Journal of Medicinal Chemistry
Article
(br, 1H), 7.95 (d, 1H, J = 8.3 Hz), 7.82 (d, 1H, J = 1.5 Hz), 7.79 (d,
1H, J = 9.1 Hz), 7.74 (dd, 1H, J = 2.0, 8.9 Hz), 7.62 (d, 1H, J = 8.8
Hz), 7.58 (dt, 1H, J = 1.7, 7.0 + 7.0 Hz), 7.42 (dt, 1H, J = 1.2, 7.0 + 7.0
Hz), 7.33 (d, 1H, J = 1.7 Hz), 4.91 (t, 1H, J = 11.0 Hz), 4.77 (dd, 1H, J
= 2.1, 11.1 Hz), 4.33 (m, 1H), 4.13 (dd, 1H, J = 3.1, 11.1 Hz), 3.97
(dd, 1H, J = 7.9, 11.1 Hz). 13C NMR 163.35, 161.48, 160.05, 155.79,
142.98, 137.18, 135.03, 133.22, 133.16, 131.50, 128.85, 128.45, 128.11,
124.62, 124.02, 123.76, 120.33, 119.36, 118.70, 116.45, 114.00, 113.08,
106.97, 105.02, 101.53. MS m/z 602.96 (M + Na)+, 604.78, 603.81,
618.64 (M + K)+, 620.48. HRMS m/z+ 602.1215 (M + Na)+, calcd
602.1207.
196.07, 170.01, 162.85, 161.51, 160.86, 155.77, 143.91, 135.09, 134.86,
133.93, 133.55, 133.02, 131.48, 128.84, 128.77, 128.42, 124.41, 123.89,
123.75, 120.26, 116.45, 113.92, 113.32, 113.28, 112.54, 106.92, 104.72,
101.63, 56.38, 48.53, 43.09, 38.65, 29.60. MS m/z 702.66 (M + Na)+.
HRMS C36H30ClN5O5S 702.1542 (M + Na), calcd 702.1554.
1-[S]-(Chloromethyl)-5-hydroxy-3-{{5-[5′-(4″-methyldithio-3″,3″-
dimethyl butyryl)indol-2′-yl-carbonyl amino]indole-2-yl}carbonyl}-
1,2-dihydro-3H-benz[e]indole (26) (DC41SMe). Yield 52.5 mg (65%);
Rf = 0.40 (2:3 THF/toluene). 1H NMR (DMF-d7) 11.68 (dd, 2H, J =
1.6, 6.7 Hz), 10.58 (s, 1H), 10.25 (s, 1H), 9.92 (s, 1H), 8.41 (d, 1H, J
= 1.9 Hz), 8.25 (d, 1H, J = 8.0 Hz), 8.22 (d, 1H, J = 1.8 Hz), 8.10 (s,
1H), 7.94 (d, 1H, J = 8.3 Hz), 7.72 (dd, 1H, J = 2.0, 8.8 Hz), 7.60−
7.52 (m, 3H), 7.48−7.39 (m, 3H), 7.29 (d, 1H, J = 1.7 Hz), 4.89 (dd,
1H, J = 8.7, 11.0 Hz), 4.75 (dd, 1H, J = 2.0, 10.9 Hz), 4.31 (m, 1H),
4.13 (dd, 1H, J = 3.3, 11.0 Hz), 3.96 (dd, 1H, J = 7.8, 11.1 Hz), 2.53
(m, 2H), 2.48 (s, 3H), 2.03 (m, 2H), 1.34 (s, 6H). 13C NMR 171.72,
163.30, 161.45, 160.83, 155.72, 143.85, 135.04, 134.81, 134.04, 133.50,
132.96, 131.42, 128.80, 128.75, 128.38, 124.36, 124.13, 123.83, 123.70,
120.21, 118.77, 116.38, 113.88, 113.30, 113.25, 112.47, 108.52, 106.87,
104.20, 101.71, 67.74, 56.33, 48.48, 42.99, 37.67, 33.51, 24.78 21.93.
MS m/z+ 764.0 (M + K)+, 748.0 (M + Na)+, 728.1 (M + K − Cl)+,
712.1(M + Na − Cl)+; m/z− 724.1 (M − H), 688.2 (M − Cl − H).
HRMS C38H36ClN5O4S2 748.1784 (M + Na), calcd 748.1795.
General Procedure for DC1−SR2 (23, 24, 25, 26,). A flask was
charged with 1-[S]-(chloromethyl)-5-hydroxy-3-{{5-[5′-nitroindol-2′-
yl-carbonyl amino]indole-2-yl}carbonyl}-1,2-dihydro-3H-benz[e]-
indole (21) (∼58 mg, 0.1 mmol), Pd/C (30 mg, 10% Pd, 50%
wet), HCl (conc) (15 μL), and DMA (25 mL). After the air was
removed by vacuum suction, H2 was conducted through hydrogen
balloon overnight. The mixture was filtered through Celite and the
solution was evaporated to give ∼50 mg (∼90%) of a brown solid
(22), which was used directly without further purification. To this
solid amine compound in 10 mL of DMA was added 0.12 mmol of the
linker (either 12 or 13 or 14 or 15) and 0.35 mmol of EDC under Ar.
After stirred overnight, two drops of 50% acetic acid was added, the
mixture was evaporated to dryness, and purified by preparative silica
gel TLC (10% DMA, 30% THF, 60% toluene) to afford DC1−SR2.
1 - [ S ] - ( C h l o r o m e t h y l ) - 5 - h y d r o x y - 3 - { { 5 - [ 5 ′ - ( 3 ″ -
methyldithiopropionyl)indol-2′-yl-carbonyl amino]indole-2-yl}-
carbonyl}-1,2-dihydro-3H-benz[e]indole (23) (DC1SMe). Yield 48.1
5-(3-(Methyldisulfanyl)propanamido)-N-(2-((9aS)-4-oxo-2,4,9,9a-
tetrahydro-1H-benzo[e]cyclopropa[c]indole-2-carbonyl)-1H-indol-
5-yl)-1H-indole-2-carboxamide (27) (DC10SMe). 1-[S]-(Chloro-
methyl)-5-hydroxy-3-{{5-[5′-(3″-methyldithiopropionyl)indol-2′-yl-
carbonyl amino]indole-2-yl}carbonyl}-1,2-dihydro-3H-benz[e]indole
(23) (15 mg, 21.9 mmol) in THF (8 mL) was 5% NaHCO3 (2
mL). After stirred at room temperature for 1 h, the mixture was diluted
with EtOAc, and the aqueous phase separated and extracted twice with
EtOAc/THF (2:1). The organic layers were combined, dried
(Na2SO4), filtered, concentrated, and purified on short SiO2 column
eluted with THF/CH2Cl2 (1:2 to 1:1) to afford 11.5 mg (83% yield)
1
mg (63%); Rf = 0.40 (3:7 acetone/toluene). H NMR (CD3COCD3)
10.91 (s, 1H), 10.88 (s, 1H), 9.64 (s, 1H), 9.56 (s, 1H), 9.27 (s, 1H),
8.35 (d, 1H, J = 1.9 Hz), 8.25 (d, 1H, J = 8.0 Hz), 8.17 (d, 1H, J = 1.9
Hz), 8.07 (s, 1H), 7.88 (d, 1H, J = 8.3 Hz), 7.64 (dd, 1H, J = 2.0, 8.1
Hz), 7.58−7.50 (m, 3H), 7.38−7.35 (m, 2H), 7.31 (d, 1H, J = 1.7 Hz),
7.26 (d, 1H, J = 1.7 Hz), 4.86 (dd, 1H, J = 8.7, 11.0 Hz), 4.80 (dd, 1H,
J = 2.3, 10.9 Hz), 4.30 (m, 1H), 4.07 (dd, 1H, J = 3.1, 11.0 Hz), 3.83
(dd, 1H, J = 8.4, 11.2 Hz), 3.09 (t, 2H, J = 7.1 Hz), 2.83 (t, 2H, J = 7.1
Hz), 2.45 (s, 3H). 13C NMR 169.56, 161.10, 160.43, 155.13, 143.50,
134.78, 134.46, 133.55, 133.34, 133.03, 132.57, 131.21, 128.80, 128.69,
128.21, 124.22, 124.02, 123.53, 123.44, 120.16, 118.79, 116.45, 113.91,
113.02, 112.95, 112.73, 106.78, 103.72, 101.63, 56.01, 47.73, 43.10,
37.25, 34.01, 23.00. MS m/z 706.66 (M + Na)+. HRMS
C35H30ClN5O4S2 706.1306 (M + Na), calcd 706.1325
1
of the title compound. H NMR (DMF-d7) 11.69 (s, 1H), 11.67 (s,
1H), 10.58 (s, 1H), 10.24 (s, 1H), 9.92 (s, 1H), 8.40 (d, 1H, J = 1.9
Hz), 8.25 (d, 1H, J = 8.3 Hz), 8.22 (d, 1H, J = 1.8 Hz), 8.10 (s, 1H),
7.95 (d, 1H, J = 8.3 Hz), 7.73 (dd, 1H, J = 2.0, 8.1 Hz), 7.61−7.52 (m,
3H), 7.47 (d, 1H, J = 1.8 Hz), 7.45−7.39 (m, 2H), 7.20 (s, 1H), 4.75
(dd, 1H, J = 2.1, 10.7 Hz), 3.98−3.95 (m, 1H), 3.83−3.78 (m, 1H),
2.94 (t, 2H, J = 7.1 Hz), 2.75 (m, 1H), 2.58 (t, 2H, J = 7.1 Hz), 2.46
(s, 3H), 1.55 (m, 1H), 1.27 (m, 1H). 13C NMR 201.37, 171.03,
162.80, 161.82, 160.90, 156.77, 144.96, 135.11, 134.88, 133.96, 133.77,
133.62, 131.49, 128.89, 128.80, 128.52, 124.42, 123.91, 123.77, 120.27,
117.05, 113.93, 113.37, 113.29, 112.55, 106.93, 104.73, 101.65, 58.30,
43.09, 38.69, 37.55, 29.60, 27.90, 21.02. MS m/z 670.40 (M + Na)+.
HRMS C35H29N5NaO4S2 670.1672 (M + Na), calcd 670.1559.
t-Butyl 5-Nitroindole-2-carboxylate(28). To a stirred solution of 5-
nitroindole-2-carboxylic acid (17) (12.8 g, 61.2 mmol) in 200 mL of
dry THF under Ar was added oxalyl chloride (12.0 mL, 137.5 mmol),
followed by 0.1 mL of DMF, which caused a vigorous evolution of gas.
After stirring for 40 min, the reaction mixture was evaporated to
dryness. The resulting solid was redissolved in 150 mL of dry THF
and cooled at ∼30 °C under Ar. A solution of potassium t-butoxide
(1.0 M in THF, 140 mL, 140 mmol) was then added dropwise over 45
min, and stirring was continued for an additional 45 min. The reaction
was quenched with 600 mL of water, neutralized with few drops of
H3PO4, and extracted with ethyl acetate (3 × 400 mL). The organic
extracts were washed with saturated aqueous NaHCO3 and water, and
then dried over MgSO4, filtered, concentrated, and crystallized with
ethanol/hexane to afford 9.62 g (85%) of the title compound (28). Rf
1-[S]-(Chloromethyl)-5-hydroxy-3-{{5-[5′-(3″-pyridi-2′-yl-
dithiopropionyl)indol-2′-yl-carbonyl amino]indole-2-yl}carbonyl}-
1,2-dihydro-3H-benz[e]indole (24) (DC1SPy). Yield 50.6 mg (61%),
1
Rf = 0.35 (1:2 THF/toluene). H NMR (DMF-d7) 11.87 (br, 1H),
11.68 (s, 2H), 10.58 (s, 1H), 10.25 (s, 1H), 10.04 (s, 1H), 8.51 (m,
1H), 8.40 (d, 1H, J = 1.8 Hz), 8.25 (d, 1H, J = 7.9 Hz), 8.20 (d, 1H, J
= 1.9 Hz), 8.10 (s, 1H), 7.94 (d, 1H, J = 8.3 Hz), 7.86 (m, 2H), 7.71
(dd, 1H, J = 2.0, 8.1 Hz), 7.60 − 7.52 (m, 3H), 7.48 (d, 1H, J = 1.5
Hz), 7.42 (m, 2H), 7.30−7.26 (m, 2H), 4.90 (dd, 1H, J = 8.7, 11.0
Hz), 4.75 (dd, 1H, J = 2.3, 10.9 Hz), 4.32 (m, 1H), 4.13 (dd, 1H, J =
3.2, 11.0 Hz), 3.96 (dd, 1H, J = 8.4, 11.2 Hz), 3.24 (t, 2H, J = 7.1 Hz),
2.80 (t, 2H, J = 7.1 Hz). 13C NMR 169.70, 161.50, 160.95, 160.85,
155.76, 150.78, 143.91, 138.78, 135.14, 134.86, 134.14, 133.72, 133.02,
129.30, 128.84, 128.78, 128.43, 124.41, 124.18, 123.88, 123.74, 122.20,
120.32, 116.43, 113.92, 113.38, 113.29, 112.63, 106.92, 104.26, 101.75,
56.37, 48.53, 43.04, 36.97, 35.57. MS m/z 748.6 (M + H)+. HRMS
C39H31ClN6O4S2 747.1611 (M + H)+, calcd 747.1615.
1 - [ S ] - ( C h l o r o m e t h y l ) - 5 - h y d r o x y - 3 - { { 5 - [ 5 ′ - ( 3 ″ -
acetylthiopropionyl)indol-2′-yl-carbonyl amino]indole-2-yl}-
carbonyl}-1,2-dihydro-3H-benz[e]indole (25) (DC1SAc). Yield 47.2
1
= 0.35 (1:5 ethyl acetate/hexane). H NMR (CDCl3), 11.63 (s, 1H),
1
mg (62%); Rf = 0.38 (1:2 THF/toluene). H NMR (DMF-d7) 11.68
8.66 (dd, 1H, J = 0.5, 1.3 Hz), 8.20 (dd, 1H, J = 0.5, 9.0 Hz), 7.48 (dd,
1H, J = 0.5, 9.1 Hz), 7.28 (dd, 1H, J = 0.9, 11.1 Hz), 1.63 (s, 9H). 13C
NMR 160.39, 142.12, 138.11, 132.10, 126.78, 120.22, 119.83, 111.98,
109.82, 82.91, 28.26. ESI MS m/z 285.43 (M + Na)+. HRMS
C13H14N2O4 285.0859 (M + Na), calcd 285.0851.
t-Butyl 5-Aminoindole-2-carboxylate (29). A 500 mL of Parr
hydrogenation bottle was charged with t-butyl 5-nitroindole-2-
carboxylate (28) (5.80 g, 22.14 mmol), Pd/C (0.6 g, 10% Pd, 50%
(s, 1H), 11.67 (s, 1H), 10.58 (s, 1H), 10.25 (s, 1H), 9.88 (s, 1H), 8.37
(d, 1H, J = 1.9 Hz), 8.25 (m, 1H), 8.22 (d, 1H, J = 1.9 Hz), 8.10 (s,
1H), 7.94 (d, 1H, J = 8.3 Hz), 7.73 (dd, 1H, J = 2.0, 8.1 Hz), 7.60−
7.50 (m, 3H), 7.45−7.39 (m, 3H), 7.30 (d, 1H, J = 1.7 Hz), 4.90 (dd,
1H, J = 8.7, 11.0 Hz), 4.77 (dd, 1H, J = 2.1, 10.7 Hz), 4.32 (m, 1H),
4.14 (dd, 1H, J = 3.1, 11.0 Hz), 3.96 (dd, 1H, J = 8.4, 11.2 Hz), 3.07 (t,
2H, J = 7.1 Hz), 2.68 (t, 2H, J = 7.1 Hz), 2.35 (s, 3H). 13C NMR
777
dx.doi.org/10.1021/jm201284m | J. Med. Chem. 2012, 55, 766−782