3080
T. E. Barta et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3078–3080
oration using methods similar to what we had used with the car-
bazole analog.
N
N
H
N
Structure–activity trends are evident in Table 1: small lipophilic
groups, like halogen, alkoxy, and alkyl, meta- to the carboxamide
(5f–l) lead to analogs with potent mitotic block activity. Substitu-
tion ortho- to the carboxamide typically lead to inactive com-
pounds in the carbazole series (5b,c), though certain small
secondary amines, such as the allylamino analog, 5e, demonstrated
mitotic block activity.6
The carboxamide group can be replaced by other functionalities.
While the nitrile (7l), hydroxyamide (8), and carboxylic acid (9)
derivatives did not significantly block mitosis, we have already
seen that the urea, 6a, and the acetamide, 6b are potent analogs.
We see also that a number of the acyl indole analogs 14b–e
(Scheme 3) had excellent in vitro activity, demonstrating that the
rigidity of the entire carbazole ring is not necessary for potency
(Table 1).
a
b
Cl
12
N
O
NH2
Cl
c
Cl
N
N
13
O
O
14a
Scheme 3. Synthesis of acyl indole analog 14a. Reagents and conditions: (a) 3-
chloro-4-fluorobenzonitrile (1.4 equiv), NaH (1.4 equiv), DMF, 0 °C 5 min, then
45 °C for 90 min (ꢀquant); (b) isobutyric anhydride (1.5 equiv), Yb(OTf)3
(0.25 equiv), nitromethane, 50 °C, 90 min, 32%; (c) DMSO, EtOH, KOH (ꢀ5 equiv),
30% aq H2O2 (ꢀ5 equiv), 20 min, 65%.
All compounds were tested in a variety of cancer cell lines.7
Table 2 shows the antiproliferative activity of the lead compound,
5a, and three optimized analogs in comparison to colcemid. Analogs
6a and 14e demonstrate superior activity to colcemid in a number of
cell lines.
There are many diverse chemical structures that influence
tubulin polymerization.1 This Letter summarizes our investigations
into some simple carbazoles and acyl indoles with promising
biological activity which appear to be tubulin inhibitors. Further
results will be presented in due course.
Table 2
Activity7 of selected analogs in cancer cell lines
NH2
O
H2N
O
H2N O
HN
N
R
Cl
Cl
References and notes
N
N
Cl
1. (a) Bacher, G.; Beckers, T.; Klenner, T.; Kuscher, B.; Nickel, B. Pure Appl. Chem.
2001, 73, 1459; (b) Cragg, G. M.; Newman, D. J. J. Nat. Prod. 2004, 67, 232; (c)
Kuppens, I. E. L. M. Curr. Clin. Pharm. 2006, 1, 57.
O
O
O
6a
14e
5a R=H
5g R=Cl
2. (a) Nguyen, T. L.; McGrath, C.; Hermone, A. R.; Burnett, J. C.; Zaharevitz, D. W.;
Day, B. W.; Wipf, P.; Hamel, E.; Gussio, R. J. Med. Chem. 2005, 48, 6107; (b)
Pelletier, P. S.; Caventon, J. Ann. Chim. Phys. 1820, 14, 69; (c) Pettit, G. R.; Singh, S.
B.; Boyd, M. R.; Hamel, E.; Pettit, R. K.; Schmidt, J. M.; Hogan, F. J. Med. Chem.
1995, 38, 1666–1672; (d) Koyanagi, N.; Nagasu, T.; Fujita, F.; Watanabe, T.;
Tsukahara, K.; Funahashi, Y.; Fujita, M.; Taguchi, T.; Yoshino, H.; Kitoh, K. Cancer
Res. 1994, 54, 1702; (e) De Brabander, M. J.; Van de Veire, R. M. L.; Aerts, F. E. M.;
Borgers, M.; Janssen, P. A. J. Cancer Res. 1976, 36, 905.
3. For examples of carbazoles with HSP90 activity, see: Veal, J. M.; Barta, T. E.; Rice,
J. W.; Partridge, J. M.; Fadden, P.; Ma, W.; Jenks, M.; Geng, L.; Hanson, G. J.;
Huang, K. H.; Barabasz, A. F.; Foley, B. E.; Otto, J.; Hall, S. E. Bioorg. Med. Chem.
Lett. 2008, 18, 3517.
Cancer cell line (nM)
1b
5a
5g
6a
14e
K562
PC3
MCF-7
SW620
HT29
16
31
7.8
31
25
2000
7000
2300
1200
4500
210
140
85
5.5
790
0.87
15
0.085
2.2
1.2
6.5
9.3
94
300
3.2
4. At Serenex, where this research was conducted, we routinely profiled
compounds for ability to bind at purine-binding domains using a proprietary
affinity medium based on resin-bound adenine. Using this technology none of the
analogs in this Letter appeared to have significant affinity for purine-binding
proteins, except for 5a and 5e, which eluted HSP90.3 For a description of the
technology, see: Graves, P. R.; Kwick, J. J.; Fadden, P.; Ray, R.; Hardeman, K.;
Coley, A. M.; Foley, M.; Haystead, T. A. J. Mol. Pharmacol. 2002, 62, 1364.
5. Barabasz, A.; Foley, B.; Otto, J. C.; Scott, A.; Rice, J. Assay Drug Dev. Technol. 2006,
4, 153. Compound 6a is identified as SC-103232 in this Letter.
logs with a urea or N-acyl moieties in place of the carboxamide were
accessible by starting from substituted 4-fluoro-nitrobenzenes
(Scheme 2). The resulting nitrobenzene compounds were reduced
to the corresponding anilines catalytically. Treatment with potas-
sium isocyanate afforded the urea 6a; acetic anhydride could be em-
ployed to obtain the acetamide 6b.
6. Juan, G.; Traganos, F.; James, W. M.; Ray, J. M.; Roberge, M.; Sauve, D. M.;
Anderson, H.; Darzynkiewicz, Z. Cytometry 1998, 32, 71.
7. Hanson, G. J.; Barta, T. E.; Geng, L.; Huang, K. H.; Veal, J. PCT Int. Appl. WO
2007035620; Chem. Abstr. 2007, 146, 379821.
Compounds incorporating simple acyl groups in the place of the
carbazole cyclohexanone ring (14a–e) were obtained via lantha-
noid salt-mediated Friedel–Crafts acylation (Scheme 3)8 using the
appropriate carboxylic acid anhydride, followed by synthetic elab-
8. Kawada, A.; Mitamura, S.; Kobayashi, S. J. Chem. Soc., Chem. Commun. 1993, 1157.