17-substituted geldanamycin derivatives
G-z Shan et al
1
81
a
b
1
00.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
.0
100.0
9
8
90.0
80.0
7
6
5
4
3
2
1
70.0
60.0
50.0
40.0
30.0
20.0
10.0
0
.00
.48
2.40
0.00
0.48
2.40
2.00
0
0
0.0
1
0
.00
12.00
0.00
0.04
8.19
0.08
24.57
Concentration of Ribavirin
ꢀmol/L)
73.71
0.16
Concentration of 2b (ꢀmol/L)
(
Figure 3 Anti-hepatitis C virus (HCV) synergistic effects of 2b (a) and ribavirin (b) with Intron A (interferon-a-2b) in GS4.3 HCV replicon cells.
(
(
m, 1H), 3.54–3.62 (m, 1H), 3.78–3.85 (m, 1H), 3.91–3.95 (m, 1H), 4.08–4.11 CDCl ): d 0.96–1.01 (m, 5H), 1.09–1.14 (s, 3H), 1.51–1.55 (m, 5H), 1.76–1.80
3
m, 1H), 4.31 (d, J¼9.6 Hz, 1H), 4.71 (br, 2H), 5.19 (s, 1H), 5.80–5.92 (m, 2H), (m, 2H), 1.81 (s, 3H), 1.90–2.00 (m, 1H), 2.03 (s, 3H), 2.21–2.29 (m, 2H),
6
.54–6.61 (m, 1H), 6.96 (d, J¼11.2Hz, 1H), 7.28 (s, 1H) and 9.17 (br, 1H). 2.35–2.46 (m, 1H), 2.65–2.80 (m, 3H), 3.27 (s, 3H), 3.37 (s, 3H), 3.41–3.76
+
MS(FAB) m/z calcd. for C H N O 629; found (M+Na ) 652.
(m, 4H), 4.32 (d, J¼10.0 Hz, 1H), 4.51–4.70 (m, 2H), 5.19 (s, 1H), 5.83–5.94
m, 2H), 6.59 (t, J¼11.2 Hz, 1H), 6.96 (d, J¼11.2 Hz, 1H), 7.16–7.21 (m, 1H),
3
3 47 3 9
(
1
7-(2¢-(S)-THFM)-17-demethoxygeldanamycin (2c). Compound 2c was
7
.26–7.32 (m, 1H) and 9.22 (d, J¼6.4 Hz, 1H). MS(ESI) m/z calcd. for C35H52N4O8
synthesized (yield 66%) as purple solid (HPLC purity: 98.7%).
a
+
6
56.4; found (M+H ) 657.3.
20
a]436¼+782.01 (c¼0.0160, CH3OH). m.p. 158–1611C. The 1H NMR
[
(
400 MHz, CDCl ): d 0.93–1.16 (m, 6H), 1.25 (s, 2H), 1.32–1.42 (m, 1H),
3
17-(2¢-(1¢-Oxa-4¢-aza-heterocyclohexyl-1¢-)ethylamino)-17-demethoxygeldana-
mycin (2h). Compound 2h was synthesized (yield 47%) as a purple solid
1
.60–1.72 (m, 2H), 1.73–1.78 (m, 2H), 1.80 (s, 3H), 1.91–1.96 (m, 2H), 2.06
(
s, 3H), 2.43–2.47 (m, 1H), 2.90–3.02 (m, 2H), 3.23 (s, 3H), 3.39 (s, 3H),
20
(
HPLC purity: 99.8%). [a]436¼+871.21 (c¼0.0189, CH3OH). m.p. 125–128 1C.
3
.27–3.36 (m, 2H), 3.79–3.96 (m, 2H), 4.20–4.37 (m, 2H), 4.97 (s, 1H),
.45–5.60 (m, 1H), 5.82–6.02 (m, 1H), 6.52–6.62 (m, 1H), 6.95–7.00
1
The H NMR (400MHz, CDCl ): d 0.89–1.03(m, 6H), 1.28–1.38 (m, 2H),
3
5
1.42–1.51 (m, 1H), 1.64–1.68 (m, 2H), 1.78 (s, 3H), 2.03 (s, 3H), 2.50–2.61
(
found (M+Na ) 652.
m, 1H) and 7.26–7.31 (m, 1H). MS(FAB) m/z calcd. for C33H47N3O9 629;
(
(
m, 4H), 2.64–2.71 (m, 4H), 2.70–2.81 (m, 1H), 3.27 (s, 3H), 3.36
s, 3H), 3.44 (d, J¼9.2Hz, 1H), 3.54 (br, 1H), 3.58 (d, J¼9.2 Hz, 1H), 3.64–
+
3
.80 (m, 4H), 4.31 (d, J¼10.0Hz, 1H), 4.41 (br, 1H), 4.86 (br, 2H), 5.19
1
7-THFM-17-demethoxygeldanamycin (2d). Compound 2d was synthesized
(
s, 1H), 5.83 (t, J¼10.0Hz, 1H), 5.87 (d, J¼9.6 Hz, 1H), 6.59 (t, J¼11.2Hz,
H), 6.96 (d, J¼11.6Hz, 1H), 7.15 (s, 1H) and 9.19 (s, 1H). MS(FAB)
(
(
yield 70%) as a purple solid (HPLC purity: 97.7%). [a]4 23 06 ¼+845.61
1
1
c¼0.0177, CH3OH). m.p. 126–1291C. The H NMR (400MHz, CDCl3):
+
m/z calcd. for C34H50N4O9 658.4; found (M+H ) 659.3.
d 0.90–1.01 (m, 6H), 1.25 (s, 2H), 1.40–1.52 (m, 1H), 1.61–1.65 (m, 2H),
1
.70–1.74 (m, 2H), 1.79 (s, 3H), 1.93–1.98 (m, 2H), 2.02 (s, 3H), 2.36–2.39
1
7-(2¢-(1¢-Azaheterocyclohexyl-1¢-)ethylamino)-17-demethoxygeldanamycin (2i).
(
m, 1H), 2.66–2.75 (m, 2H), 3.26 (s, 3H), 3.36 (s, 3H), 3.42–3.49 (m, 1H),
Compound 2i was synthesized (yield 42%) as a purple solid (HPLC purity:
20
3
1
1
.56–3.62 (m, 1H), 3.79–3.95 (m, 2H), 4.08–4.11 (m, 1H), 4.31 (d, J¼10.0 Hz,
1
9
9.9%). [a]436¼+904.91 (c¼0.0156, CH3OH). m.p. 211–214 1C. The H NMR
H), 4.80 (br, 1H), 5.19 (s, 1H), 5.85 (t, J¼11.2Hz, 1H), 5.90 (d, J¼10.0 Hz,
(400 MHz, CDCl ): d 0.85–0.98 (m, 6H), 1.01–1.36 (m, 4H), 1.48–1.51 (m, 3H),
3
H), 6.58 (t, J¼11.4 Hz, 1H), 6.95 (d, J¼11.6Hz, 1H), 7.27 (s, 1H) and 9.16
1.62–1.70 (m, 5H), 1.81 (s, 3H), 2.03 (s, 3H), 2.32–2.37 (m, 4H), 2.42 (s, 1H),
+
(
s, 1H). MS(FAB) m/z calcd. for C H N O 629; found (M+Na ) 652.
33 47 3 9
2.59–2.67 (m, 4H), 2.74–2.86 (m, 1H), 3.27 (s, 3H), 3.37 (s, 3H), 3.43
(
d, J¼9.2 Hz, 1H), 3.58 (d, J¼9.2 Hz, 1H), 3.68 (br, 1H), 4.31
d, J¼10.0 Hz, 1H), 4.50 (br, 1H), 4.78 (br, 2H), 5.19 (s, 1H), 5.83
(t, J¼10.4 Hz, 1H), 5.93 (d, J¼9.6 Hz, 1H), 6.56 (t, J¼11.6Hz, 1H), 6.97
d, J¼11.6 Hz, 1H), 7.25 (br, 1H) and 9.19 (s, 1H). MS(FAB) m/z calcd. for
1
7-(3¢,4¢-Methylenedioxybenzylamino)-17-demethoxygeldanamycin (2e). Com-
(
pound 2e was synthesized (yield 74%) as a purple solid (HPLC purity: 98.4%).
a] 42 306 ¼+431.21 (c¼0.0177, CH3OH). m.p. 206–2101C. The 1H NMR
[
(
(
(
(
400 MHz, CDCl ): d 0.99–1.03 (m, 6H), 1.80 (s, 3H), 2.03 (s, 3H), 2.41–2.47
3
+
C H N O 656.4; found (M ) 656.3.
35 52 4 8
m, 1H), 2.68 (d, 1H), 2.73–2.77 (m, 1H), 2.88 (br, 1H), 2.95 (br, 1H), 3.27
s, 3H), 3.37 (s, 3H), 3.44–3.60 (m, 2H), 4.18 (br, 1H), 4.31 (d, J¼10.0 Hz, 1H),
1
7-[(1¢R,5¢S)-6¢,6¢-dimethylbicyclo[3.1.1]heptan-3¢-yl)methanamine]-17-
4
6
1
.48–4.68 (m, 2H), 4.79 (br, 2H), 5.19 (s, 1H), 5.84–5.93 (m, 2H), 5.99 (d, 2H),
.36 (br, 1H), 6.58 (t, J¼11.5Hz, 1H), 6.73–6.82 (m, 3H), 6.96 (d, J¼12.0Hz,
demethoxygeldanamycin (2j). Compound 2j was synthesized (yield 56%) as a
purple solid (HPLC purity: 99.7%). [a] ¼+625.01 (c¼0.0156, CH OH). m.p.
2
0
4
36
3
H), 7.30 (s, 1H), 8.02 (br, 1H) and 9.16 (s, 1H). MS(ESI) m/z calcd. for
+
1
1
30–1331C. The H NMR (400MHz, CDCl ): d 0.87–0.98 (m, 6H), 1.02
3
C36H45N3O10 679.3; found (M+Na ) 702.2.
(
(
(
s, 3H), 1.31 (s, 3H), 1.55–1.60 (m, 3H), 1.72 (m, 1H), 1.80 (s,3H), 1.93–1.98
m, 6H), 2.03 (s, 3H), 2.31–2.77 (m, 5H) 3.27 (s, 3H), 3.37 (s, 3H), 3.40–3.60
m, 4H), 4.30 (d, J¼10.0Hz, 2H), 4.37 (br, 1H), 4.72 (br, 2H), 5.19 (s, 1H),
17-(1¢-Diethylphosphonate-methylamine)-17-demethoxygeldanamycin (2f). Com-
pound 2f was synthesized (yield 56%) as a purple solid (HPLC purity: 98.4%).
20
1
5.86 (t, J¼11.2Hz, 1H), 5.90 (d, J¼10.0 Hz, 1H), 6.38 (br,1H), 6.58
[
a]436¼+733.31 (c¼0.0161, CH3OH). m.p. 174–177 1C. The H NMR (300 MHz,
CDCl3): d 0.94–1.04 (m, 6H), 1.36 (m, 6H), 1.60–1.82 (br, 1H), 1.83–1.91 (m, 6H),
.95–2.02 (m, 3H), 2.18 (s, 1H), 2.31–2.39 (m, 1H), 2.68–2.71 (m, 2H), 3.28
s, 3H), 3.36 (s, 3H), 3.43 (d, J¼9.2 Hz, 1H), 3.58 (d, J¼9.2 Hz, 1H), 3.91–4.02
m, 2H), 4.15–4.21 (m, 4H), 4.33 (d, J¼10.0Hz, 1H), 4.78 (br, 2H), 5.27 (s, 1H),
.81 (s, 1H), 5.90 (s, 1H), 6.32 (br, 1H), 6.67 (t, J¼11.2 Hz, 1H),6.9
(
t, J¼11.5Hz, 1H), 6.95 (d, J¼11.5 Hz, 1H) and 9.14 (s, 1H). MS(FAB) m/z
+
calcd. for C38H55N3O8 681.4; found (M ) 681.3.
1
(
1
7-(3¢-(2¢-Amino-5¢-nitropyridin) ethylamine)-17-demethoxygeldanamycin (2k).
(
Compound 2k was synthesized (yield 40%) as a purple solid (HPLC purity:
5
20
1
9
8.3%). [a]436¼+566.71 (c¼0.0150, CH3OH). m.p. 131–134 1C. The H NMR
(400 MHz, CDCl3): 0.94–1.01 (m, 6H), 1.26–1.28 (m, 2H), 1.52
s, 1H), 1.68 (s, 2H), 1.80 (s, 3H), 2.02 (s, 3H),2.38–2.42 (m, 1H), 2.67–2.71
7-(2¢-(N-ethylpyrrolidinyl)-methylamino)-17-demethoxygeldanamycin (2g). Com- (m, 2H), 2.74–2.76 (m, 2H), 3.27 (s, 3H), 3.36 (s, 3H), 3.46–3.47 (m, 1H), 3.72
(
d, J¼11.6Hz, 1H) and 9.07 (s, 1H). MS(FAB) m/z calcd. for C H N O P
33 50 3 11
+
d
6
95; found (M+Na ) 718.
(
1
pound 2g was synthesized (yield 86%) as a purple solid (HPLC purity: 96.2%). (d, 1H), 3.84 (br, 1H), 4.31 (d, J¼10.0Hz, 1H), 4.75 (br, 2H), 5.19 (s, 1H), 5.56
[
a] 42 ¼+843.81 (c¼0.0159, CH OH). m.p.106–109 1C. The H NMR (400 MHz,
0
1
(br, 1H), 5.83–5.90 (m, 2H), 6.46 (br, 1H), 6.58 (t, J¼11.2 Hz, 1H), 6.96
36
3
The Journal of Antibiotics