Synthesis and biological evaluation of novel benzodioxinocarbazoles (BDCZs) as potential anticancer agents

Article abstract of DOI:10.1016/j.bmcl.2010.05.088

We report the efficient synthesis and biological evaluation of new benzodioxinoindolocarbazoles heterocycles (BDCZs) designed as potential anticancer agents. Indolic substitution and maleimide variations were performed to design a new library of BDCZs and their cytotoxicity were evaluated on two representative cancer cell lines. Several derivatives have shown a marked cytotoxicity with IC₅₀ values in the nanomolar range. Results are reported in this Letter.

Full text of DOI:10.1016/j.bmcl.2010.05.088

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4670–4674
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of novel benzodioxinocarbazoles (BDCZs) as
potential anticancer agents
a
a
b
Nathalie Ayerbe a, Sylvain Routier a, , Isabelle Gillaizeau , Carmen Maiereanu , Daniel-Henry Caignard ,
*
Alain Pierré b, Stéphane Léonce b, Gérard Coudert a,
*
a Institut de Chimie Organique et Analytique, UMC CNRS 6005, rue de Chartres, BP 6759, 45057 Orléans cedex 2, France
b Institut de Recherches SERVIER, Division Recherche Cancérologie, 125 Chemin de Ronde, 78290 Croissy sur Seine, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the efficient synthesis and biological evaluation of new benzodioxinoindolocarbazoles hetero-
cycles (BDCZs) designed as potential anticancer agents. Indolic substitution and maleimide variations
were performed to design a new library of BDCZs and their cytotoxicity were evaluated on two represen-
tative cancer cell lines. Several derivatives have shown a marked cytotoxicity with IC50 values in the
nanomolar range. Results are reported in this Letter.
Received 27 March 2010
Revised 20 May 2010
Accepted 20 May 2010
Available online 26 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Benzodioxine
Indolocarbazole
Cytotoxicity
Indole
Heterocycle
Potential anticancer agent
The indolocarbazole alkaloids are a family of natural products
isolated from marine invertebrates and cultures of diverse micro-
organisms.1 Rebeccamycin (Fig. 1), an important member of this
family, is potent inhibitor of topoisomerase I. Its biological activi-
ties have made it a high profile lead compound for the develop-
ment of anticancer drugs,2 and several analogues (i.e., NB-506
and J-107088 or edotecarin) have entered clinical trials.3
A number of research groups, including ours, have sought to
synthesize various simplified derivatives (Fig. 2), lacking the sugar
moiety to obtain strong protein kinase inhibitors and/or in vitro
cytotoxic agents.4 In order to develop such selective series, bioisos-
teric replacement of one indole ring by another heteroaryl moiety
appears indeed to be a valid alternative compared to the restrictive
synthesis of glycosylated compounds.5
alyzed cross-coupling reaction starting from intermediate VII and
2-trialkylstannylbenzodioxine.
Structural variations were performed on the indolic part, for
fine-tuning developments and for establishing structure–activity
relationships. Electron rich and acceptor/donor hydrogen bond
groups were used. In addition, to induce a selective cytotoxic activ-
ity and to increase water solubility of our new heterocyclic scaf-
fold, we though to introduce a dimethylaminoalkyl chain onto
the maleimide moiety.4e–i
The synthesis began with the construction of the upper side
of the molecule via a Stille palladium cross-coupling reaction7
R
N
NHR
O
N
O
O
O
On the background of these findings, we describe herein the
preparation of new potential anticancer lead compounds bearing
an original benzodioxinocarbazole moiety.4f For the establishment
of primary structure–activity relationships of these new function-
alized carbazoles, cell studies were performed.
OH
N
H
N
H
N
N
Cl
HO
OH
Cl
OH
O
O
We endeavored to prepare original benzodioxino-pyrrolocar-
bazoles (BDCZs) V (Fig. 3) using a general synthetic route that re-
HO
HO
OH
OMe
Rebeccamycin R = H
NSC 655 649 R = (CH2)2N(C2H5)2
OH
OH
NB-506 R = CHO
J-107088 R = CH(CH2OH)2
lied on a photochemically induced 6p-electrocyclization as a key
step.4a,d,6 The synthetic strategy is also based on a Stille Pd(0)-cat-
* Corresponding authors.
E-mail address: gerard.coudert@univ-orleans.fr (G. Coudert).
Figure 1.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.05.088

N. Ayerbe et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4670–4674
4671
(Table 1) to afford in fair to good yields desired compounds 16–27.
Reactions were performed starting from 2-trimethylstannyl-ben-
zodioxine and indolo-derivatives 1–158 in the presence of
Pd(PPh3)4 and CuI in dioxane at 65 °C or 100 °C. The palladium
cross-coupling reaction could be conducted with N-Me, N-Boc or
N-H maleimide and Boc protected or unprotected indolyl com-
pounds. Indole could be functionalized by electro-donor or -with-
drawing groups. For benzyloxy derivatives (entries 5–8, 12–15)
best yields were obtained after protection of the indolyl nitrogen
with a Boc group.8
It is worth noting that ring-opened phenols 28 or 29 were iso-
lated as separable by-products starting from 7 or 8, respectively.
As previously demonstrated, these phenolic derivatives result from
the ring opening of the benzodioxane moiety obtained via a spon-
taneous [4+2] cycloaddition/ring opening sequence.9
R
N
R
N
O
O
O
O
O
O
Het/Ar
Y
X
N
H
R = H, CH3, (CH2)2N(CH3)2
II X,Y = O
I
R = H, -CH3, -(CH2)2N(CH3)2
Het/Ar = naphthalene, quinoline,
indane...
III X = NH, Y= O
IV X = NH, Y= NH
Figure 2. Examples of indolocarbazoles bioisosteres I–IV.
R1
R1
Next, our attention turned to study the key cyclization step.
Good results were obtained by performing a photochemical in-
duced 6p-electrocyclization (Table 2). This key step was accom-
O
N
O
N
O
O
O
R
O
plished by submitting coupled derivatives 16–27 to irradiation
(UV 500 W DEMA-lamp) and led to the attempted BDCZs 30–
40.10 The reaction was conducted in the presence of an excess of
diiodine in order to induce a further spontaneous aromatization.
Starting from unprotected derivatives 17–19 or 23–25, the reac-
tion led respectively to carbazoles 31–33 or 36–38 isolated as the
sole products in moderate yields (entries 2–4, 7–9). With Boc
derivatives (entries 1, 5, 6, 10, 11), both processes of b-elimination
and of aromatization concomitantly occurred which afforded a
separable mixture of attempted BDCZS and phenolic derivatives
41–45. It is noteworthy that the Boc protective group of the indolyl
nitrogen survives to the experimental conditions whereas the
maleimide Boc protection is cleaved (entries 10 and 11).
R
O
N
N
O
H
P
VI
V Benzodioxinocarbazoles (BDCZs)
R = H, F, OH
R1 = CH3, H, -(CH2)2N(CH3)2
R1
O
N
O
Pd(0)
O
O
Br
VI
R
M
N
P
To fully prepare our derivatives for biological assays and to en-
hance their solubility, additional reactions were next performed
(Table 3). Maleimide substitution was carried out by heating the
starting carbazoles 31–35 in the presence of N,N-dimethylethyl-
enediamine (entries 1–5).11 The transimidification process led to
VII
VIII
M = SnR3
P = H, Boc
R1 = H, CH3, Boc
Figure 3. General synthetic scheme.
Table 1
Stille palladium cross-coupling procedurea
R1
N
R1
N
R1
N
O
O
O
O
O
O
O
Pd(0)
Br
O
R
R
R
O
O
HO
O
SnMe3
N
N
N
R2
16-27
R2
R2
1-15
28-29
Entry
Compound
R
R1
R2
Time
CuI (mol %)
Productsb (yields %)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
H
H
5-F
6-F
5-OBn
6-OBn
5-OBn
6-OBn
H
5-F
6-F
5-OBn
6-OBn
5-OBn
6-OBn
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
Boc
H
H
H
H
1 h
20
20
10
10
20
10
20
10
10
10
10
10
10
10
10
16c (82%)
17 (79%)
18 (81%)
19 (82%)
Degradation
20 (64%)
21 (76%), 28 (20%)
22 (84%), 29 (16%)
23 (76%)
24 (82%)
25 (85%)
Degradation
Degradation
26 (69%)
1 h 45 min
1 h 40 min
45 min
1 h
50 min
50 min
30 min
2 h
2 h40
1 h50
1 h
1 h
1 h10
2 h
H
Boc
Boc
H
H
H
H
H
Boc
Boc
Boc
Boc
27 (65%)
a
b
c
Reagents and conditions: (a) PdCl2(PPh3)2 10 mol %, CuI 10 or 20 mol %, dioxane 65 °C.
Yields are indicated as isolated products.
The reaction was conducted at 100 °C.

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N. Ayerbe et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4670–4674
Table 2
Photochemical stepa
R1
N
R1
N
R1
N
O
O
O
O
O
O
O
O
hν, I2
R
R
O
R
O
toluene
O
HO
N
N
N
R2
30-40
R2
R2
16-27
41-45
Entry
Compound
R
R1
R2
Time
30 min
1 h 10 min
30 min
30 min
40 min
30 min
45 min
40 min
1 h 30 min
30 min
Productsb (yields %)
1
2
3
4
5
6
7
8
9
16
17
18
19
21
22
23
24
25
26
27
H
H
5-F
6-F
5-OBn
6-OBn
H
5-F
6-F
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
Boc
Boc
Boc
H
H
30 (23%)c
31(51%)
32 (55%)
33 (38%)
34 (38%)c
35 (21%)c
36 (52%)
37 (25%)
38 (24%)
39 (27%)c,d
40 (27%)c,d
H
Boc
Boc
H
H
H
10
11
5-OBn
6-OBn
Boc
Boc
30 min
a
Conditions: h
m
, 500 W DEMA-lamp, I2 (14.0 equiv), toluene.
Yields are indicated as isolated product.
Starting from 16, 21, 22, 26 and 27, the corresponding opened compounds 41 (12%), 42 (13%), 43 (22%), 44 (non determined) and 45 (27%, R1 = H) were, respectively,
b
c
isolated as by-products.
d
R1 = H.
Table 3
Deprotections of BDCZs 30–40 and maleimide reactions
R1
N
R1
N
O
O
O
O
R
a
b
and/or
R
O
O
O
N
O
N
H
R2
31-35, 39-40
46-56
Entry
1a
Starting materials
R
R1
R2
H
Productsd (yields %)
46 (75%)
R
R1
31
32
33
34
35
H
CH3
CH3
CH3
CH3
CH3
H
N
N
N
N
N
2a
5-F
H
47 (75%)
5-F
3a
6-F
H
48 (76%)
6-F
4a
5-OBn
6-OBn
Boc
Boc
49 (89%)
5-OBn
6-OBn
5a
50 (75%)
6b
7b
8b
9b
34
35
39
40
5-OBn
6-OBn
5-OBn
6-OBn
CH3
CH3
H
Boc
Boc
Boc
Boc
51 (79%)
52 (94%)
53 (80%)
54 (74%)
5-OH
6-OH
5-OH
6-OH
CH3
CH3
H
H
H
10b,c
11b,c
49
50
5-OBn
6-OBn
H
H
5512 (98%)
5-OH
6-OH
N
N
N
N
56 (71%)
a
b
c
Reagents and conditions: NH2(CH2)2N(CH3)2, rflx, 22 h.
Reagents and conditions: BBr3 (2.0 equiv), CH2Cl2, 0 °C (15 min) then rt (1 h15 min).
Additional neutralization step with aqueous Na2CO3 solution.
Yields are indicated as isolated products.
d
the desired products 46–50 in good yields. To achieve the BDCZs,
removal of the benzyl group was performed from 34, 35, 39, 40
and from newly formed 49 and 50 compounds using BBr3 in
dichloromethane (entries 6–11). As attempted, spontaneous
removal of the Boc protective groups was observed under acid or
basic conditions.
Antiproliferative activities of the newly synthesized compounds
31–33, 36–38, 46–48 and 51–56 were evaluated toward two tumor

N. Ayerbe et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4670–4674
4673
cell lines: murine leukemia L1210 and human prostate carcinoma
DU145 and compared with those of rebeccamycin (Table 4). The
cytotoxicity of compounds was measured using a conventional
microculture tetrazolium assay. As expected, significant variations
of the cytotoxicity were observed according to the nature and the
position of substituents.
The unprotected NH maleimide derivatives 36, 37, 38 are quite
inactive against L1210 cell line. Some SAR in indolocarbazole
Table 4
In vitro antiproliferative activities against a murine leukemia (L1210) and a human prostate cancer (DU145)
Entry Compound
IC50 L1210
M)
IC50 DU145
M)
Entry Compound
IC50 L1210
M)
IC50 DU145
M)
(
l
(
l
(
l
(l
N(CH3)2
O
N
N
O
1
2
3
4
Rebeccamycin
—
0.14
ND
8
47
0.63
0.96
O
F
O
N
H
CH3
N(CH3)2
O
N
O
O
O
31 0.64
32 0.64
33 2.2a
ND
9
48
0.23
1.2
O
O
O
O
N
H
N
H
F
CH3
N
CH3
N
O
O
O
O
O
0.29
10
51 28.1
13.0
O
O
F
HO
O
O
N
H
N
H
CH3
N
CH3
N
O
O
O
O
O
0.32
11
52 21.3
2.0
O
O
O
O
N
H
N
H
F
HO
HO
H
H
N
N
O
O
O
5
6
O
36 24.8
1.6
8.4
12
13
O
O
53
54
0.33
0.82
O
O
N
H
N
H
H
H
N
N
O
O
O
37 12.5
0.58
0.89
O
F
F
O
O
N
H
N
HO
HO
H
H
N(CH3)2
O
N
O
O
N
N
O
O
O
7
38 13.0
3.3
14
55
0.074
0.179
O
O
N
O
N
H
H
N(CH3)2
O
N(CH3)2
O
N
O
8
46 0.2
0.65
56
0.18
0.45
O
O
O
N
O
N
H
HO
H
a
Precipitate. IC50 values are the average of at least four determinations in triplicate obtained in independent experiments. Variation between replicates was less than 5%.

4674
N. Ayerbe et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4670–4674
Bossard, C.; Mérour, J. Y. Bioorg. Med. Chem. 2008, 16, 5303; (d) Coudert, G.;
Ayerbe, N.; Lepifre, F.; Routier, S.; Caignard, D. H.; Renard, P.; Hickman, J.;
Pierré, A.; Léonce, S. WO 2004037831; Chem. Abstr. 2004, 140, 339333.; (e)
Bailly, C.; Goossens, J.-F.; Laine, W.; Anizon, F.; Prudhomme, M.; Ren, J.; Chaires,
J. B. J. Med. Chem. 2000, 43, 4711; (f) Dowlati, A.; Remick, S. C.; Majka, S.; Ingalis,
S.; Hoppel, C.; Spiro, T.; Gerson, S.; Willson, J. K. V. Proc. Am. Soc. Clin. Oncol.
1999, 18, 181a; (g) Long, B. H.; Balasubramanian, B. N. Expert Opin. Ther. Pat.
2000, 10, 635; (h) Marminon, C.; Pierré, A.; Pfeiffer, B.; Pérez, V.; Léonce, S.;
Joubert, A.; Bailly, C.; Renard, P.; Hickman, J.; Prudhomme, M. J. Med. Chem.
2003, 46, 609; (i) Zhang, G.; Shen, J.; Cheng, H.; Zhu, L.; Fang, L.; Luo, S.; Muller,
M.; Lee, G. E.; Wei, L.; Du, Y.; Sun, D.; Wang, P. G. J. Med. Chem. 2005, 48, 2600.
5. Animati, F.; Berettoni, M.; Bigioni, M.; Binaschi, M.; Felicetti, P.; Gontrani, L.;
Incani, O.; Madami, A.; Monteagudo, E.; Olivieri, L.; Resta, S.; Rossi, C.;
Cipollone, A. ChemMedChem 2008, 3, 266.
analogues series confirms this result. Despite the presence of a
lipophilic methyl group on the maleimide moiety, N-methyl malei-
mide compounds 31 and 32 exhibit a surprising and significant
cytotoxicity. This cell activity decreased by changing the position
of the fluorine atom (33) or by introducing hydroxyl function (51
or 52). In this sub-class, sub micromolar cell effects seem to be
dependent from either lipophilicity, minimal steric hindrance and
position of the substituents (C-5 vs C-6) on the indolic part.
Substitution of the maleimide with a N,N-dimethylaminoethyl
chain resulted in more soluble derivatives that retained better
cytotoxicity. The N,N-dimethylaminoethyl substitution induced a
clear improvement of the cytotoxicity compared to their NH or
N-methyl substituted counterparts. Compounds 46, 47, 48, 55,
and 56 inhibited the cellular proliferation in the nanomolar range.
Without any indolyl substituent or in the presence of fluorine atom
at C-5 or C-6 position of the indole ring, IC50 were limited to some
hundred nanomolar. For compounds 55 and 56, the presence of
hydrophilic function on the indolyl part enhanced considerably
the cytotoxicity. Indolic C-5 position was privileged and compound
55 was the most active of this subset with IC50’s (L1210) of 74 nM.
Without exception, all compounds described were significantly
less cytotoxic on the HT29 than on the L1210 cell lines. As seen
with tests on L1210, compound 55 was the most potent with an
IC50 (HT29) of 179 nM.
6. (a) Routier, S.; Coudert, G.; Mérour, J. Y. Tetrahedron Lett. 2001, 42, 7025; (b)
Faul, M. M.; Engler, T. A.; Sullivan, K. A.; Grutsch, J. L.; Clayton, M. T.; Martinelli,
M. J.; Pawlak, J. M.; Le Tourneau, M.; Coffey, D. S.; Pedersen, S. W.; Kolis, S. P.;
Furness, K.; Malhotra, S.; Al-Awar, R. S.; Ray, J. E. J. Org. Chem. 2004, 69, 2967.
7. Representative procedure for the preparation of 16–27: To
a solution of
compound 2 (176 mg, 0.59 mmol) in 1,4-dioxane (10 mL) were successively
added under argon 2-trimethylstannylbenzodioxine (200 mg, 1.49 mmol),9
20 mol % of copper iodide and 10 mol of PdCl2(PPh3)2. The reaction mixture
was poured under stirring in a pre-heated oil bath (100 °C) for 1 h 45 min. After
cooling, the solution was filtered over Celite and the precipitate was washed
wit EtOAc (20 mL). The combined organic layers were removed under reduced
pressure. The crude was purified without any further treatment by flash
chromatography on silica gel (petroleum ether/EtOAc 6:4) to afford compound
17 as a red solid (79% yield). Mp: 219–221 °C; Rf: 0.41 (petroleum ether/EtOAc
7:3); 1H NMR (acetone-d6, 250 MHz): d 3.04 (s, 3H), 5.67 (dd, 1H, J = 1.6 Hz and
J = 7.8 Hz), 6.67 (dt, 1H, J = 7.8 Hz and J = 1.6 Hz,), 6.74–6.88 (m, 2H), 6.96 (dt,
1H, HAr, J = 7.8 Hz and J = 1.0 Hz), 7.15 (dt, 1H, J = 7.8 Hz and J = 1.0 Hz), 7.25 (s,
1H), 7.53 (d, 1H, J = 7.8 Hz), 7.72 (d, 1H, J = 7.8 Hz), 7.91 (d, 1H, J = 2.8 Hz), 10.99
(br s, 1H, NH, exchangeable D2O); 13C NMR (DMSO-d6, 62.9 MHz): d 24.0 (CH3),
105.1 (Cq), 112.1 (CH), 116.1 (CH), 116.2 (CH), 119.3 (Cq), 120.3 (CH + Cq),
121.0 (CH), 122.0 (CH), 124.4 (CH), 124.7 (CH), 126.5 (Cq), 130.3 (Cq), 130.8
(CH), 131.1 (CH), 136.0 (Cq), 140.9 (Cq), 141.1 (Cq), 169.4 (C@O), 170.3 (C@O);
HRMS (TOF ES+) m/z [M+Na]+ calcd for C21H14N2O423Na: 381.0851; found
381.0848.
In order to find the biological target of our new lead compounds,
DNA flow cytometric analyses were next performed on compounds
33, 47, 48, 55, 56 using propidium iodide staining. Compound 33 was
the sole derivative inducing an accumulation of cells in G1 phase
(53% at 50
accumulation of cells (47, 62% at 5
at 1 M). The most cytotoxic compound 55 was also the most active
lM). Compounds 47, 55 and 56 showed a G2 + M phase
8. (a) Sanchez-Martinez, C.; Faul, M. M.; Shih, C.; Sullivan, K. A.; Grutsch, J. L.;
Cooper, J. T.; Kolis, S. P. J. Org. Chem. 2003, 68, 8008; (b) Marminon, C.; Pierré,
A.; Pfeiffer, B.; Pérez, V.; Léonce, V.; Joubert, A.; Bailly, C.; Renard, P.;
Prudhomme, M. J. Med. Chem. 2003, 46, 609.
9. (a) Lepifre, F.; Buon, C.; Roger, P.-Y.; Bouyssou, P.; Coudert, G. Tetrahedron Lett.
2004, 45, 8257; (b) Ayerbe, N.; Routier, S.; Gillaizeau, I.; Tardy, S.; Coudert, G.
Lett. Org. Chem. 2010, 7, 121.
l
M; 55, 77% at 0.5 M; 56, 48%
l
l
on the cell cycle. This original derivative is two times more active
than rebeccamycin. Further investigations onto DNA showed a
strong intercalation but topoisomerase I or II inhibitions were quite
insufficient to explain the observed cytotoxicity (data not shown).
In conclusion, new indolocarbazole analogues based on original
benzodioxinoindolocarbazoles heterocycles (BDCZs) has been pre-
pared. The efficient synthetic strategy employed a Stille palladium
cross-coupling approach combined with a photochemical induced
10. Representative procedure for the preparation of 30–40. A solution of compound
17 (150 mg, 0.418 mmol) and diiodine (1.50 g, 5.91 mmol) in toluene (500 mL)
was irradiated for 1 h 10 min in a quartz vessel with a ‘DEMA UV-lamp TQ-718
at 500 W. The reaction mixture was diluted with EtOAc (150 mL) and washed
with an aqueous solution of sodium thiosulfite 20% (80 mL) The organic layers
were evaporated under reduced pressure and the residue was washed
successively with Et2O (2 Â 50 mL), THF (50 mL). The filtrate was removed
under reduced pressure and the crude material was purified by flash
chromatography (petroleum ether/EtOAc 6:4) to afford compound 31 as a
yellow solid (76 mg, 51%). Mp: 258 °C (dec.); Rf: 0.59 (petroleum ether/EtOAc
6:4); 1H NMR (DMSO-d6, 250 MHz): d 3.02 (s, 3H), 7.10 (m, 4H), 7.27 (dt, 1H,
J = 7.4 Hz and J = 2.2 Hz,), 7.48–7.55 (m, 2H), 8.71 (d, 1H, J = 7.4 Hz), 12.18 (br s,
1H, NH, exchangeable D2O); 13C NMR (DMSO-d6, 62.9 MHz): d 23.7 (CH3),
111.8 (CH), 114.0 (Cq), 114.9 (Cq), 116.7 (CH), 117.1 (CH), 120.6 (CH), 124.3
(CH), 125.3 (2 Â CH), 128.1 (CH), 129.7 (Cq), 130.5 (Cq), 132.1 (Cq), 135.3 (Cq),
140.5 (Cq), 140.6 (Cq), 142.3 (Cq), 157.7 (Cq), 166.0 (C@O), 167.7 (C@O); HRMS
(TOF ES+) m/z [M+Na]+ calcd for C21H12N2O423Na: 379.0689; found 379.0690.
11. Representative procedure for the preparation of 46–50. A solution of compound
35 (45 mg, 0.8 mmol) in N,N-dimethylethylenediamine (4 mL) was refluxed for
22 h. After evaporation, the residue was triturated in methanol and filtered to
afford 50 as a yellow solid (75% yield). Mp: 262 °C; Rf: 0.21 (acetone); 1H NMR
(CDCl3, 250 MHz): d 2.57 (s, 6H), 2.94 (t, 2H, J = 5.1 Hz), 3.88 (t, 2H, J = 5.1 Hz),
5.25 (s, 2H), 6.55 (dd, 1H, J = 2 Hz and J = 8.8 Hz), 6.65 (dd, 1H, J = 1.7 Hz and
J = 7.7 Hz), 6.78 (d, 1H, J = 2 Hz), 6.86–7.03 (m, 3H), 7.37–7.49 (m, 3H), 7.56–
7.59 (m, 2H), 8.13 (d, 1H, J = 8.8 Hz), 11.07 (br s, 1H, NH, exchangeable D2O).
NMR DEPT 135 (CDCl3, 62.9 MHz): d 34.9 (CH2), 45.7 (2 Â CH3), 58.1 (CH2), 70.5
(CH2), 96.9 (CH), 110.9 (CH), 116.2 (CH), 117.8 (CH), 124.3 (2 Â CH), 125.4 (CH),
127.5 (2 Â CH), 128.0 (CH), 128.7 (2 Â CH). HRMS (TOF ES+) m/z [M+Na]+ calcd
for C31H25N3O523Na: 542.1691; found 542.1688.
6p-electrocyclisation. The synthesis was generalized to several
substituted indoles, and maleimide substitutions led to the series
of representative original BDCZs. Compound 55 was the most active
derivative with a strong effect on cell cycle. Efforts are being made to
find the biological target and to optimize the structure of our lead.
References and notes
1. Sánchez, C.; Méndez, C.; Salas, J. A. Nat. Prod. Rep. 2006, 23, 1007.
2. (a) Rodrigues Pereira, E.; Belin, L.; Sancelme, M.; Prudhomme, M.; Ollier, M.;
Rapp, M.; Sevère, D.; Riou, J. F.; Fabbro, D.; Meyer, T. J. Med. Chem. 1996, 39,
4471; (b) Bailly, C.; Riou, J. F.; Colson, P.; Houssier, C.; Rodrigues Pereira, E.;
Prudhomme, M. Biochemistry 1997, 36, 3917; (c) Bailly, C. Curr. Med. Chem.
1999, 6, 39; (d) Prudhomme, M. Eur. J. Med. Chem. 2003, 38, 123; (e)
Prudhomme, M. Curr. Med. Chem. Anticancer Agents 2004, 4, 509.
3. (a) Yoshinari, T.; Ohkubo, M.; Fukasawa, K.; Egashira, S.; Hara, Y.; Matsumoto,
M.; Nakai, K.; Arakawa, H.; Morishima, H.; Nishimura, S. Cancer Res. 1999, 59,
4271; (b) Arakawa, H.; Morita, M.; Kodera, T.; Okura, A.; Ohkubo, M.;
Morishima, H.; Nishimura, S. Jpn. J. Cancer Res. 1999, 90, 1163; (c) Denny, W.
A. IDrugs 2004, 7, 173; (d) Saulnier, M. G.; Balasubramanian, B. N.; Long, B. H.;
Frennesson, D. B.; Ruedinger, E.; Zimmermann, K.; Eummer, J. T.; Laurent, D. R.,
St.; Stoffan, K. M.; Naidu, B. N.; 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, D. R.; Vyas, D. M. J. Med. Chem. 2005, 48, 2258.
4. (a) Routier, S.; Ayerbe, N.; Mérour, J. Y.; Coudert, G.; Bailly, C.; Pierré, A.;
Pfeiffer, B.; Caignard, D. H.; Renard, P. Tetrahedron 2002, 58, 6621; (b) Routier,
S.; Peixoto, P.; Mérour, J. Y.; Coudert, G.; Dias, N.; Bailly, C.; Leonce, S.; Caignard,
D. H. J. Med. Chem. 2005, 48, 1401; (c) Lefoix, M.; Coudert, G.; Routier, S.;
Pfeiffer, B.; Caignard, D. H.; Hickman, J.; Pierré, A.; Golsteyn, R. M.; Léonce, S.;
12. Removal of the benzyl group give compound 55 as an orange–yellow solid
(98%). Mp >360 °C; Rf: 0.07 (acetone); 1H NMR (DMSO-d6, 250 MHz): d 2.18 (s,
6H), 3.68 (t, 2H, J = 6 Hz), 7.01 (dd, 1H, J = 2.4 Hz and J = 8.9 Hz), 7.11 (m, 4H),
7.37 (d, 1H, J = 8.9 Hz), 8.18 (d, 1H, J = 2.4 Hz). NMR DEPT 135 (DMSO-d6,
62.9 MHz): d 36.2 (CH2), 46.0 (2 Â CH3), 57.6 (CH2), 109.7 (CH), 113.3 (CH),
117.6 (CH), 117.9 (CH), 118.6 (CH), 126.0 (CH), 126.1 (CH). HRMS (TOF ES+) m/z
[M+Na]+ calcd for C24H19N3O523Na: 452.1222; found 452.1218.