140 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 1
Ngo et al.
(C-18), 158.9 (C-16), 170.0 (C-25′), 171.6 (C-38′), 172.2 (C-26),
172.8 (C-24), 174.6 (C-22′); IR (cm-1) 2962, 1737, 1651, 1236;
[R]D +38.5 (c 1.2, CH2Cl2); HR-EI-MS m/z 1137.5935 (M+, calcd
for C65H81N6O12 1137.5912).
Compound 28. Reaction was performed with compound 27 (35
mg, 0.03 mmol) to give quantitatively compound 28 (29 mg). H
1
NMR (500 MHz, MeOD) δ 0.64 (m, 3H, H-21), 0.77-0.87 (m,
6H, H-36′, H-37′), 1.06 (m, 3H, H-21′), 1.21 (m, 1H, H-35′), 1.28
(m, 1H, H-20), 1.49 (m, 1H, H-35′), 1.51 (m, 1H, H-11), 1.57 (m,
1H, H-20), 1.80-2.15 (m, 7H, H-20′, H-28′, H-29′, H-34′), 1.93
(s, 3H, H-27), 2.03 (m, 1H, H-2′), 2.16 (m, 1H, H-11), 2.57 (m,
2H, H-1′, H-10), 2.59 (s, 3H, H-23), 2.70 (m, 3H, H-19, H-41′),
2.85 (m, 1H, H-8), 2.96 (m, 1H, H-10), 3.10 (m, 1H, H-1′), 3.28
(m, 2H, H-30′), 3.40 (m, 1H, H-8), 3.66 (s, 3H, H-23′), 3.67 (s,
3H, H-25), 3.70 (s, 1H, H-2), 3.76 (s, 3H, H-22), 3.79-4.50 (m,
7H, H-5′, H-19′, H-27′, H-33′, H-40′), 4.97 (m, 1H, H-8′), 5.28
(m, 1H, H-6), 5.38 (s, 1H, H-4), 5.35 (m, 1H, H-24′), 5.56 (m, 1H,
H-8′), 5.77 (m, 3H, H-7, H-3′, H-24′), 6.27 (s, 1H, H-17), 6.30 (s,
1H, H-14), 6.90-7.47 (m, 4H, Har); 13C NMR (75 MHz, MeOD)
δ (main carbons) 7.7 (C-21), 11.0 (C-21′, C-36′), 15.2 (C-37′), 21.3
(C-27), 24.2 (C-29′), 24.7 (C-35′), 27.0 (C-20′), 29.3 (C-28′), 30.5
(C-20), 31.0 (C-2′), 33.5 (C-1′), 36.2 (C-41′), 37.4 (C-34′), 37.7
(C-23), 42.9 (C-5), 44.6 (C-11), 47.1 (C-30′), 49.2 (C-8), 50.0 (C-
10), 51.7 (C-25), 53.0 (C-23′), 54.6 (C-8′), 55.2 (C-22), 57.6 (C-
5′), 58.6 (C-33′), 60.4 (C-40′), 60.6 (C-27′), 62.6 (C-24′), 62.9 (C-
19′), 65.2 (C-19), 76.4 (C-4), 82.5 (C-2), 94.2 (C-17), 108.0 (C-
9′), 111.3 (C-14′), 117.6 (C-11′), 119.5 (C-15), 120.1 (C-12′), 122.6
(C-13′), 123.9 (C-14), 124.6 (C-3′, C-13), 125.0 (C-7), 129.5 (C-
10′), 131.3 (C-6), 134.6 (C-4′), 136.6 (C-15′), 154.7 (C-18), 159.0
(C-16), 169.3 (C-31′), 170.0 (C-25′), 171.7 (C-26), 173.0 (C-24),
174.6 (C-22′); IR (cm-1) 3384, 2360, 1650, 1244; [R]D -2 (c 1.32,
MeOH); HR-EI-MS m/z 1162.5688 (M+, calcd for C62H80N7O15
1162.5712).
Compound 29. Reaction was performed with nor-anhydrovin-
blastine 4 (31 mg, 0.04 mmol) and methyl bromoacetate (6 mg,
0.04 mmol) to give, after purification, compound 29 (27 mg, 77%).
1H NMR (500 MHz, CDCl3) δ 0.68 (t, J ) 7.8 Hz, 3H, H-21),
1.09 (t, J ) 7.4 Hz, 3H, H-21′), 1.13 (m, 1H, H-20), 1.69 (m, 1H,
H-20), 1.76 (m, 1H, H-11), 2.02 (s, 3H, H-27), 2.08 (m, 2H, H-20′),
2.15 (m, 1H, H-2′), 2.16 (m, 1H, H-11), 2.38 (m, 2H, H-1′, H-10),
2.51 (s, 1H, H-19), 2.67 (s, 3H, H-23), 2.78 (d, J ) 16.0 Hz, 1H,
H-8), 3.22 (m, 2H, H-1′, h10), 3.30 (dd, J ) 16.0 and 3.8 Hz, 1H,
H-8), 3.39 (m, 1H, H-19′), 3.66 (s, 3H, H-26′), 3.71 (s, 1H, H-2),
3.72 (s, 3H, H-23′), 3.73 (s, 3H, H-25), 3.80 (m, 4H, H-19′, H-22),
4.80 (m, 1H, H-5′), 4.84 (m, 1H, H-8′), 4.82 (s, 2H, H-24′), 4.99
(d, J ) 17.5 Hz, 1H, H-5′), 5.21 (d, J ) 10.5 Hz, 1H, H-6), 5.31
(s, 1H, H-4), 5.69 (m, 1H, H-8′), 5.76 (s, 1H, H-3′), 5.80 (dd, J )
10.5 Hz, 4.7 Hz, 1H, H-7), 6.05 (s, 2H, H-14, H-17), 7.18-7.32
(m, 3H, H-12′, H-13′, H-14′), 7.99 (d, J ) 7.9 Hz, 1H, H-11′),
8.83 (s, 1H, H-16′); 13C NMR (75 MHz, CDCl3) δ 8.0 (C-21), 11.8
(C-21′), 21.1 (C-27), 26.9 (C-20′), 28.8 (C-2′), 30.5 (C-20), 33.5
(C-1′), 38.1 (C-23), 42.5 (C-5), 44.6 (C-11), 50.1 (C-8), 50.3 (C-
10), 52.2 (C-25), 52.6 (C-26′), 53.0 (C-12), 53.3 (C-23′), 53.6 (C-
19′), 54.3 (C-18′), 54.8 (C-8′), 55.8 (C-22), 59.6 (C-24′), 60.3 (C-
5′), 65.2 (C-19), 76.3 (C-4), 79.6 (C-3), 82.9 (C-2), 94.1 (C-17),
101.7 (C-9′), 111.2 (C-14′), 117.5 (C-15), 118.9 (C-11′), 121.4 (C-
3′), 121.9 (C-14), 122.3 (C-12′), 123.6 (C-13), 124.5 (C-13′), 124.8
(C-7), 129.2 (C-10′), 129.8 (C-6), 132.2 (C-4′), 134.3 (C-15′), 136.6
(C-17′), 153.6 (C-18), 158.4 (C-16), 166.2 (C-25′), 170.9 (C-24),
171.5 (C-26), 173.7 (C-22′); IR (cm-1) 1741, 1233; [R]D +48 (c
0.78, CHCl3); HR-EI-MS m/z 851.4232 (M+, calcd for C48H59N4O10
851.4231).
Compound 26. Reaction was performed with compound 25 (36
1
mg, 0.03 mmol) to give quantitatively compound 26 (34 mg). H
NMR (500 MHz, MeOD) δ 0.64 (m, 3H, H-21), 0.77-0.87 (m,
6H, H-36′, H-37′), 1.06 (m, 3H, H-21′), 1.21 (m, 1H, H-35′), 1.28
(m, 1H, H-20), 1.49 (m, 1H, H-35′), 1.51 (m, 1H, H-11), 1.57 (m,
1H, H-20), 1.80-2.15 (m, 7H, H-20′, H-28′, H-29′, H-34′), 1.93
(s, 3H, H-27), 2.03 (m, 1H, H-2′), 2.16 (m, 1H, H-11), 2.57 (m,
2H, H-1′, H-10), 2.65 (s, 3H, H-23), 2.70 (s, 1H, H-19), 2.85 (m,
1H, H-8), 2.96 (m, 1H, H-10), 3.10 (m, 1H, H-1′), 3.40 (m, 1H,
H-8), 3.54 (m, 2H, H-30′), 3.66 (s, 3H, H-23′), 3.67 (s, 3H, H-25),
3.70 (s, 1H, H-2), 3.79 (s, 3H, H-22), 4.00 (d, J ) 15.9 Hz, 1H,
H-19′), 4.13 (d, J ) 15.9 Hz, 1H, H-19′), 4.24 (d, J ) 15.8 Hz,
1H, H-5′), 4.37 (m, 2H, H-5′, H-27′), 4.60 (m, 1H, H-33′), 4.95 (d,
J ) 14.6 Hz, 1H, H-8′), 5.28 (m, 1H, H-6), 5.38 (s, 1H, H-4), 5.39
(m, 1H, H-24′), 5.56 (d, J ) 14.6 Hz, 1H, H-8′), 5.79 (m, 3H,
H-7, H-3′, H-24′), 6.28 (s, 1H, H-17), 6.55 (s, 1H, H-14), 7.17 (m,
2H, Har), 7.35 (d, J ) 7.9 Hz, 1H, Har), 7.61 (d, J ) 7.5 Hz, 1H,
Har), 7.79 (s, 1H, H-16′); 13C NMR (75 MHz, MeOD) δ (main
carbons) 7.7 (C-21), 11.0 (C-21′, C-36′), 15.2 (C-37′), 21.3 (C-
27), 24.2 (C-29′), 24.7 (C-35′), 27.0 (C-20′), 29.3 (C-28′), 30.5
(C-20), 31.0 (C-2′), 33.5 (C-1′), 37.4 (C-34′), 37.7 (C-23), 42.9
(C-5), 44.6 (C-11), 47.1 (C-30′), 49.2 (C-8), 50.0 (C-10), 51.7 (C-
25), 53.0 (C-23′), 54.6 (C-8′), 55.2 (C-22), 57.6 (C-5′), 58.6 (C-
33′), 60.6 (C-27′), 62.6 (C-24′), 62.9 (C-19′), 65.2 (C-19), 76.4
(C-4), 82.5 (C-2), 94.2 (C-17), 108.0 (C-9′), 111.3 (C-14′), 117.6
(C-11′), 119.5 (C-15), 120.1 (C-12′), 122.6 (C-13′), 123.9 (C-14),
124.6 (C-3′, C-13), 125.0 (C-7), 129.5 (C-10′), 131.3 (C-6), 134.6
(C-4′), 136.6 (C-15′), 154.7 (C-18), 159.0 (C-16), 169.3 (C-31′),
170.0 (C-25′), 171.7 (C-26), 173.0 (C-24), 174.6 (C-22′); IR (cm-1
)
3396, 1650, 1246; [R]D -4 (c 1.1, MeOH); HR-EI-MS m/z
1047.5416 (M+, calcd for C58H75N6O12 1047.5443).
Compound 27. Reaction was performed with nor-anhydrovin-
blastine 4 (31 mg, 0.04 mmol) and compound 18 (26 mg, 0.04
mmol) to give, after purification, compound 27 (35 mg, 65%) as a
translucent oil. 1H NMR (500 MHz, CDCl3) δ 0.67 (m, 3H, H-21),
0.83 (t, J ) 7.4 Hz, 3H, H-36′), 0.97 (t, J ) 6.6 Hz, 3H, H-37′),
1.06 (t, J ) 7.0 Hz, 3H, H-21′), 1.11 (m, 1H, H-20), 1.20 (m, 1H,
H-35′), 1.58 (m, 1H, H-35′), 1.66 (m, 2H, H-11, H-20), 1.85-2.24
(m, 9H, H-2′, H-20′, H-28′, H-29′, H-34′, H-11), 2.03 (s, 3H, H-27),
2.36 (m, 1H, H-1′, H-10), 2.67 (s, 3H, H-23), 2.70 (s, 1H, H-19),
2.81 (m, 1H, H-8), 2.83 (m, 1H, H-41′), 3.05 (m, 1H, H-41′), 3.20
(m, 2H, H-1′, H-10), 3.27 (m, 1H, H-19′), 3.30 (m, 1H, H-8), 3.54
(m, 2H, H-30′), 3.66 (s, 3H, H-23′), 3.70 (s, 1H, H-2), 3.72 (s, 3H,
H-25), 3.80 (s, 3H, H-22), 4.08 (m, 1H, H-19′), 4.44 (m, 1H, H-27′),
4.51 (d, J ) 16.6 Hz, 1H, H-5′), 4.60 (m, 1H, H-33′), 4.65 (d, J )
14.0 Hz, 1H, H-24′), 4.77 (m, 1H, H-8′), 4.84 (m, 1H, H-40′), 4.97
(m, 1H, H-5′), 4.99 (s, 2H, H-43′), 5.07 (s, 2H, H-45′), 5.2 (s, 1H,
H-6), 5.30 (s, 1H, H-4), 5.71 (s, 1H, H-3′), 5.75 (m, 1H, H-8′),
5.80 (m, 1H, H-7), 6.02 (s, 1H, H-17), 6.04 (s, 1H, H-14), 6.06 (d,
J ) 14.0 Hz, 1H, H-24′), 6.83 (d, J ) 7.9 Hz, 1H, H-39′),
7.14-7.33 (m, 14H, Har), 8.78 (s, 1H, H-16′); 13C NMR (75 MHz,
CDCl3) δ (main carbons) 8.2 (C-21), 11.6 (C-21′, C-36′), 15.4 (C-
37′), 21.2 (C-27), 24.5 (C-35′), 24.9 (C-29′), 27.0 (C-20′), 27.9
(C-28′), 29.0 (C-2′), 29.5 (C-20), 34.0 (C-1′), 36.3 (C-41′), 37.1
(C-34′), 38.0 (C-23), 42.3 (C-5), 45.0 (C-11), 47.6 (C-30′), 48.5
(C-40′), 50.2 (C-8), 50.3 (C-10), 52.3 (C-25), 53.0 (C-23′), 53.2
(C-12), 54.1 (C-18′), 55.8 (C-22), 56.9 (C-33′), 57.0 (C-8′), 58.3
(C-19′), 59.2 (C-24′), 60.5 (C-27′), 60.4 (C-5′), 65.2 (C-19), 66.9
(C-43′), 67.6 (C-45′), 76.6 (C-4), 80.3 (C-3), 83.2 (C-2), 93.9 (C-
17), 100.5 (C-9′), 111.5 (C-14′), 118.7 (C-15), 119.1 (C-11′), 121.1
(C-14), 122.8 (C-3′), 122.8 (C-12′), 124.4 (C-7), 124.6 (C-13′),
125.0 (C-13), 128.2-128.7 (10 Car), 129.8 (C-6), 130.5 (C-10′),
133.0 (C-4′), 134.6 (C-15′), 135.6 (2 Cq.ar), 135.9 (C-17′), 154.6
(C-18), 158.9 (C-16), 170.0 (C-25′), 170.8 (C-38′), 171.0 (C-42′,
C-44′), 172.2 (C-26), 172.8 (C-24), 174.6 (C-22′); IR (cm-1) 2962,
2358, 1739, 1656, 1243; [R]D +18 (c 1.2, CH2Cl2); HR-EI-MS m/z
1342.6667 (M+, calcd for C76H92N7O15 1342.6651).
Computational Procedures. All calculations were performed
on a PC workstation. All modeling studies were performed using
Sybyl 7.3 software. The MMFF94 force field was used for
minimization and partial charge calculations, a dielectric constant
of 1.0 being employed. Compounds 22 and 27 were subjected
to an unrestrained molecular dynamics simulation at 1600 K for
20 000 fs. Conformations were sampled every 100 fs during the
simulation, resulting in 200 randomized structures. Each of these
conformers was minimized and compared with others with a
rms of 0.3 Å. The obtained structures were ranked according to
energy. They were analyzed using Sybyl 7.3 software, and
superimposition of conformers was based on the backbone atoms
of vinblastine. Docking experiments on compounds 22 and 27