Synthesis, cytotoxic activities and cell cycle arrest profiles of naphtho[2,1-α]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dione glycosides

Article abstract of DOI:10.1016/j.bmcl.2011.04.145

Naphtho[2,1-α]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dione (NPCD) is known to be a very potent and selective cyclin D1-CDK4 inhibitors and could induce strong G1 phase arrest in breast tumor cell lines. In this work, the synthesis of five NPCD glycosides and

Full text of DOI:10.1016/j.bmcl.2011.04.145

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3531–3535
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Bioorganic & Medicinal Chemistry Letters
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Synthesis, cytotoxic activities and cell cycle arrest profiles of
naphtho[2,1-a]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dione glycosides
Ning Ding a,b, Xiaoguang Du c, Wei Zhang a, Zhichao Lu d, Yingxia Li a,
⇑
a Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China
b State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica Chinese Academy of Science, Shanghai 201203, China
c Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica Chinese Academy of Science, Shanghai 201203, China
d School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Naphtho[2,1-a]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dione (NPCD) is known to be a very potent and
Received 20 January 2011
Revised 12 April 2011
Accepted 30 April 2011
Available online 5 May 2011
selective cyclin D1-CDK4 inhibitors and could induce strong G1 phase arrest in breast tumor cell lines.
In this work, the synthesis of five NPCD glycosides and their cytotoxic activities against eight tumor cell
lines are presented, as well as the investigation of their cell cycle arrest profiles. The results showed that
the introduction of a sugar moiety onto NPCD did not affect much of their cytotoxic activities, while the
subtle structure of the sugar moiety affected the underlying mechanism strongly. In addition, NPCD
showed distinct cell-cycle arrest profiles in BxPC3 prostate cells and MCF-7 breast cells, while NPCD gly-
cosides shared similar cell cycle arrest profiles in MCF-7 and BxPC3 cells, which also indicated that not
only the indolocarbazole framework as well known before but the sugar moiety can have a profound
impact on the mechanism of action for these types of compounds.
Keywords:
Indolocarbazole
Cytotoxic
Rebeccamycin
Cell-cycle
Ó 2011 Elsevier Ltd. All rights reserved.
Glycoside
The glycosylated indolo[2,3-
a
]carbazole represents an interest-
With our continuous interest in the effect of sugar attach-
ments to a planar aromatic molecule on the biological activities10
and in order to search for potential antitumor agents of NPCD
class with high developability value, we decide to synthesize
and evaluate NPCD glycosides on the tumor cell growth inhibitory
activities.
ing class of compounds that exhibit diverse biological activities.1
There are two classes of indolocarbazole glycosides, differ both in
structure and in mechanism of action (Fig. 1). The staurosporine
class containing two glycosidic bonds linked to the indolocarbazole
heterocycle is inhibitors of protein kinases.2 In contrast, the rebec-
camycin3 class of indolocarbazole glycosides has a single glycosidic
linkage and has shown remarkable activity in the poisoning of DNA
topoisomerase I.4 And this latter class is currently under evaluation
in the clinic for treatment of a variety of malignancies including
advanced renal carcinoma, metastatic or locally recurrent colorec-
tal cancer and stage IIIB or IV breast cancer.5
Previous studies11 have shown that rebeccamycin with just a
single N-glycosidic bond favors a single conformation in which
the pyranose oxygen atom grips the indole NH group through
an intramolecular hydrogen bond (Fig. 1). Whereas when the in-
dole NH proton of indolocarbazole glycosides is replaced with a
methyl group, which is certain to prevent intramolecular hydro-
gen bonding, the biological activity is severely compromised in
all cases tested.12 As for NPCD glycoside, since one indole ring
is replaced by a naphthyl ring, the oxygen atom in the sugar ring
thus has no chance to form an intramolecular hydrogen bond
like that it performs in rebeccamycin. However, our present
study showed that all of NPCD glycosides tested still displayed
tumor cell growth inhibitory activities as strong as NPCD. And
interestingly the subsequent cell cycle arrest investigation indi-
cated that the underlying mechanism might be very different
from that of NPCD. The results obtained will render new clues
to the understanding of the anticancer profile for these types
of compounds.
Recently, several aryl[
been developed as very potent CDK (cyclin-dependent kinases)
inhibitors.6 For instance, naphtho[2,1-
]pyrrolo[3,4-c]carbazole-
a]pyrrolo[3,4-c]carbazole analogues have
a
5,7(6H,12H)-dione7 (NPCD, Fig. 1), in which one indole ring is re-
placed by a naphthyl ring, is a very potent and selective cyclin
D1-CDK4 inhibitors. Cyclin-CDK complexes regulate the progres-
sion of cells through the cell cycle. To date, strong evidence sug-
gests a G1-phase role for D-type cyclins through associate with
CDK4 and CDK6.8 Our previous work9 has proved that NPCD can
cause long-lasting growth arrest in G1 phase and cell death of
breast cancer cell lines at an IC50 of 3–8 lM. Decreased phosphor-
ylation of Rb by D1-CDK4/6 and decreased p27kip1 protein level
may be part of the underlying mechanism.9
Several typical sugar heads, such as
-ribopyranosyl, b- -glucopyranosyl, b-
deoxy-b-
atom of NPCD (1a–e, Table 1).13
a
-
L
-rhamnopyranosyl,
a-
D
D
D-ribofuranosy, 2-
D
-ribofuranosyl were introduced onto the indole nitrogen
⇑
Corresponding author. Tel.: +86 21 51980120; fax: +86 21 51980127.
E-mail address: liyx417@fudan.edu.cn (Y. Li).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.04.145

3532
N. Ding et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3531–3535
H
N
H
H
N
O
N
O
O
O
O
N
N
N
N
N
H
O
Cl
Cl
H
O
H
Me
OH
NPCD
HO
MeO
NHMe
HO
H3CO
Staurosporine
Rebeccamycin
Figure 1. Chemical structures of staurosporine, rebeccamycin and NPCD.
and 12 were deesterified and the resulting intermediates were
then protected by PMB groups on the sugar hydroxyls to form com-
pounds 13 and 14, respectively. Upon treated with oxalyl chloride
and sodium methoxide at a low temperature (À60 °C), compounds
13 and 14 were converted to 2d and 2e smoothly.
Table 1
Structures of NPCD and its glycosides 1a–e
H
N
O
O
The new NPCD glycosides were screened for their tumor cell
growth inhibitory activities by 74 h drug exposure. The IC50 values
of NPCD glycosides 1a–e along with NPCD for comparison against
eight tumor cell lines are presented in Table 2. All the NPCD glyco-
sides displayed good antitumor cell growth activities as strong as
NPCD. These results indicated that introduction of a sugar moiety
onto NPCD did not affect much of the cytotoxic activities.
N
Sugar
Compound
R
NPCD
1a
1b
H
a
a
Analysis of cell cycle profile with FACS revealed that NPCD
treatment of MCF-7 breast cells at a concentration of 10 lM for
-
L
-Rhamnopyranosyl
-D-Ribopyranosyl
24 h significantly arrested the cells at G1 phase, as evidenced by
an increased percentage of the cells at G1 phase and a correspond-
ing decrease in the percentage of the cells at S phase (Fig. 2). How-
ever, NPCD glycosides 1a–e did not show any G1-phase arrest,
instead slight to strong S phase arrests were observed at a concen-
1c
1d
1e
b-
b-
D
-Glucopyranosyl
-Ribofuranosyl
D
2-Deoxy-b-D-ribofuranosyl
All of the NPCD glycosides were synthesized following an opti-
mized modular synthetic approach developed by Faul et al.14
(Scheme 1). The key intermediates maleimides 3a–e were pre-
pared in good yields by condensation of (N-glycosyl indolyl)-3-gly-
oxylyl esters 2a–e with the complementary naphthylacetamide in
the presence of t-BuOK. Deprotection of the PMB groups on the su-
gar rings of 3a–e provided compounds 4a–e. Cyclizations of 4a–e
to the N-glycosyl naphthylcarbazoles 1a–e were achieved by irra-
diation of their dry acetone solution with Osram Hg HP (HQL
125W) lamp for 48 h.
tration of 10 lM (Fig. 2). These results suggested the underlying
mechanisms of NPCD glycosides might be very different from that
of NPCD. In addition, the different cell cycle arrest profiles of NPCD
glycosides between themselves revealed that the subtle structure
of sugar moiety in these compounds affected the underlying mech-
anism strongly.
Although we have proved before that NPCD targeted D1-CDK4/
6 and thus induced G1-phase arrest in several breast tumor cell
lines including MCF-79, this has not been proved in other gland cell
lines before. But interestingly, when BxPC3 prostate cells were
(N-Glycosyl indolyl)-3-glyoxylyl esters 2a–c which contain the
sugar moiety of pyranosyl configuration were prepared as shown
in Scheme 2. Direct coupling of the free sugars with indoline
heated at reflux in ethanol furnished the indoline N-glycosides
treated with NPCD (10 lM), a significant increased percentage of
the cells at G2/M phase was observed (Fig. 3), which suggested that
NPCD might target the critical regulators of G2/M progression8 of
BxPC3 cells. The different cell-cycle arrest profiles of NPCD in
MCF-7 and BxPC3 cells make it an interesting molecule for biolog-
ical research.
In contrast, the NPCD glycosides, especially for 1c–e, which dis-
played clear S phase arrest effect in MCF-7 cells, still induced
strong S phase arrest in BxPC3 cells. The results suggested that
these NPCD glycosides probably targeted the same cell-cycle regu-
lators in BxPC3 cells as those in MCF-7 cells, respectively, which
indicated the sugar moieties played a more important role here
than their aglycon part (NPCD part) during the interaction with
their targets, otherwise they might change much of the cell cycle
arrest profiles as NPCD did. The detailed mechanisms of NPCD
and its glycosides on the cell cycles both in MCF-7 and BxPC3 cells
were under investigation.
5a–c (a-glycosidic bond for 5a, a-glycosidic bond for 5b, b-glyco-
sidic bond for 5c). Upon treated by DDQ, crude 5a–c were con-
verted to indolyl N-glycosides 6a–c smoothly, which were then
protected on the sugar hydroxyls by PMB groups to provide
7a–c. Compounds 2a–c were then prepared in good yields by treat-
ment of indolyl N-glycosides 7a–c in Et2O with oxalyl chloride, fol-
lowed by sodium methoxide at a temperature of À60 °C.
The synthesis of (N-glycosyl indolyl)-3-glyoxylyl esters 2d and
2e, which both contain the sugar moiety of furanosyl configuration,
were described in Scheme 3. Ribofuranosyl per-acetate 8 was em-
ployed as the glycosyl donor to be coupled with indoline to form
the N-(b-
DDQ to convert the indoline moiety to an indole ring (compound
10). While for the preparation of N-(2-deoxy-b- -ribofuranosyl) in-
dole 12, p-methyl benzoyl protected 2-deoxy- -ribofuranosyl
D-ribofuranosyl) indoline 9, which was then treated with
D
In conclusion, we have conducted the synthesis and evaluation
of a panel of NPCD glycosides on their cytotoxic activities as well as
cell cycle arrest profiles in MCF-7 and BxPC3 cells. Glycosides 1a-e
shared a same planar aromatic aglycon (NPCD) and showed almost
a-D
chloride 11 was employed as the donor to carry out the glycosyla-
tion with indole directly in the presence of NaH. Compounds 10

N. Ding et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3531–3535
3533
NH2
H
N
H
N
O
O
O
O
O
(i)
(iii)
+
O
O
N
N
R
O
R'
3a-e: R = ( PMBO)m-sugars
(ii)
N
4a-e:
R = ( HO)m-sugars
1a-e: R = ( HO)m-sugars
R
2a-e: R = ( PMBO)m-sugars
Scheme 1. General route to the synthesis of NPCD glycosides. Reagents and conditions: (i) t-BuOK, THF, 42% for 3a, 46% for 3b, 58% for 3d, 73% for 3e; (ii) DDQ, CH2Cl2/H2O (v/
v = 10:1), 51% for 4a, 60% for 4b, 31% for 4c over two steps, 58% for 4d, 39% for 4e; (iii) hv, acetone, 60% for 1a, 75% for 1b, 72% for 1c, 64% for 1d, 50% for 1e.
OH
(i)
(ii)
O
+
N
N
(OH)m
N
H
R
O
O
(OH)m
(OH)m
R
R
6a-c
5a-c
O
O
O
(iv)
(iii)
N
O
+
N
O
(OPMB)m
(OPMB)m
R
R
7a-c
2a-c
Scheme 2. General route to the synthesis of 2a–c. Reagents and conditions: (i) EtOH, reflux; (ii) DDQ, 1,4-dioxane, 38% for 6a, 60% for 6b, 47% for 6c; (iii) NaH, PMBCl, THF,
44% for 7a, 33% for 7b, 85% for 7c; (iv) (COCl)2, MeONa, MeOH, THF 88% for 2a, 75% for 2b, 82% for 2c.
AcO
(i)
O
N
N
(ii)
OAc
+
N
H
OAc
OAc
OAc
OAc
O
O
AcO
OAc
AcO
AcO
8
9
10
(iv, v)
O
O
O
O
O
N
Cl
+
(iii)
O
(iv, v)
N
R
O
O
O
N
O
H
O
PMBO
OPMB
11
12
13
R = OPMB
14 R = H
O
O
O
(vi)
N
R
O
2d
R = OPMB
2e R = H
PMBO
OPMB
Scheme 3. General route to the synthesis of 2d–e. Reagents and conditions: (i) EtOH, H2O, 80 °C, 52%; (ii) DDQ, 1,4-dioxane, 73%; (iii) NaH, CH3CN, 0 °C, 73%; (iv) MeONa,
MeOH; (v) NaH, PMBCl, THF, 88% for 13 over two steps, 34% for 14, over 2 steps; (vi) (COCl)2, MeONa, MeOH, THF 88% for 2d, 62% for 2e.

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N. Ding et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3531–3535
Table 2
Cytotoxic activities of NPCD and its glycosides on eight tumor cell lines (IC50, in lM)
BxPC3
PC3
MCF-7
MDA-MB-435
MDA-MB-231
MDA-MB-468
A549
HCT116
1a
1b
1c
1d
1e
NPCD
7.3 2.9
6.6 1.7
5.4 1.8
5.3 2.1
7.4 3.1
8.3 2.5
2.7 0.2
2.1 0.6
2.3 0.9
2.4 0.9
2.6 0.8
5.9 1.3
4.5 1.0
4.8 2.3
6.1 3.5
5.3 3.0
7.3 3.5
8.3 4.2
3.6 0.1
3.3 0.3
3.5 0.2
3.2 0.1
4.1 0.5
5.7 1.5
4.7 0.8
3.3 0.2
2.7 0.2
2.4 0.3
3.3 0.0
8.1 0.6
5.0
3.4
6.1
4.4
9.1
>10
2.8
2.0
2.8
2.1
3.4
2.6
3.1 0.8
6.0 0.7
5.1 0.0
3.8 0.3
8.7 1.0
5.7 1.3
References and notes
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Mahler, M.; Beaulieu, F.; Bachand, C.; Lee, F. Y.; Fairchild, C. R.; Stadnick, L. K.;
Rose, W. C.; Solomon, C.; Wong, H.; Martel, A.; Wright, J. J.; Kramer, R.; Langley,
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D. L. J. Org. Chem. 2000, 65, 7541; (e) Anizon, F.; Belin, L.; Moreau, P.; Sancelme,
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3. Nettleton, D. E.; Doyle, T. W.; Krishnan, B.; Matsumoto, G. K.; Clardy, J.
Tetrahedron Lett. 1985, 26, 4011.
4. Anizon, F.; Belin, L.; Moreau, P.; Sancelme, M.; Voldoire, A.; Prudhomme, M.;
Ollier, M.; Severe, D.; Riou, J. F.; Bailly, C.; Fabbro, D.; Meyer, T. J. Med. Chem.
1997, 40, 3456.
Figure 2. MCF-7 Cell-cycle arrest profile of compounds 1a–e and NPCD (10 lM for
each compound).
5. Chisholm, J. D.; Vranken, D. V. J. Org. Chem. 2000, 65, 7541.
6. (a) Zhu, G.; Conner, S.; Zhou, X.; Shih, C.; Brooks, H. B.; Considine, E.; Dempsey,
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Bioorg. Med. Chem. Lett. 2003, 13, 1231; (b) Routier, S.; Peixoto, P.; Mérour, J.-Y.;
Coudert, G.; Dias, N.; Bailly, C.; Pierré, A.; Léonce, S.; Caignard, D.-H. J. Med.
Chem. 2005, 48, 1401; (c) Bourderioux, A.; Kassis, P.; Mérour, J.-Y.; Routier, S.
Tetrahedron 2008, 64, 11012.
7. Sanchez-Martinez, C.; Shih, C.; Faul, M. M.; Zhu, G.; Paal, M.; Somoza, C.; Li, T.;
Kumrich, C. A.; Winneroski, L. L.; Xun, Z.; Brooks, H. B.; Patel, B. K. R.; Schultz, R.
M.; DeHahn, T. B.; Spencer, C. D.; Watkins, S. A.; Considine, E.; Dempsey, J. A.;
Ogg, C. A.; Campbell, R. M.; Anderson, B. A.; Wagner, J. Bioorg. Med. Chem. Lett.
2003, 13, 3835.
8. See reviews: (a) Mclnnes, C. Drug Discovery Today 2008, 13, 875; (b)
Malumbres, M.; Pevarello, P.; Barbacid, M.; Bischoff, J. R. Trends Pharmacol.
Sci. 2007, 29, 16.
9. Sun, Y.; Li, Y. X.; Wu, H. J.; Wu, S. H.; Wang, Y. A.; Luo, D. Z.; Liao, D. Z. J. Cancer
2011, 2, 36.
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5183; (b) Gui, M.; Shi, D.; Huang, M.; Zhao, Y.; Sun, Q.; Zhang, J.; Chen, Q.; Feng,
J.; Liu, H.; Li, M.; Li, Y.; Geng, M.; Jian, D. Invest. New Drugs 2010, 28, 1.
11. Facompré, M.; Carrasco, C.; Vezin, H.; Chisholm, J. D.; Yoburn, J. C.; Van
Vranken, D. L.; Bailly, C. Chem. Biol. Chem. 2003, 4, 386.
12. (a) Bailly, C.; Qu, X. G.; Graves, D. E.; Prudhomme, M.; Chaires, J. B. Chem. Biol.
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Aubertin, A. M. J. Med. Chem. 1998, 41, 1631.
Figure 3. BxPC3 cell-cycle arrest profile of compounds 1a–e and NPCD (10 lM for
each compound).
13. Data for 1a–e: 14-(
a
-
L
-Rhamnopyranosyl)-naphtho[2,1-
a
]pyrrolo[3,4-c]
carbazole-5,7(6H,12H)-dione (1a): 1H NMR (600 MHz, DMSO-d6)
d
11.41
the same tumor cell growth inhibitory activities as that of NPCD in
general, but they displayed different cell cycle arrest profiles from
NPCD and each other both in MCF-7 and BxPC3 cells. In addition,
NPCD showed distinct cell cycle arrest profile in BxPC3 prostate
cells from that in MCF-7 breast cells. However, NPCD glycosides
shared similar cell cycle arrest profiles in MCF-7 to those in BxPC3
cells. These results indicated that not only the indolocarbazole
framework as well known before1,6,15 but the sugar moiety can
have a profound impact on the mechanism of action. The results
obtained will render new clues to the understanding of the anti-
cancer profile for these types of compounds.
(s,1H, –NH), 9.37 (d, 1H, J = 8.4 Hz), 9.26 (d, 1H, J = 8.0 Hz), 8.47 (d, 1H,
J = 8.8 Hz), 8.41 (d, 1H, J = 9.2 Hz), 8.10 (d, 1H, J = 9.2 Hz), 8.07 (d, 1H,
J = 7.7 Hz), 7.75 (t like, 1H, J = 7.0, 7.7 Hz), 7.67 (t like, 1H, J = 7.0, 8.4 Hz),
7.53 (t like, 1H, J = 7.0, 8.4 Hz), 7.40 (t like, 1H, J = 7.0, 7.3 Hz), 6.39 (s, 1H), 5.73
(d, 1H, J = 5.1 Hz, –OH), 5.11 (d, 1H, J = 5.5 Hz, –OH), 5.09 (d, 1H, J = 5.9 Hz, –
OH), 4.70 (s, 1H), 3.84 (t, 1H, J = 5.0, 5.9 Hz), 3.57 (td, 1H, J = 5.1, 9.5 Hz), 3.42–
3.47 (m, 1H), 1.17 (d, 3H, J = 5.8 Hz); 13C NMR (150 MHz, DMSO-d6) d 170.3,
169.8, 142.3, 141.3, 131.9, 130.7, 128.1, 128.1, 128.0, 127.9, 127.0, 126.4, 125.5,
124.3, 122.7, 122.2, 121.6, 121.3, 121.2, 118.1, 117.0, 87.6, 75.4, 73.0, 72.2,
71.4, 17.9; ESI–MS (m/z): 483.1 [M+H]+, (Calcd 483.15). 14-(b-
ribopyranosyl)-naphtho[2,1- ]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dione
D-
a
(1b): 1H NMR (600 MHz, DMSO-d6) d 11.41 (s,1H, –NH), 9.53 (d, 1H, J = 8.4 Hz),
9.24 (d, 1H, J = 8.1 Hz), 8.56 (d, 1H, J = 9.1 Hz), 8.10 (dd, 2H, J = 7.7, 9.1 Hz), 8.02
(d, 1H, J = 8.4 Hz), 7.76 (t like, 1H, J = 7.3, 7.7 Hz), 7.71 (t like, 1H, J = 7.3, 8.4 Hz),
7.59 (t like, 1H, J = 7.3, 7.7 Hz), 7.46 (t like, 1H, J = 7.3, 7.7 Hz), 6.34 (d, 1H,
J = 9.5 Hz, H-1), 5.12 (d, 1H, J = 3.0 Hz, –OH), 5.00 (d, 1H, J = 6.6 Hz, –OH), 4.91
(d, 1H, J = 6.5 Hz, –OH), 4.48 (ddd, 1H, J = 2.6, 6.6, 9.5 Hz), 3.99–4.05 (m, 2H),
3.84–3.88 (m, 2H); 13C NMR (150 MHz, DMSO-d6) d 170.4, 169.8, 143.0, 141.6,
132.1, 130.5, 128.4, 128.3, 128.1, 128.1, 127.4, 127.3, 126.9, 125.8, 125.3, 122.5,
122.3, 121.8, 121.7, 121.5, 116.6, 115.3, 85.6, 71.7, 67.2, 66.6, 65.9; ESI–MS (m/
Acknowledgments
This work is supported by National High-tech R&D Program of
China (2011AA09070105) and the State Key Laboratory of Drug
Research (SIMM0812KF-08).
z): 483.1 [M+H]+, (Calcd 483.15). 14-(b-
]pyrrolo[3,4-c]carbazole-5,7(6H, 12H)-dione (1c): 1H NMR (400 MHz,
D-glucopyranosyl)-naphtho[2,1-
a

N. Ding et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3531–3535
3535
DMSO-d6) d: 11.45 (s, 1H), 9.54 (d, J = 9.0 Hz, 2H), 9.46 (d, J = 8.3 Hz, 1H), 9.29
(d, J = 7.9 Hz, 1H), 9.24 (d, J = 8.0 Hz, 1H), 8.53 (d, J = 9.2 Hz, 1H), 8.18–8.03 (m,
4H), 7.98 (dd, J = 8.8, 4.5 Hz, 2H), 7.84 – 7.57 (m, 6H), 7.47 (dd, J = 14.1, 7.1 Hz,
2H), 6.02 (d, J = 9.2 Hz, 1H), 5.98 (d, J = 9.2 Hz, 1H), 5.27 – 5.17 (m, 3H), 5.15 (d,
J = 4.9 Hz, 1H), 5.10 (d, J = 5.8 Hz, 1H), 4.96 (t, J = 5.5 Hz, 1H), 4.80 (t, J = 5.7 Hz,
1H), 4.69 (d, J = 5.7 Hz, 1H), 4.17 (m, 1H), 3.99–3.79 (m, 4H), 3.78–3.52 (m, 3H),
3.51–3.39 (m, 3H); 13C NMR (101 MHz, DMSO-d6) d: 170.4, 169.9, 169.8, 144.9,
142.8, 141.5, 132.3, 132.2, 130.7, 130.6, 128.4, 128.2, 128.2, 128.1, 127.7, 127.5,
127.3, 127.1, 127.0, 125.9, 125.4, 125.2, 124.3, 122.5, 122.4, 122.3, 122.0, 121.9,
121.7, 121.4, 120.6, 118.2, 116.7, 115.3, 112.0, 88.9, 86.5, 80.6, 79.2, 77.8, 77.6,
70.4, 69.8, 69.5, 68.8, 61.0, 60.5; ESI–MS (m/z): 499.1 [M+H]+, (Calcd 499.15).
142.6, 132.2, 130.6, 128.4, 128.4, 128.3, 128.2, 127.5, 127.4, 127.3, 126.0, 125.4,
122.8, 122.3, 122.2, 117.1, 92.4, 70.0, 69.2, 61.2, 48.6; ESI–MS (m/z): 483.1
[M+H]+, (Calcd 483.15). 14-(b-
D-ribofuranosyl)-naphtho[2,1-a]pyrrolo[3,4-
c]carbazole-5,7(6H,12H)-dione (1e): 1H NMR (600 MHz, DMSO-d6) d 11.4 (s,
1H), 9.52 (d, 1H, J = 8.4 Hz), 9.25 (d, 1H, J = 8.0 Hz), 8.58 (d, 1H, J = 7.3 Hz), 8.15
(d, 1H, J = 9.2 Hz), 8.11 (d, 1H, J = 7.3 Hz), 8.04 (d, 1H, J = 8.0 Hz), 7.77 (td, 1H,
J = 1.1, 7.7 Hz), 7.71 (td, 1H, J = 1.4, 8.4 Hz), 7.62 (td, 1H, J = 1.0, 8.0 Hz), 7.47
(tlike, 1H, J = 7.3, 7.7 Hz), 6.54 (dd, 1H, J = 2.2, 11.0 Hz, H-1), 5.01 (d, 1H,
J = 2.6 Hz, –OH), 4.96 (d, 1H, J = 5.1 Hz, –OH), 4.08–4.12 (m, 2H, H-3, H-4),
3.92–3.99 (m, 2H, H-5ab), 2.16–2.19 (m, 1H, H-2a), 1.97–2.02 (m, 1H, H-2b);
13C NMR (150 MHz, DMSO-d6) d 170.4, 169.7, 142.0, 140.8, 132.2, 130.6, 128.3,
128.3, 128.2, 128.1, 127.2, 127.0, 127.2, 127.0, 125.6, 125.2, 123.1, 122.2, 121.9,
121.3, 116.9, 87.8, 69.4, 67.8, 66.6, 59.8, 32.4, 20.8, 14.1; ESI–MS (m/z): 453.2
[M+H]+, (Calcd 453.14).
14-(b-D-ribofuranosyl)-naphtho[2,1-a]pyrrolo[3,4-c] carbazole-5,7 (6H,12H)-
dione (1d): 1H NMR (600 MHz, DMSO-d6) d 11.43 (s,1H, –NH), 9.56 (d, 1H,
J = 8.4 Hz), 9.25 (d, 1H, J = 8.0 Hz), 8.63 (d, 1H, J = 8.4 Hz), 8.17 (d, 1H,
J = 8.0 Hz), 8.10 (dd, 2H, J = 7.7, 9.1 Hz), 7.77 (t like, 1H, J = 7.0, 7.7 Hz), 7.71
(t like, 1H, J = 7.3, 8.1 Hz), 7.60 (t like, 1H, J = 7.3, 8.1 Hz), 7.49 (t like, 1H, J = 7.3,
7.7 Hz), 6.40 (d, 1H, J = 7.0 Hz, H-1), 5.29 (t like, 1H, J = 4.7, 5.2 Hz, –OH), 5.19
(d, 1H, J = 4.8Hz, –OH), 5.17 (d, 1H, J = 5.5 Hz, –OH), 4.65–4.68 (m, 1H), 4.00–
4.18 (m, 2H), 3.80–3.91 (m, 2H); 13C NMR (150 MHz, DMSO-d6) d 170.4, 169.7,
14. (a) Faul, M. M.; Winneroski, L. L.; Kumrich, C. A. J. Org. Chem. 1998, 63, 6053–
6058; (b) Faul, M. M.; Winneroski, L. L.; Kumrich, C. A. Tetrahedron Lett. 1999,
40, 1109.
15. Pagano, N.; Wong, E. Y.; Breiding, T.; Liu, H.; Wilbuer, A.; Bregman, H.; Shen, Q.;
Diamond, S. L.; Meggers, E. J. Org. Chem. 2009, 74, 8997.