Synthesis and biological evaluations of novel indenoisoquinolines as topoisomerase i inhibitors

Article abstract of DOI:10.1016/j.bmcl.2011.10.019

A series of novel indenoisoquinoline derivatives were synthesized. The anticancer activities of these molecules were tested in human cancer cell lines A549, HepG2, and HCT-116. These compounds were also tested for their activity of topoisomerase I (top1)

Full text of DOI:10.1016/j.bmcl.2011.10.019

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1276–1281
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluations of novel indenoisoquinolines
as topoisomerase I inhibitors
⇑
⇑
Xiaoyun Zhang, Rubing Wang, Li Zhao, Na Lu, Jubo Wang, Qidong You, Zhiyu Li , Qinglong Guo
Department of Medicinal Chemistry, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009,
People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel indenoisoquinoline derivatives were synthesized. The anticancer activities of these mol-
ecules were tested in human cancer cell lines A549, HepG2, and HCT-116. These compounds were also
tested for their activity of topoisomerase I (top1) inhibition. Among them, compound 25 was found to
be 10-times more potent in cell-killing activity for both cell lines HepG2 and HCT-116 than reported com-
Received 11 August 2011
Revised 4 October 2011
Accepted 7 October 2011
Available online 24 October 2011
pound 11, with IC50 of 0.019 and 0.093 lM, respectively. Compound 25 was also found to have stronger
top1 inhibition activity than 11 in our inhibition assay. Further in vivo evaluations of compound 25 are in
progress and will be reported in due course.
Keywords:
Top1 inhibitor
Anticancer
Ó 2011 Elsevier Ltd. All rights reserved.
Indenoisoquinolone
Synthesis
Indenoisoquinolone derivate
DNA-topoisomerase I (top1) is widely considered as an impor-
tant enzyme to relax supercoiled DNA for transcription, replication,
and mitosis.1 Thus, DNA-topoisomerase I (top1) has been identified
as a promising cancer therapeutic target.2 Two camptothecin (CPT)
derivatives, irinotecan (1, Camptosar) and topotecan (2, Hycamp-
tin), are the only topoisomerase I (top1) inhibitors approved by
the FDA as anticancer drugs3,4 (Fig. 1). However, their clinical utility
was limited by several disadvantages such as easy hydrolysis of the
lactone ring to a hydroxy carboxylate which binds to human serum
albumin,5 and the rapid reversibility of ternary DNA–enzyme–cam-
ptothecin complex after drug removal, necessitating long infusion
time for maximum activity.6 Moreover, some cancer cells developed
resistance to camptothecin.7 Thus, these problems recommended
further development of other non-camptothecin top1 inhibitors
with better pharmacokinetic features.
profile revealed a strong resemblance with camptothecin deriva-
tives (irinotecan and topotecan) in twenty years later (Fig. 1).
Indenoisoquinoline, unlike the camptothecins, is hydrolytically sta-
ble but alternatively suffered from intrinsically low biological activ-
ity. As a result, considerable effort had been devoted to improve the
biological activity of indenoisoquinolines.10–27,32–34 Novel insights
had been gleaned regarding the contributions of the indenone ring,
isoquinoline ring, and lactam side chain toward the biological activ-
ity.15,16,20–27 Previous investigation4 demonstrated that the biologi-
cal activity of indenoisoquinolines (4–6) was improved by
introducing a nitro substituent on the isoquinoline ring and a meth-
ylenedioxy-substitute on the indenone ring. After that,24 a detailed
study indicated that compounds with a methoxy group at the 9-po-
sition of indenoisoquinolines (7–9) afforded superior biological
activity. Further modifications on the lactam side chain yielded
new lead compounds (10–13) with potent biological activity.25
The chemical structures of compounds 4–13 are provided in
Figure 2.
In 19788,9 indenoisoquinoline 3 (NSC 314622) was first synthe-
sized, and was found to be a novel top1 inhibitor. Its cytotoxicity
The present work was undertaken to further improve the bio-
logical activity of previously reported indenoisoquinolines with a
nitro group on the isoquinoline ring and a 9-methoxygroup on
the indenone ring. Two series of compounds were synthesized. In
the first series, the nitro substituent on the isoquinoline ring re-
mains unchanged and modification were made to the indenone
ring with the electron-donating methoxy substituent replaced by
the electron-withdrawing substituent fluorine and chlorone, the
other series of analogues were prepared by reducing the strong
Abbreviations: DNA, deoxyribonucleic acid; Top1, DNA-topoisomerase I; CPT,
camptothecin; FDA, food and drug administration; 1H NMR, hydrogen-1 nuclear
magnetic resonance spectroscopy; 13C NMR, 13C nuclear magnetic resonance
spectroscopy; MS, mass spectrometry; IR, infrared; A549, non-small cell lung
carcinoma; HepG2, human hepatocellular liver carcinoma cell line; HCT-116,
human colon cancer cell line; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltet-
razolium bromide; IC50, half maximal inhibitory concentration; TopoGEN, topoiso-
merase I drug screening kit.
⇑
Corresponding authors. Tel./fax:+86 25 83271017.
E-mail addresses: Zhiyuli@cpu.edu.cn, Zhiyuli@263.net (Z. Li).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.10.019

X. Zhang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1276–1281
1277
Figure 1. Structure of irinotecan, topotecan and NSC314622.
electron-withdrawing nitro substituent to the corresponding
aniline in an effort to further explore the effect of the nitro group.
The synthesis of advanced indenoisoquinoline analogues 10, 11,
21–38 was described in Scheme 1. Condensation of homophthalic
anhydrides 1428 with Schiff bases 15–1729 provided carboxylic
acids 18–20. The cis-configuration was established by the observed
coupling constant of 6 Hz for the two methine protons.30 These
carboxylic acids were subjected to oxidative Friedel–Crafts ring
closure with thionyl chloride7 and aluminum chloride15,24 to pro-
vide indenoisoquinolines 21–23. Compounds 21–23 were treated
with appropriate amines in refluxing 1,4-dioxane to give target
compounds 24–38 (Scheme 1). The chemical data including 1H
NMR, 13C NMR, MS, IR, and elemental analysis of compounds 25
and 36 were provided in references and notes.31
In order to explore the importance of the electron-withdrawing
nitro group on the isoquinoline ring, compounds 52–54 were syn-
thesized (Scheme 2) with the nitro substituent replaced with an
electron-donating aniline-type amino group. Compounds 21–23
were treated with appropriate amines in refluxing 1,4-dioxane to
provide target compounds 39–51 (Scheme 2).
All the synthesized indenoisoquinoline derivatives were
screened for cytotoxicity on three human cancer cell lines A549
(non-small cell lung carcinoma), HepG2 (human hepatocellular li-
ver carcinoma cell line) and HCT-116 (human colon cancer cell
line) using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltet-
razolium bromide) assay. These compounds were also screened
for their ability to stabilize the ternary DNA-enzyme-camptothecin
complex using a topoisomerase I drug screening kit (TopoGEN,
Inc.). From the biological data presented in Tables 1 and 2, the sub-
stitution pattern at the indenoisoquinoline 3-position, 9-position,
and the lactam side chain has a pronounced effect on the biological
activities of the molecules.
From the data in Table 1, the biological activity is greatly im-
proved, for both cytotoxicity and top1 inhibition, with the utiliza-
tion of the nitro group at 3-position of indenoisoquinolines. As the
lead compound 10 and 11, two molecules displayed superb cyto-
toxicity (0.023
lM, 0.16 lM, 0.168 lM, and 4 nM, 0.27 lM,
0.84 M, respectively) and potent top1 inhibition (++++ and +++
l
respectively). Like compound 10 and 11, analogues 23 and 36–38
also contain a methoxy substituent on the indenone ring. Com-
pound 36 (0.014 lM, 0.024 lM, 0.043 lM, top1 inhibition ++++)
with a methylpiperazinyl lactam side chain, was more potent than
reported compound 11 in the biological assays. Compound 38
(4 nM, 0.29 lM, 0.27 lM) with a propylamino lactam side chain
showed similar cytotoxicity to that of the lead compound 11. The
results were identical to the previously identified that methoxy
substituent was optimally suited for enhancing the biological
activity of the indenoisoquinoline 9-position. Furthermore, utiliz-
ing optimal lactam side chains (such as a morpholine, an imidazole
and a methylpiperazinyl group) were identified to improve the bio-
logical activity of the indenoisoquinolines.
Although the methoxy group was the only substituent identi-
fied in the previous study to enhance both the cytotoxicity and
the top1 inhibition of these analogues, the electron-withdrawing
fluorine atom at the 9-position (analogues 25–27, showed in Table
1) provided compounds equally as cytotoxic as camptothecin. Fur-
thermore, when the 9-position fluorine atom was combined with a
methylpiperazinyl-substituted lactam nitrogen, the resulting ana-
logue 25 (top1 inhibition +++++) showed the strongest activity of
top1 inhibition among them, which was 10-times more potent
than that of the lead compound 11. In addition, Compound
26, 27 and 29 all possessed submicromolar IC50 values and
moderate or potent top1 inhibition. The results demonstrated
that modification of a methoxy group at the 9-position to the
O
O
O
O
O
O
O
R
N
R
O2N
N
R
N
O2N
O
O2N
O
7:R=Cl
8:R=N3
N
O
N
O
10:R=
11:R=
12:R=
13:R=
4:R=Cl
5:R=N3
N
.
9:R=NH2 HCl
H
.
N
6:R=NH2 HCl
OH
N(CH3)2
Figure 2. Structure of the mentioned indenoisoquinolines.

1278
X. Zhang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1276–1281
Scheme 1. The synthesis indenoisoquinolines.
R
R
O
O
a
N
Cl
N
Cl
O2N
H2N
O
O
52: R=F
21: R=F
53: R=Cl
22: R=Cl
54: R=OCH3
23: R=OCH3
R
O
b
N
H2N
O
R1
45: R=Cl; R1=
46: R=Cl; R1=
N
N
O
N
47: R=OCH3; R1=
48: R=OCH3; R1=
N
N
O
N
39: R=F; R1=
40: R=F; R1=
N
N
O
N
CH2CH3
49: R=OCH3; R1=
CH2CH2OH
N
41: R=F; R1=
42: R=F; R1=
43: R=F; R1=
N
CH2CH3
CH2CH2OH
50: R=OCH3; R1=
51: R=OCH3; R1=
N
NHCH2CH2OH
N
N
N
N
44: R=F; R1=
N
Scheme 2. The synthesis indenoisoquinolines.

X. Zhang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1276–1281
1279
Table 1
Cytotoxicities and topoisomerase I inhibitory activities of indenoisoquinoline analogues
Compound
R
R1
A549 (lM)
HepG2 (
l
M)
HCT-116 (
lM)
Top1 Cleavagea
TCPT
TPT
N
N
N
N
0.064
0.19
2.24
2.21
66.3
88.1
++++
++++
N
N
O
10
OCH3
0.023
0.16
0.168
++++
11
OCH3
0.0042
0.27
0.84
+++
N
21
22
23
F
Cl
OCH3
Cl
Cl
Cl
22.4
0.749
3.88
>100
25.2
25.8
>100
54.0
5.72
+++
+++
++
N
N
O
N
24
F
>100
>100
>100
+++
25
F
0.021
0.019
0.0932
+++++
26
27
28
F
F
F
–N(CH2CH2OH)2
–NHCH2CH2OH
–N(CH2CH3)2
0.068
0.031
3.52
0.54
0.49
2.77
0.162
0.207
0.741
++
+++
++
N
N
–N(CH(CH3)2)2
29
30
F
F
0.035
18.5
0.91
14.8
0.159
2.68
+++
++
N
O
31
Cl
3.03
>100
>100
+++
N
N
32
Cl
4.03
7.18
1.13
+++
33
34
Cl
Cl
–N(CH2CH3)2
–NHCH2CH2CH3
3.28
1.18
9.42
1.38
1.79
1.13
++++
++
N
N
35
36
Cl
0.00482
0.014
2.21
1.23
+++++
++++
N
N
OCH3
0.024
0.043
N
37
38
OCH3
OCH3
0.61
6.83
0.29
12.3
0.27
0/+
++
–NHCH2CH2CH3
0.00427
a
The compounds were tested at concentrations ranging up to 100 nM. The activity of the compounds to produce top1-mediated DNA cleavage was expressed semi-
quantitatively as follows: +: weak activity; ++: modest activity; +++: similar activity as 100 nM camptothecin; ++++ or +++++: greater activity than 100 nM camptothecin.
Table 2
Cytotoxicities and topoisomerase I inhibitory activities of indenoisoquinoline analogues
Compound
R
F
F
R1
A549 (
lM)
HepG2 (
l
M)
HCT-116 (
l
M)
Top1 Cleavagea
N
N
O
N
39
40
1.56
16.3
0.747
+
0.93
1.24
3.82
++
41
42
F
F
–N(CH2CH2OH)2
–NHCH2CH2OH
0.75
0.16
40.7
1.21
0.233
1.08
++
++
N
N
43
44
F
F
2.69
0.51
61.8
0.86
1.85
1.03
++++
N
++++
(continued on next page)

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X. Zhang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1276–1281
Table 2 (continued)
Compound
R
R1
A549 (lM)
HepG2 (
l
M)
HCT-116 (
l
M)
Top1 Cleavagea
N
N
N
N
O
N
O
N
45
46
47
Cl
7.55
27.3
2.97
++
++
++
Cl
1.69
0.29
1.95
OCH3
1.63
12.3
6.82
48
49
OCH3
OCH3
0.63
0.25
12.9
0.71
13.7
+++
+
–N(CH2CH3)2
0.672
N
N
50
OCH3
0.038
39.7
41.5
+
N
51
OCH3
0.045
0.53
0.870
+
52
53
54
F
Cl
OCH3
Cl
Cl
Cl
11.1
6.24
1.85
55.5
30.7
>100
0.654
>100
>100
++++
++
++
a
The compounds were tested at concentrations ranging up to 100 nM. The activity of the compounds to produce top1-mediated DNA cleavage was expressed semi-
quantitatively as follows: +: weak activity; ++; modest activity; +++: similar activity as 100 nM camptothecin; ++++ or +++++: greater activity than 100 nM camptothecin.
electron-withdrawing fluorine atom led to enhancement of top1
inhibition, especially combined with a methylpiperazinyl-substi-
tuted lactam nitrogen.
References and notes
1. Redinbo, M. R.; Stewart, L.; Kuhn, P.; Champoux, J. J.; Hol, W. G. Science 1998,
279, 1504.
Further, above results inspired us to synthesize a new series of
compounds with the fluorine atom substituted with a chlorine
atom. Six compounds were provided in Table 1, five of them
showed potent top1 inhibitory activity (top1 inhibition +++ or
greater). For example, compound 35 showed an IC50 value of
4 nM against A549 and it showed strong top1 inhibition with a
resemblance to that of compound 25. It displayed that a chlorine
atom at the 9-position also conferred potent biological activity.
In an effort to further define the effect of the substituents with
different electronic effects on the isoquinoline ring, a series of no-
vel analogues possessing an amino substituent on the isoquinoline
ring were synthesized, in conjunction with a methoxy, fluoro, or
chloro substituent on the indenone ring. In Table 2, compound
43, 44 and 52 exhibited potent top1 inhibition (top1 inhibition
++++, ++++, ++++). Other compounds were found to have weak
top1 inhibition. It was possible to make a conclusion that the fluoro
group was important for top1 inhibition of these compounds, espe-
cially when combined with optimal lactam side chains.
2. Rasheed, Z. A.; Rubin, E. H. Oncogene 2003, 22, 7296.
3. Garcia-Carbonero, R.; Supko, J. G. Clin. Cancer Res. 2002, 8, 641.
4. Morrell, A.; Antony, S.; Kohlhagen, G.; Pommier, Y.; Cushman, M. Bioorg. Med.
Chem. Lett. 2004, 14, 3659.
5. Burke, T. G.; Mi, Z. J. Med. Chem. 1994, 37, 40.
6. van Warmerdam, L. J.; Creemers, G. J.; Rodenhuis, S.; Rosing, H.; de Boer-
Dennert, M.; Schellens, J. H.; ten Bokkel Huinink, W. W.; Davies, B. E.; Maes, R.
A.; Verweij, J.; Beijnen, J. H. Cancer Chemother. Pharmacol. 1996, 38, 254.
7. Li, T. K.; Liu, L. F. Annu. Rev. Pharmacol. Toxicol. 2001, 41, 53.
8. Mark, C.; Cheng, L. J. Org. Chem. 1978, 43, 3781.
9. Kohlhagen, G.; Paull, K. D.; Cushman, M.; Nagafuji, P.; Pommier, Y. Mol.
Pharmacol. 1998, 54, 50.
10. Ioanoviciu, A.; Antony, S.; Pommier, Y.; Staker, B. L.; Stewart, L.; Cushman, M. J.
Med. Chem. 2005, 48, 4803.
11. Strumberg, D.; Pommier, Y.; Paull, K.; Jayaraman, M.; Nagafuji, P.; Cushman, M.
J. Med. Chem. 1999, 42, 446.
12. Cushman, M.; Jayaraman, M.; Vroman, J. A.; Fukunaga, A. K.; Fox, B. M.;
Kohlhagen, G.; Strumberg, D.; Pommier, Y. J. Med. Chem. 2000, 43, 3688.
13. Jayaraman, M.; Fox, B. M.; Hollingshead, M.; Kohlhagen, G.; Pommier, Y.;
Cushman, M. J. Med. Chem. 2002, 45, 242.
14. Fox, B. M.; Xiao, X.; Antony, S.; Kohlhagen, G.; Pommier, Y.; Staker, B. L.;
Stewart, L.; Cushman, M. J. Med. Chem. 2003, 46, 3275.
15. Nagarajan, M.; Xiao, X.; Antony, S.; Kohlhagen, G.; Pommier, Y.; Cushman, M. J.
Med. Chem. 2003, 46, 5712.
16. Nagarajan, M.; Morrell, A.; Fort, B. C.; Meckley, M. R.; Antony, S.; Kohlhagen, G.;
Pommier, Y.; Cushman, M. J. Med. Chem. 2004, 47, 5651.
17. Xiao, X.; Antony, S.; Kohlhagen, G.; Pommier, Y.; Cushman, M. Bioorg. Med.
Chem. 2004, 12, 5147.
18. Antony, S.; Kohlhagen, G.; Agama, K.; Jayaraman, M.; Cao, S.; Durrani, F. A.;
Rustum, Y. M.; Cushman, M.; Pommier, Y. Mol. Pharmacol. 2005, 67, 523.
19. Xiao, X.; Miao, Z. H.; Antony, S.; Pommier, Y.; Cushman, M. Bioorg. Med. Chem.
Lett. 2005, 15, 2795.
20. Morrell, A.; Antony, S.; Kohlhagen, G.; Pommier, Y.; Cushman, M. Bioorg. Med.
Chem. Lett. 2006, 16, 1846.
21. Xiao, X.; Antony, S.; Pommier, Y.; Cushman, M. J. Med. Chem. 2005, 48, 3231.
22. Morrell, A.; Jayaraman, M.; Nagarajan, M.; Fox, B. M.; Meckley, M. R.;
Ioanoviciu, A.; Pommier, Y.; Antony, S.; Hollingshead, M.; Cushman, M.
Bioorg. Med. Chem. Lett. 2006, 16, 4395.
23. Nagarajan, M.; Morrell, A.; Ioanoviciu, A.; Antony, S.; Kohlhagen, G.; Agama, K.;
Hollingshead, M.; Pommier, Y.; Cushman, M. J. Med. Chem. 2006, 49, 6283.
24. Morrell, A.; Antony, S.; Kohlhagen, G.; Pommier, Y.; Cushman, M. J. Med. Chem.
2006, 49, 7740.
25. Morrell, A.; Placzek, M.; Parmley, S.; Antony, S.; Dexheimer, T. S.; Pommier, Y.;
Cushman, M. J. Med. Chem. 2007, 50, 4419.
26. Morrell, A.; Placzek, M. S.; Steffen, J. D.; Antony, S.; Agama, K.; Pommier, Y.;
Cushman, M. J. Med. Chem. 2007, 50, 2040.
27. Morrell, A.; Placzek, M.; Parmley, S.; Grella, B.; Antony, S.; Pommier, Y.;
Cushman, M. J. Med. Chem. 2007, 50, 4388.
In conclusion, a series of novel indenoisoquinoline derivatives
were synthesized based upon previously reported lead compound
11. Our work has led to the discovery of more potent compounds
than 11. For example, compound 25 was found to be 10-times
more potent in cell-killing activity for both cell lines HepG2 and
HCT-116 than reported compound 11, with IC50 of 0.019 and
0.093 lM, respectively. Compound 25 was also found to have
stronger top1 inhibition activity than 11 in our inhibition assay.
Further in vivo evaluations of compound 25 are in progress and
will be reported in due course.
Acknowledgments
This work was supported by, the National Natural Science
Foundation of China (No. 21072232), and the National Natural-
Science Foundation of China (No. 91029744).
Supplementary data
28. Whitmore, W. F.; Cooney, R. C. J. Am. Chem. Soc. 1944, 66, 1237.
29. Yus, M.; Soler, T.; Foubelo, F. J. Org. Chem. 2001, 66, 6207.
30. Cushman, M.; Cheng, L. J. Org. Chem. 1978, 43, 286.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.10.019.

X. Zhang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1276–1281
1281
31. 6-(3-[(1-Methylpiperazinyl)-1-propyl])-9-fluoro-3-nitro-5,6-di-hydro-5,11-
dioxo-11H-indeno[1,2-c]isoquinoline (25) mp 236–239 °C; EI-MS (m/
z):450[M]+; IR(KBr): 3415, 2816, 1667, 1613, 1500, 1347, 795 cmÀ1; Anal.
calcd for C24H23FN4O4: C 63.99, H 5.15, N 12.44 Found: C 64.11, H 5.09, N
12.29; 1H NMR (300 MHz, CDCl3): d 9.16(s, 1H, Ar-H), 8.82(d, 1H, J = 8.7 Hz, Ar-
H), 8.49(d, 1H, J = 8.7 Hz, Ar-H), 7.94(m, 1H, Ar-H), 7.43(m, 1H, Ar-H), 7.21(m,
1H, Ar-H), 4.64(t, 2H, J = 7.8 Hz, CON–CH2–), 2.61(br s, 13H, piperazine-H),
2.04(m, 2H, –CH2–CH2–CH2–).6-(3-[(1-Methylpiperazinyl)-1-propyl])-3-nitro-
9-methoxy-5,6-dihydro5,11-dioxo-11H-indeno[1,2-c]isoquinoline (36) mp
197–199 °C; MS-EI (m/z):462[M]+; IR(KBr): 3466, 3417, 2840, 1675, 1609,
1506, 1332, 1121, 853, 791 cmÀ1; Anal. calcd for C25H26N4O5: C 64.92, H 5.67, N
12.11 Found: C 64.88, H 5.69, N 12.08; 1H NMR (300 MHz, CDCl3): d 9.16(d, 1H,
J = 2.4 Hz, Ar-H), 8.78(d, 1H, J = 9 Hz, Ar-H), 8.44(dd, 1H, J1 = 2.4 Hz, J2 = 9 Hz,
Ar-H), 7.76(d, 1H, J = 8.4 Hz, Ar-H), 7.27(d, 1H, J = 2.7 Hz, Ar-H), 6.92(dd, 1H,
J1 = 2.7 Hz, J2 = 8.4 Hz, Ar-H), 4.60(t, 2H, J = 7.5 Hz, CON–CH2–), 3.94(s, 3H, –
OCH3), 2.51(br s, 13H, piperazine-H), 2.06(m, 2H, –CH2–CH2–CH2–).
32. Kiselev, E.; Dexheimer, T. S.; Pommier, Y.; Cushman, M. J. Med. Chem. 2010, 53,
8716.
33. Peterson, K. E.; Cinelli, M. A.; Morrel, A. E.; Metha, A.; Dexheimer, T. S.; Agama,
K.; Antony, S.; Pommier, Y.; Cushman, M. J. Med. Chem. 2011, 54, 4937.
34. Khadlka, D. B.; Cho, W. J. Bioorg. Med. Chem. 2011, 19, 724.