R. Zhang et al. / Bioorg. Med. Chem. 19 (2011) 7023–7032
7031
4
.62 (t, J = 6.7 Hz, 4H), 2.95 (t, J = 6.7 Hz, 4H), 2.47–2.56 (m, 20H);
132.90, 132.48, 129.09, 128.50, 126.92, 122.72, 121.76, 120.91,
114.96, 57.51, 56.27, 55.27, 54.86, 53.38, 48.65, 45.88, 42.91;
HRMS (ESI), m/z (M+H) : calcd 438.2055, obsd 438.2070.
1
3
C
3
NMR (CDCl ) d 182.74, 139.33, 138.29, 137.25, 134.76,
+
1
1
32.93, 132.66, 129.16, 128.50, 127.01, 122.80, 121.79, 120.97,
14.95, 57.82, 55.85, 53.61, 53.41, 48.23; HRMS (ESI), m/z
+
(
M+H) : calcd 759.2724, obsd 759.2751.
4.3.11. 7-Chloro-2-(2-(piperazin-1-yl)ethyl)anthra[1,9-cd
]pyrazol-6(2H)-one (24)
4
.3.6. 1,3-Bis(N-(2-(7-chloro-6-oxo-6H-dibenzo[cd,g]indazol-2-
Piperazine 20 was reacted with 14 in a 1.5:1 mole ratio to pro-
duce 24 as a reddish-orange solid in 50% yield; mp: 121–122 °C; H
1
yl)-ethyl)-piperazin-1-yl)propane (16)
The bispiperazine 11 was reacted with 14 in a 1:2.2 mole ratio
3 1 2
NMR (CDCl ) d 8.18 (dd, J = 6.6 Hz, J = 2.5 Hz, 1H), 7.97 (d,
to produce 16 as a reddish-orange solid in 45% yield; mp: 98–
J = 6.6 Hz, 1H), 7.49–7.71 (m, 4H), 4.62 (t, J = 6.7 Hz, 2H), 2.94 (t,
1
13
1
7
4
00 °C; H NMR (CDCl
.99 (d, J = 6.6 Hz, 2H), 7.60–7.71 (m, 4H), 7.51–7.58 (m, 4H),
.62 (t, J = 6.7 Hz, 4H), 2.96 (t, J = 6.7 Hz, 4H), 2.57 (br, 8H), 2.42
3
) d 8.19 (dd, J
1
= 6.5 Hz, J
2
= 2.5 Hz, 2H),
J = 6.7 Hz, 2H), 2.84 (t, J = 4.7 Hz, 4H), 2.50 (t, J = 4.7 Hz, 4H);
C
NMR (CDCl ) d 182.70, 139.32, 138.22, 137.20, 134.76, 132.90,
3
132.50, 129.13, 128.47, 126.95, 122.76, 121.77, 120.93, 114.97,
13
+
(
br, 8H), 2.32 (t, J = 6.7 Hz, 4H) 1.66 (m, 2H); C NMR (CDCl
3
) d
58.48, 54.75, 48.10, 46.09; HRMS (ESI), m/z (M+H) : calcd
1
1
5
7
82.69, 139.29, 138.22, 137.21, 134.74, 132.90, 132.52, 129.12,
367.1320, obsd 367.1388.
28.47, 126.95, 122.76, 121.78, 120.93, 114.95, 57.82, 55.85,
+
3.61, 53.41, 48.23; HRMS (ESI), m/z (M+H) : calcd 773.2881, obsd
Acknowledgments
73.2890.
Supported by grants from the Canadian Institutes of Health Re-
search, the Canada Research Chairs Program, a Canada Research
Chair in Drug Development to Brian Hasinoff and an NIH Grant
CA090787 to Jack Yalowich.
4
.3.7. 1,4-Bis(N-(2-(7-chloro-6-oxo-6H-dibenzo[cd,g]indazol-2-
yl)-ethyl)-piperazin-1-yl)-2-trans-butene (17)
The bispiperazine 12 was reacted with 14 in a 1:2.2 mole ratio
to produce 17 as a reddish-orange solid in 40% yield; mp: 110–
1
1
2
11 °C; H NMR (CDCl
3
) d 8.20–8.23 (m, 2H), 8.01 (d, J = 6.9 Hz,
= 6.6 Hz,
= 1.9 Hz, 4H), 2.95–3.03 (m, 8H), 2.54–2.62 (m, 8H), 2.40–2.48
Supplementary data
H), 7.74–7.53 (m, 8H), 5.63–5.69 (m, 2H), 4.65 (dt, J
1
J
2
include MOL files and InChiKeys of the most important compounds
described in this article.
1
3
(
m, 8H);
3
C NMR (CDCl ) d 182.74, 139.35, 138.30, 137.26,
1
1
4
7
34.77, 132.94, 132.57, 129.18, 128.55, 128.52, 127.02, 122.81,
21.80, 120.98, 114.97, 60.40, 60.35, 57.82, 53.38, 53.04, 48.24,
8.22, 45.84; MS (ESI m/z): HRMS (ESI), m/z (M+H) : calcd
85.2881, obsd 785.2910.
+
References and notes
4
.3.8. 1,6-Bis(N-(2-(7-chloro-6-oxo-6H-dibenzo[cd,g]indazol-2-
1. Nitiss, J. L. Nat. Rev. Cancer 2009, 9, 327.
2
3
.
.
Nitiss, J. L. Nat. Rev. Cancer 2009, 9, 338.
Liang, H.; Wu, X.; Guziec, L. J.; Guziec, F. S., Jr.; Larson, K. K.; Lang, J.; Yalowich, J.
C.; Hasinoff, B. B. J. Chem. Inf. Model. 2006, 46, 1827.
yl)-ethyl)-piperazin-1-yl)hexane (18)
The bispiperazine 13 was reacted with 14 in a 1:2.2 mole ratio
to produce 18 as a reddish-orange solid in 50% yield; mp: 93–
4. Hasinoff, B. B.; Liang, H.; Wu, X.; Guziec, L. J.; Guziec, F. S., Jr.; Yalowich, J. C.
1
Bioorg. Med. Chem. 2008, 16, 3959.
9
7
4
2
4 °C; H NMR (CDCl
.98 (d, J = 6.9 Hz, 2H), 7.60–7.71 (m, 4H), 7.50–7.57 (m, 4H),
.62 (t, J = 6.8 Hz, 4H), 2.96 (t, J = 6.8 Hz, 4H), 2.58 (br, 8H), 2.27–
.45 (m, 12H), 1.39–1.54 (m, 4H) 1.24–1.36 (m, 4H); C NMR
) d 182.67, 139.30, 138.21, 137.20, 134.75, 132.90, 132.51,
3
) d 8.19 (dd, J
1
= 6.4 Hz, J
2
= 2.5 Hz, 2H),
5.
Hasinoff, B. B.; Zhang, R.; Wu, X.; Guziec, L. J.; Guziec, F. S., Jr.; Marshall, K.;
Yalowich, J. C. Bioorg. Med. Chem. 2009, 17, 4575.
6. Zhang, R.; Wu, X.; Guziec, L. J.; Guziec, F., Jr.; Chee, G.-L.; Yalowich, J. C.;
1
3
Hasinoff, B. B. Bioorg. Med. Chem. 2010, 18, 3974.
7.
Antonini, I.; Santoni, G.; Lucciarini, R.; Amantini, C.; Sparapani, S.; Magnano, A.
(
CDCl
3
J. Med. Chem. 2006, 49, 7198.
1
5
29.12, 128.47, 126.95, 122.76, 121.79, 120.92, 114.98, 58.64,
7.85, 53.43, 53.21, 48.21, 27.51, 26.80; HRMS (ESI), m/z (M+H) :
8. Gago, F. Methods 1998, 14, 277.
9. Pindur, U.; Jansen, M.; Lemster, T. Curr. Med. Chem. 2005, 12, 2805.
+
10. Martinez, R.; Chacon-Garcia, L. Curr. Med. Chem. 2005, 12, 127.
calcd 815.3350, obsd 815.3355.
1
1
1. Zolova, O. E.; Mady, A. S.; Garneau-Tsodikova, S. Biopolymers 2010, 93, 777.
2. Dawson, S.; Malkinson, J. P.; Paumier, D.; Searcey, M. Nat. Prod. Rep. 2007, 24,
1
09.
4
.3.9. N,N-Bis(2-((2-(7-chloro-6-oxo-6H-dibenzo[cd,g]indazol-2-
1
3. Cholody, W. M.; Kosakowska-Cholody, T.; Hollingshead, M. G.; Hariprakasha,
yl)ethyl)-methylamino)ethyl) piperazine (21)
H. K.; Michejda, C. J. J. Med. Chem. 2005, 48, 4474.
The piperazine 20 was reacted with 19 in a 1:2.2 mole ratio to
14. Galisteo, J.; Navarro, P.; Campayo, L.; Yunta, M. J.; Gomez-Contreras, F.; Villa-
Pulgarin, J. A.; Sierra, B. G.; Mollinedo, F.; Gonzalez, J.; Garcia-Espana, E. Bioorg.
Med. Chem. 2010, 18, 5301.
produce 21 as a reddish-orange solid in 38% yield; mp: 90–92 °C;
1
3 1 2
H NMR (CDCl ) d 8.18 (dd, J = 5.6 Hz, J = 2.3 Hz, 1H), 7.96 (d,
1
5. Szumilak, M.; Szulawska-Mroczek, A.; Koprowska, K.; Stasiak, M.; Lewgowd,
J = 7.0 Hz, 1H), 7.50–7.70 (m, 4H), 4.58 (t, J = 6.6 Hz, 2H), 3.00 (t,
J = 6.6 Hz, 2H), 2.56 (t, J = 6.9 Hz, 2H), 2.34–2.39 (m, 13H), 2.23 (s,
W.; Stanczak, A.; Czyz, M. Eur. J. Med. Chem. 2010, 45, 5744.
16. Casero, R. A., Jr.; Woster, P. M. J. Med. Chem. 2009, 52, 4551.
17. Gentry, A. C.; Pitts, S. L.; Jablonsky, M. J.; Bailly, C.; Graves, D. E.; Osheroff, N.
Biochemistry 2011, 50, 3240.
8. Edwards, C.; Ray, N. C.; Gill, M. I. A.; Alcindor, J.; Finch, H.; Fitzgerald, M. F. WO
2007042815, 2007.
19. Bjorndal, M. T.; Fygenson, D. K. Biopolymers 2002, 65, 40.
1
3
3
1
1
3
H); C NMR (CDCl ) d 182.68, 139.40, 138.13, 137.20, 134.78,
32.92, 132.50, 129.10, 128.53, 126.93, 122.72, 121.77, 120.91,
15.08, 57.49, 56.05, 55.18, 53.04, 48.60, 42.79; HRMS (ESI), m/z
1
+
(
M+H) : calcd 761.2881, obsd 761.2879.
2
0. McGhee, J. D. Biopolymers 1976, 15, 1345.
2
1. Fortune, J. M.; Osheroff, N. Prog. Nucleic Acid Res. Mol. Biol. 2000, 64, 221.
4
.3.10. 7-Chloro-2-[2-[(2-(4-methyl-piperazin-1-
22. Li, T. K.; Liu, L. F. Annu. Rev. Pharmacol. Toxicol. 2001, 41, 53.
2
2
2
2
3. Hasinoff, B. B.; Kozlowska, H.; Creighton, A. M.; Allan, W. P.; Thampatty, P.;
yl)ethyl)methylamino]ethyl]-anthra[1,9-cd]pyrazol-6(2H)-one
Yalowich, J. C. Mol. Pharmacol. 1997, 52, 839.
4. Leteurtre, F.; Kohlhagen, G.; Paul, K. D.; Pommier, Y. J. Natl. Cancer Inst. 1994,
(
23)
1
-Methylpiperazine 22 was reacted with 19 in a 1:1.1 mole ra-
86, 1239.
5. Capranico, G.; Palumbo, M.; Tinelli, S.; Mabilia, M.; Pozzan, A.; Zunino, F. J. Mol.
tio to produce 23 as a reddish-orange solid in 57% yield; mp: 113–
1
Biol. 1994, 28, 1218.
1
(
15 °C; H NMR (CDCl
d, J = 7.0 Hz, 1H), 7.50–7.70 (m, 4H), 4.58 (t, J = 6.6 Hz, 2H), 3.00 (t,
J = 6.6 Hz, 2H), 2.56 (t, J = 6.9 Hz, 2H), 2.34–2.39 (m, 13H), 2.23 (s,
3 1 2
) d 8.16 (dd, J = 5.6 Hz, J = 2.3 Hz, 1H), 7.96
6. Burden, D. A.; Froelich-Ammon, S. J.; Osheroff, N. Methods Mol. Biol. 2001, 95,
283.
27. Hasinoff, B. B.; Wu, X.; Begleiter, A.; Guziec, L.; Guziec, F. S., Jr.; Giorgianni, A.;
1
3
Yang, S.; Jiang, Y.; Yalowich, J. C. Cancer Chemother. Pharmacol. 2006, 57, 221.
3
3
H); C NMR (CDCl ) d 182.67, 139.32, 138.14, 137.18, 134.75,