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H.K. Agarwal et al. / European Journal of Medicinal Chemistry 100 (2015) 197e209
CDCl3)
d
166.94, 163.22, 150.65, 134.18, 109.92, 87.86, 85.66, 72.22,
4.1.11.3. 3-({2-[4-(closo-1,7-Carboranyl)butyl]amino}-2-oxoethyl)
72.58, 62.96, 55.11, 43.93, 41.47, 39.13, 35.64, 25.71, 25.91, 17.96,
thymidine (30). Rf: 0.47 (DCM/MeOH, 9/1, v/v), yield: 12 mg, 71%. 1H
18.39, 13.20, -5.42, -4.77. Accurate mass HRMS (ESIþ): m/z calcd for
NMR (400 MHz, CD3OD)
d
7.90 (s,1H), 6.29 (t, J ¼ 6.5 Hz,1H), 4.54 (s,
C
28H59B10N3NaO6Si2 (M þ Na)þ 720.4843, found 720.4894.
2H), 4.32e4.44 (m, 1H), 3.86e3.95 (m, 1H), 3.81 (dd, J ¼ 2.7 and
12.0 Hz, 1H), 3.73 (dd, J ¼ 3.3 and 12.0 Hz, 1H), 3.47 (s, 1H),
3.10e3.21 (m, 2H), 2.18e2.33 (m, 2H), 1.95e2.05 (m, 2H), 1.92 (s,
3H), 1.55e3.31 (br. m, 10H), 1.35e1.49 (m, 4H). 13C NMR (100 MHz,
4.1.10.2. 30,50-Bis-O-(tert-butyldimethylsilyl)-3-({2-[3-(closo-1,7-
carboranyl)propyl]amino}-2-oxoethyl)thymidine (26). Rf: 0.64
(DCM/MeOH, 19/1, v/v), yield: 13 mg, 20%. 1H NMR (400 MHz,
CD3OD)
CD3OD) d 169.88, 165.26, 152.40, 136.94, 110.69, 89.00, 87.32, 78.04,
72.12, 62.83, 56.96, 44.37, 41.51, 39.99, 37.85, 30.09, 28.47, 13.30.
Accurate mass HRMS (ESIþ): m/z calcd for C18H35B10N3NaO6
(M þ Na)þ 520.3427, found 520.3444, 1017.7020 (2M þ Na)þ.
d
7.63 (s, 1H), 6.28 (dd, J ¼ 6.3 and 7.5 Hz, 1H), 4.54 (s, 2H),
4.45e4.51 (m, 1H), 3.92e3.98 (m, 1H), 3.89 (dd, J ¼ 3.2 and 11.4 Hz,
1H), 3.83 (dd, J ¼ 3.1 and 11.4 Hz, 1H), 3.47 (s, 1H), 3.14 (t, J ¼ 6.6 Hz,
2H), 2.26 (ddd, J ¼ 2.8, 5.9 and 13.3 Hz, 1H), 2.14e2.22 (m, 1H), 2.02
(t, J ¼ 8.8 Hz, 2H), 1.93 (s, 3H), 1.55e3.31 (br. m, 10H), 1.53e1.66 (m,
2H), 0.94 and 0.96 (two s, 18H), 0.13 and 0.15 (two s, 12H). 13C NMR
4.1.12. General procedure for the synthesis of compound 32e35
A mixture of compound 31 [39] (52 mg, 0.1 mmol) and amino-
alkyl-closo-1,7-carborane [35] (0.3 mmol) in anhydrous CH3CN (2 mL)
was refluxed overnight. The solvent was evaporated and residue was
purified by silica gel column chromatography DCM/acetone (9/1, v/v)
as the solvent system to produce a white amorphous solid.
(100 MHz, CD3OD)
d 169.91, 165.03, 152.22, 136.07, 110.72, 89.36,
87.26, 73.82, 64.26, 56.90, 44.37, 41.96, 39.68, 35.28, 31.11, 26.33,
26.53, 18.93, 19.36, 13.44, ꢀ4.49, ꢀ5.17. Accurate mass HRMS
(ESIþ): m/z calcd for C29H61B10N3NaO6Si2 (M þ Na)þ 734.5000;
found 734.5054.
4.1.12.1. 30,50-Bis-O-(tert-butyldimethylsilyl)-N4-[2-(closo-1,7-
carboranyl)ethyl]-5-methyl-20-deoxycytidine (32). Rf: 0.52 (DCM/
4.1.10.3. 30,50-Bis-O-(tert-butyldimethylsilyl)-3-({2-[4-(closo-1,7-
carboranyl)butyl]amino}-2-oxoethyl)thymidine (27). Rf: 0.63 (DCM/
MeOH, 19/1, v/v), yield: 32 mg, 48%. 1H NMR (400 MHz, CDCl3)
acetone, 9/1, v/v), yield: 53 mg, 87%. 1H NMR (400 MHz, CDCl3)
d 7.59
(s, 1H), 6.32 (t, J ¼ 6.7 Hz, 1H), 5.48 (br s, 1H), 4.37e4.44 (m, 1H),
3.92e3.73 (m, 3H), 3.48e3.57 (m, 2H), 2.97 (s, 1H), 2.32e2.42 (m,
1H), 2.29 (t, J ¼ 7.3, 2H),1.95e2.04 (m,1H),1.93 (s, 3H),1.55e3.31 (br.
m, 10H), 0.92 and 0.89 (two s, 18H), 0.11, 0.10, 0.07 and 0.06 (four s,
d
7.52 (s, 1H), 6.35 (dd, J ¼ 5.9 and 7.7 Hz,1H), 5.87 (t, J ¼ 5.2 Hz,1H),
4.57 (s, 2H), 4.34e4.42 (m, 1H), 3.92e3.96 (m, 1H), 3.87 (dd, J ¼ 2.4
and 11.4 Hz,1H), 3.76 (dd, J ¼ 2.2 and 11.4 Hz,1H), 3.22 (q, J ¼ 6.4 Hz,
2H), 2.90 (s, 1H), 2.27 (ddd, J ¼ 2.4, 5.7 and 13.0 Hz, 1H), 1.96e2.06
(m, 3H), 1.94 (s, 3H), 1.55e3.31 (br. m, 10H), 1.24e1.46 (m, 4H), 0.89
and 0.93 (two s,18H), 0.07 and 0.12 (two s,12H). 13C NMR (100 MHz,
12H). 13C NMR (100 MHz, CDCl3)
d 163.87, 157.52, 139.14, 103.98,
90.11, 89.35, 87.71, 87.52, 73.44, 64.34, 56.89, 36.78, 32.50, 27.50,
27.26, 19.96, 19.51, 14.96, 14.66, ꢀ3.31, ꢀ3.76, ꢀ3.8, ꢀ3.83. Accurate
mass HRMS (ESIþ): m/z calcd for C26H58B10N3O4Si2 (M þ H)þ
640.4969, found 640.5021.
CDCl3)
d 166.83, 163.21, 150.68, 134.06, 109.89, 87.81, 85.61, 72.20,
62.94, 54.77, 43.93, 41.44, 39.10, 36.39, 29.03, 27.11, 25.69, 25.90,
17.95, 18.37, 13.20, ꢀ5.44, ꢀ4.79. Accurate mass HRMS (ESIþ): m/z
calcd for C30H63B10N3NaO6Si2 (M þ Na)þ 748.5156, found 748.5128.
4.1.12.2. 30,50-Bis-O-(tert-butyldimethylsilyl)-N4-[3-(closo-1,7-
carboranyl)propyl]-5-methyl-20-deoxycytidine (33). Rf: 0.5 (DCM/
acetone, 9/1, v/v), yield: 20 mg, 40%. 1H NMR (400 MHz, CDCl3)
4.1.11. General procedure for the synthesis of compounds 28e30
THF (1 mL) was added to compounds 25e27 (0.034 mmol) and
TBAF (75 mL,1 M solution in THF, 0.075 mmol). The reaction mixture
was stirred at room temperature for 2 h, the solvents were evap-
orated under reduced pressure, and the residue was purified by
silica gel chromatography using DCM/MeOH, 9/1, v/v as solvent
system to produce a white amorphous solid.
d
7.51 (s, 1H), 6.38 (t, J ¼ 6.25 Hz, 1H), 4.85 (br s, 1H), 4.36 (m, 1H),
3.84e3.92 (m, 2H), 3.76 (m, 1H), 3.47 (m, 2H), 2.90 (s, 1H), 2.36 (m,
1H), 1.93e2.02 (m, 3H), 1.88 (s, 3H), 1.66e1.68 (m, 2H), 1.55e3.31
(br. m, 10H), 0.92 and 0.88 (two s, 18H), 0.10, 0.09, 0.06 and 0.05
(four s, 12H). 13C NMR (100 MHz, CDCl3)
d 163.08, 156.22, 137.51,
101.20, 87.61, 85.81, 75.70, 71.83, 62.85, 55.07, 42.17, 40.15, 34.21,
30.21, 25.92,18.56,18.17,13.29, ꢀ4.42, ꢀ4.74, ꢀ5.21, ꢀ5.26. Accurate
mass HRMS (ESIþ): m/z calcd for C27H59B10N3O4Si2Na (M þ Na)þ
676.4945, found 676.4980.
4.1.11.1. 3-({2-[2-(closo-1,7-Carboranyl)ethyl]amino}-2-oxoethyl)
thymidine (28). Rf: 0.51 (DCM/MeOH, 9/1, v/v), yield: 15 mg, 93%. 1H
4.1.12.3. 30,50-Bis-O-(tert-butyldimethylsilyl)-N4-[4-(closo-1,7-
carboranyl)butyl]-5-methyl-20-deoxycytidine (34). Rf: 0.56 (DCM/
acetone, 9/1, v/v), yield: 60 mg, 94%. 1H NMR (400 MHz, CDCl3)
NMR (400 MHz, CD3OD)
d
7.91 (s,1H), 6.28 (t, J ¼ 6.6 Hz,1H), 4.53 (s,
2H), 4.37e4.44 (m, 1H), 3.89e3.94 (m, 1H), 3.81 (dd, J ¼ 2.9 and
12.0 Hz, 1H), 3.72 (dd, J ¼ 3.6 and 12.0 Hz, 1H), 3.53 (s, 1H), 3.20 (t,
J ¼ 7.9 Hz, 2H), 2.21e2.32 (m, 2H), 2.18 (t, J ¼ 7.9 Hz, 2H),1.92 (s, 3H),
d
7.49 (s, 1H), 6.37 (t, J ¼ 6.51 Hz, 1H), 4.95 (s, 1H), 4.35 (m, 1H),
1.55e3.31 (br. m, 10H). 13C NMR (100 MHz, CD3OD)
d 169.90,165.26,
3.83e3.93 (m, 2H), 3.75 (m, 1H), 3.49 (m, 2H), 2.89 (s, 1H), 2.35 (m,
1H), 1.90e2.00 (m, 3H), 1.87 (s, 3H), 1.48e1.56 (m, 2H), 1.55e3.31
(br. m, 10H), 1.33e1.44 (m, 2H), 0.91 and 0.87 (two s, 18H), 0.10,
0.09, 0.05 and 0.04 (four s, 12H). 13C NMR (100 MHz, CDCl3)
152.38, 137.03, 110.69, 89.02, 87.38, 72.13, 62.83, 57.28, 44.37, 41.51,
40.24, 36.58, 13.26. Accurate mass HRMS (ESIþ): m/z calcd for
C
16H31B10NaN3O6 (M þ Na)þ 492.3114, found 492.3158.
d
163.02, 156.18, 137.30, 101.31, 87.59, 85.78, 76.20, 71.81, 62.84,
4.1.11.2. 3-({2-[3-(closo-1,7-Carboranyl)propyl]amino}-2-oxoethyl)
54.99, 42.15, 40.70, 36.57, 28.93, 27.37, 25.95, 18.54, 18.16,
13.31, ꢀ4.43, ꢀ4.75, ꢀ5.22, ꢀ5.28. Accurate mass HRMS (ESIþ): m/z
calcd for C28H61B10N3O4Si2Na (M þ Na)þ 691.5065, found 691.5049.
thymidine (29). Rf: 0.54 (DCM/MeOH, 9/1, v/v), yield: 14 mg, 83%.
1H NMR (400 MHz, CD3OD)
d
7.90 (s, 1H), 6.29 (t, J ¼ 6.5 Hz, 1H),
4.54 (s, 2H), 4.37e4.46 (m, 1H), 3.88e3.96 (m, 1H), 3.82 (dd, J ¼ 2.8
and 12.0 Hz, 1H), 3.74 (dd, J ¼ 3.3 and 12.0 Hz, 1H), 3.49 (s, 1H), 3.13
(t, J ¼ 6.3 Hz, 2H), 2.21e2.34 (m, 2H), 2.02 (t, J ¼ 8.3 Hz, 2H), 1.93 (s,
3H), 1.53e1.66 (m, 2H), 1.55e3.31 (br. m, 10H). 13C NMR (100 MHz,
4.1.13. General procedure for the synthesis of compounds 35e37
Compounds 32e34 (0.08 mmol) were dissolved in THF (1 mL)
and TBAF (0.17 mmol, 1 M solution in THF). The reaction mixture
was stirred at room temperature for 2 h, the solvent evaporated
under reduced pressure, and the residue was purified by silica gel
chromatography using DCM/MeOH (9/1, v/v) as solvent system to
produce a white amorphous solid.
CD3OD)
d 169.93, 165.16, 152.31, 136.88, 110.61, 89.91, 87.25, 72.03,
62.74, 56.95, 44.33, 41.44, 39.70, 35.29, 31.04, 13.21. Accurate mass
HRMS (ESIþ): m/z calcd for C17H33B10N3NaO6 (M þ Na)þ 506.3270,
found 506.3274.