, 116.5, 115.8, 113.6, 64.3, 63.7, 62.5, 61.6, 61.2, 60.5, 55.6,
52.3, 51.8, 40.8 ppm. IR (film): ν = 3362, 2960, 2924, 2854, 1749,
1
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red nitrate salt (5.5 mg, 38%). H NMR (300 MHz, [D6]DMSO):
1696, 1613, 1587, 1530, 1489, 1459, 1384, 1337, 1260, 1210, 1085,
1015, 866, 796, 749, 699, 630 cm–1. HRMS (ESI): calcd. for
C33H35ClN6O2Rh (M – NO3)+ 685.1560; found 685.1561.
4d: 1H NMR (300 MHz, [D6]DMSO): δ = 9.36 (d, J = 8.5 Hz, 1
H), 9.16 (d, J = 5.2 Hz, 1 H), 8.83 (d, J = 7.7 Hz, 1 H), 8.03 (dd,
J = 8.3, 5.2 Hz, 1 H), 7.76 (d, J = 8.5 Hz, 1 H), 7.64 (ddd, J = 8.2,
7.1, 1.1 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 1 H), 3.94–3.27 (m, 11 H),
3.18 (s, 3 H), 3.01–2.88 (m, 1 H) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 169.2, 168.8, 151.8, 151.6, 148.9, 141.1, 135.9, 130.4,
127.3, 125.2, 124.9, 123.6, 121.6, 120.2, 115.5, 114.1, 113.8, 38.5,
δ = 9.32 (d, J = 8.5 Hz, 1 H), 9.14 (d, J = 5.1 Hz, 1 H), 8.81 (d, J
= 7.9 Hz, 1 H), 8.01 (dd, J = 7.9, 5.2 Hz, 1 H), 7.73–7.60 (m, 2 H),
7.47–7.24 (m, 6 H), 4.90 (s, 2 H), 4.07–3.95 (m, 1 H), 3.94–3.66 (m,
6 H), 3.65–3.51 (m, 1 H), 3.30–3.15 (m, 2 H), 3.07–2.95 (m, 1 H),
2.81–2.67 (m, 1 H) ppm. 13C NMR (63 MHz, [D6]DMSO): δ =
168.7, 168.5, 152.1, 151.8, 149.2, 149.1, 141.4, 137.1, 135.8, 130.1,
128.6, 127.45, 127.36, 125.3, 124.9, 123.7, 121.7, 120.3, 115.7,
113.8, 42.8, 40.9, 36.8, 35.8, 33.4 ppm. IR (film): ν = 3443, 2925,
˜
1751, 1700, 1621, 1584, 1525, 1494, 1387, 1343, 1228, 1180, 1143,
1108, 942, 909, 825, 794, 747, 700, 658, 630, 498, 440 cm–1. HRMS:
calcd. for C30H26IN3O2RhS3 (M
785.9275.
–
NO3)+ 785.9281; found
38.4, 37.0, 36.3, 32.4, 23.8 ppm. IR (film): ν = 3355, 2960, 1752,
˜
1691, 1626, 1584, 1524, 1493, 1439, 1407, 1380, 1334, 1259, 1223,
1085, 1014, 795, 739, 693, 658, 614, 551, 489 cm–1. HRMS (ESI):
calcd. for C24H22ClN3O2RhS3 (M – NO3)+ 617.9612; found
617.9607.
Protein Kinase Assays. Kinase Profiling: The protein kinase selectiv-
ity profile of complex 4e at an assay concentration of 1 nM was
derived from an active-site-directed affinity screening against 451
human protein kinases (KINOMEscan, DiscoveRx). Pim1 inhibi-
1
4e: H NMR (300 MHz, [D6]DMSO): δ = 11.34 (s, 1 H) 9.35 (d, J
= 8.2 Hz, 1 H), 9.16 (d, J = 5.0 Hz, 1 H), 8.81 (d, J = 7.7 Hz, 1 tion: Inhibition data were obtained by a conventional radioactive
H), 8.02 (dd, J = 8.3, 5.3 Hz, 1 H), 7.75 (d, J = 8.2 Hz, 1 H), 7.63
(t, J = 7.3 Hz, 1 H), 7.43 (t, J = 7.5 Hz, 1 H), 3.94–3.25 (m, 11 H),
3.00–2.87 (m, 1 H) ppm. 13C NMR (63 MHz, [D6]DMSO): δ =
170.5, 170.0, 151.8, 148.7, 141.4, 136.0, 131.1, 127.2, 125.1, 125.0,
123.6, 121.7, 120.1, 115.4, 115.1, 113.8, 37.0, 36.3, 32.3 ppm. IR
assay in which Pim1 activity was measured by the degree of phos-
phorylation of the P70 S6 kinase substrate with [γ-33P]ATP (Per-
kin–Elmer). Accordingly, different concentrations of the rhodium
complexes were preincubated at room temperature for 30 min with
Pim1 (Millipore) and P70 S6 kinase substrate (AnaSpec) and the
phosphorylation reaction was subsequently initiated by adding
(film): ν = 3412, 3226, 2927, 2851, 1752, 1705, 1618, 1584, 1524,
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Eur. J. Inorg. Chem. 2012, 813–821
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
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