Synthesis, cytotoxicity and topoisomerase II inhibitory activity of lomefloxacin derivatives

Article abstract of DOI:10.1016/j.bmcl.2013.03.037

A novel series of amide derivatives of lomefloxacin were synthesized and evaluated for their topoisomerase I and II inhibitory activity as well as cytotoxicity against a panel of five human cancer cell lines. Of the compounds prepared compounds 9d and 9g exhibited strong inhibition against topoisomerase II at 100 μM. In addition, docking studies were performed to predict the inhibition mode.

Full text of DOI:10.1016/j.bmcl.2013.03.037

Bioorganic & Medicinal Chemistry Letters 23 (2013) 2974–2978
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, cytotoxicity and topoisomerase II inhibitory activity
of lomefloxacin derivatives
a,b,
You Zhou b,c, Xiaoli Xu b,c, Yuan Sun b,c, Huaping Wang b,c, Haopeng Sun b,c, , Qidong You
⇑
⇑
a State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
b Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
c Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of amide derivatives of lomefloxacin were synthesized and evaluated for their topoisomerase
I and II inhibitory activity as well as cytotoxicity against a panel of five human cancer cell lines. Of the com-
pounds prepared compounds 9d and 9g exhibited strong inhibition against topoisomerase II at 100 lM. In
Received 7 January 2013
Revised 7 March 2013
Accepted 11 March 2013
Available online 20 March 2013
addition, docking studies were performed to predict the inhibition mode.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Lomefloxacin derivatives
Topoisomerase I and II inhibitory activity
Docking study
DNA topoisomerases, generally classified as types I and II, are
critical cellular enzymes necessary for cell proliferation by solving
topological problems in the process of DNA replication.1–3 Topoiso-
merase I produces a single strand break in DNA allowing relaxation
of DNA supercoils. On the other hand, topoisomerase II controls
DNA topology by transient cleavage of the DNA double helix.4
Due to the critical role of these enzymes for the cell proliferative
process, topoisomerases have become one of the major targets
for the design of novel antitumor drugs.5,6 To date, drugs from
the camptothecin (CPT, 1) family and etoposide (2) are clinically
used to target topoisomerase I and topoisomerase II, respectively.
Unfortunately, the therapeutic potential of 1 and its derivatives,
topotecan (3) and irinotecan (4), is severely hindered due to their
rapid inactivation through lactone ring hydrolysis at physiological
pH (Scheme 1).7 In order to overcome the E-ring-opening inactiva-
tion of camptothecins, metabolically stable non-CPT derivatives
have been developed without a lactone ring in their skeleton com-
pared with camptothecins.8–11
suggested that our scaffold modification approach based on 1 has
yielded new generation of topoisomerase I inhibitors for cancer
treatment.
In order to extend the scaffold of the anticancer drug candidates
targeting topoisomerase I, we designed and synthesized a novel
series of compounds based on the most active compound (5) in
the previous work (Fig. 1). The two fluoro atoms and one 3-meth-
ylpiperazine group on the quinolone ring of 5 were retained. It is
widely reported that the fluoro atom could improve the metabolic
characteristics of compounds by prolonging the half-lives, and the
piperazine could enhance the water solubility of compounds.
Meanwhile, the scaffold hopping method is used in the modifica-
tion of 5 by breaking the benzothiazole ring to aniline amide group.
The amide group was expected to improve the solubility and rigid-
ity of 5. Substituents with different electronic properties were
introduced onto the phenyl group of aniline to investigate the im-
pact of their electronic effects on the biological profile. Further-
more, the effects of increased flexibility of central linkage and
replacement of the phenyl group of aniline by other aromatic rings
on biological activity were investigated, respectively. Total 12 new
compounds (9a–9l, Scheme 2) were synthesized and evaluated for
Top I and Top II inhibition activities and for cytotoxicity against
five cancer cell lines (HCT-116, MDA-MB-231, A549, Bel7402 and
KB).
Previously we reported that a novel series of topoisomerase I
inhibitors were designed and synthesized on the basis of 1 using
scaffold modification strategy (Fig. 1).12 The original framework
of 1 was changed into a combination of the quinolone skeleton
and benzimidazole group or its bioisoesters having a single carbon
bond. The result of MTT test and topoisomerases inhibition test
The synthetic routes for the target compounds are described in
Scheme 2. The lomefloxacin hydrochloride (6) as starting material
was commercially available. As shown in Scheme 2, the compound
6 was protected by Boc group using Boc2O under NaOH condition
to give compound 7 in 90.6% yield. Subsequently, 7 was condensed
⇑
Corresponding authors. Tel./fax: +86 25 83271216 (H.S.); tel.: +86 25 83271351
(Q.Y.).
E-mail addresses: sunhaopeng@163.com (H. Sun), youqidong@gmail.com
(Q. You).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.03.037

Y. Zhou et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2974–2978
2975
O
O
O
O
HO
OH
O
O
O
OH
N
O
O
O
N
MeO
OMe
O
OH
Camptothecin
Etoposide
1
2
N
N
HO
O
N
O
N
N
O
N
N
O
O
N
O
O
OH
OH O
Topotecan
Irinotecan
3
4
O
O
N
N
N
OH
Na
O
O
O
OH
O
OH
1
Scheme 1. Lactone ring hydrolysis of 1.
Break
O
O
F
N
C
A
B
N
N
Y
Z
R3
D
R2
O
N
R1
F
E
O
X
OH O
N
Y
Z
R3
N
X
R1
R2
O
N
O
O2N
O
N
N
F
Ar
F
N
O
H
N
N
F
NH
F
NH
Break
5
Figure 1. Compound generation by scaffold modification.
with various aromatic amines in the presence of BOP to provide a
series of amide derivatives (8a–8l) in 24.0–66.4% yield. Lastly, the
removal of the Boc groups from compounds 8a–8l using TFA affor-
ded the target compounds (9a–9l) in 76.4–97.2% yield.13 The final
products were purified by column chromatography and analytical
data of 4 representative compounds were described in the refer-
ence section.14,15
derivatives displayed potent cytotoxic activities against cancer cell
lines tested (Table 1). Compound 9a, which contains an unsubsti-
tuted aromatic benzene ring, showed moderate cytotoxic activity
on MDA-MB-231, Bel7402 and KB cell lines, but weak cytotoxic
activity on A549 and HCT-116 cell lines. In comparison with 9a,
compounds (9b, 9c, 9h) containing electron donating substituents
on the benzene ring displayed better cytotoxicity on A549 and
HCT-116 cell lines, indicating a different mode of action involved.
It is noteworthy that the introduction of specific electron with-
drawing groups into the benzene ring of 9a (9e, 9g, 9k) could
apparently enhance the in vitro cytotoxicity. When evaluated on
the MDA-MB-231 cell line, compound 9k showed a high cytotoxic-
MTT assay16 was performed to evaluate the cytotoxic activities
of our synthesized compounds against five different cancer cell
lines including A549 (human lung carcinoma cell line), HCT-116
(human colorectal cancer cell line), MDA-MB-231 (human breast
cancer cell line), Bel7402 (human hepatocarcinoma cell line) and
KB (oral human epidermoid carcinoma cancer cell line), with 10-
OH CPT and compound 5 as positive controls. Most of these
ity in the micromolar range (IC50 = 0.98
lM), higher than com-
pound 5 (IC50 = 2.0 M). Compounds 9e and 9g also showed
l

2976
Y. Zhou et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2974–2978
O
N
O
O
O
N
F
X
R4
R3
F
COOH
ii
F
COOH
HCl
N
H
n
R1
i
N
N
N
N
N
F
R2
N
F
HN
F
Boc
Boc
6
7
8a-8k
a: X=C, R1=H, R2=H, R3=H, R4=H, n=0
b: X=C, R1=OH, R2=H, R3=H, R4=H, n=0
c: X=C, R1=NH2, R2=H, R3=H, R4=H, n=0
d: X=N, R1=H, R2=H, R3=Cl, R4=H, n=0
e: X=C, R1=H, R2=NO2, R3=H, R4=H, n=0
f: X=C, R1=H, R2=NO2, R3=Me, R4=H, n=0
g: X=C, R1=F, R2=H, R3=H, R4=NO2, n=0
h: X=C, R1=H, R2=H, R3=OMe, R4=H, n=0
O
N
O
F
X
R4
N
n
R1
H
iii
N
R3
HN
F
R2
i: X=C, R1=H, R2=H, R3=COCH3, R4=H, n=0
j: X=C, R1=H, R2=H, R3=OMe, R4=H, n=1
k: X=C, R1=H, R2=H, R3=OCF3,R4=H, n=0
9a-9k
O
N
O
N
O
N
O
N
O
N
F
F
COOH
ii
F
S
iii
N
H
S
N
H
N
N
N
N
F
N
F
HN
F
Boc
Boc
9l
8l
7
Scheme 2. Synthesis of lomefloxacin derivatives. Reagents and conditions: (i) THF/NaOH (aq), Boc2O, rt; (ii) BOP/DMAP, TEA, CH2Cl2, rt; (iii) TFA, CH2Cl2, rt.
etoposide as positive controls.17 As shown in Figure 2A, the result
clearly showed that none of tested compounds possessed inhibi-
tory activity on topoisomerase I, which means benzo-heterocycle
Table 1
Result of cytotoxicity of compounds synthesized against five cancer cells
group is closely correlated with topoisomerase I inhibitory activity.
In the topoisomerase II inhibition assay (Fig. 2B), supercoiled plas-
mid DNA was treated with human topoisomerase II in the presence
of the reference compound (etoposide) or tested compounds at a
Compounds/cells
IC50 (lM)
A549
HCT-116
MDA-MB-231
Bel7402
KB
0.6
10-OH CPT
5
0.07
0.9
39.3
24.8
5.9
3.3
3.24
3.7
1.7
9.7
4.0
7.0
0.3
1.1
12.7
5.37
2.7
0.06
2.0
7.4
7.43
9.5
4.8
3.25
4.2
6.9
7.3
5.6
0.2
1.6
6.0
>50
4.8
4.9
1.0
29.1
2.9
0.9
4.4
5.05
2.8
1.6
1.7
3.9
3.2
2.6
concentration of 100 lM. Inhibition of topoisomerase II was clearly
9a
9b
9c
9d
9e
9f
9g
9h
9i
specifically detected with the reference compound (etoposide),
which produced a marked level of DNA double stranded breaks,
corresponding to linear DNA. Linear DNA bands were also observed
for some of the tested compounds. From the enzyme assay, 6 active
compounds with inhibitory effect on topoisomerase II enzyme
were identified. Figure 2B shows that compounds 9d and 9g were
active inhibitors on topoisomerase II enzyme with comparable ex-
3.3
2.71
11.8
2.6
3.8
4.6
1.4
2.35
8.66
5.4
>50
10.3
2.0
42.6
1.63
1.4
tent to etoposide at a concentration of 100 lM, whereas com-
9j
9k
9l
25.3
0.98
>50
1.32
20.2
pounds 9e, 9i, 9f and 9k appeared to be less active than
etoposide. The result indicated that the introduction of various
electron withdrawing groups into the benzene ring of 9a could
generate a series of derivatives with topoisomerase II inhibitory
activity.
In summary, results of topoisomerases inhibition assays indi-
cated that the new synthesized lomefloxacin derivatives exerted
their antitumor activities through specific inhibition of human
topoisomerase II activity without any human topoisomerase I
inhibitory activity. However, there was no remarkable correlation
between cytotoxicity and topoisomerase II inhibitory activity,
which implied that we can not exclude the possibility that other
targets can be involved in the mechanism of action of the active
compounds.
>50
43.5
comparable cytotoxic activity against cancer cell lines tested.
These results indicated that the decrease of aromatic ring electron
density was advantageous to the cytotoxicity. When benzene ring
was replaced with pyridine or thiazole, the resulting compounds,
9d and 9l, demonstrated moderate or weak cytotoxicity on cancer
cell lines, respectively. Compared with 9h, compound 9j with an
additional CH2 group showed comparable antiproliferative activity
against HCT-116 and KB cell lines, but decreased cytotoxicity
against MDA-MB-231 and Bel7402 cell lines.
In summary, we have prepared a series of lomefloxacin deriva-
tives and conducted preliminary analysis of the impact of electron
property on the in vitro cytotoxicity. Of the compounds prepared
compounds 9d, 9e, 9g and 9k showed comparable cytotoxic activ-
ity against cancer cell lines tested.
To verify the binding mode of lomefloxacin derivatives, com-
pounds 9g and 9a were docked into the ATP-binding domain of hu-
man topoisomerase IIa, respectively. ATP-binding domain is the
probable binding site for etoposide as reported earlier.18 We car-
ried out a docking study using CDOCKER in Discovery Studio 3.0
and the docking results are shown in Figure 3. An analysis of the
docked compound 9a to the ATP-binding domain showed that
Topoisomerases inhibition assays were used to assess the ef-
fects of all the 12 synthesized compounds on the catalytic activity
of human topoisomerase I and II (Topogen), with camptothecin and

Y. Zhou et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2974–2978
2977
(A)
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
16 17
(B)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Figure 2. Topoisomerase I (A) and II (B) inhibitory activities of the tested compounds. All compounds were examined in a final concentration of 100
lM. (A) lane 1: relaxed
DNA only, lane 2: ScDNA + 1% DMSO, lane 3: ScDNA + Topo I, lane 4: ScDNA + Topo I + camptothecin, lane 5: ScDNA + Topo I + compound 5, lanes 6–17: ScDNA + Topo
I + compounds in order of 9d, 9k, 9e, 9g, 9i, 9f, 9l, 9a, 9b, 9c, 9h and 9j. (B) lane 1: relaxed DNA only, lane 2: ScDNA + Topo II, lane 3: ScDNA + Topo II + etoposide, lanes 4–7
and 9–16: ScDNA + Topo II + compounds as the same as the order of (A), lane 8: linear DNA only.
Figure 3. (A) Molecular docking between compound 9a and ATP-binding domain of human topo II
site of topo II are shown as sticks. The representation of the compound is colored by the atom type (carbon, orange; oxygen, red; nitrogen, blue; fluoro, cyan). (B) Molecular
docking between compound 9g and ATP-binding domain of human topo II
a. Compound 9a is depicted by stick. The key residues of the ATP-binding
a
a
. Compound 9g in stick representation is described as above.
3. Redinbo, M. R.; Stewart, L.; Kuhn, P.; Champoux, J. J.; Hol, W. G. Science 1998,
compound 9a occupies the ATP-binding site in an unreasonable
conformation, which would lead to increased internal energy. In
contrast, molecular docking study revealed compound 9g to have
a stable binding pattern to the ATP-binding domain, which was
matching with previously reported docking results of other topoi-
somerase II inhibitors.19 Compound 9g was found to has strong
intermolecular contacts with Arg 98, Gly164 and Ser149. The nitro
group attached to the benzene ring forms two hydrogen bonds
with Asn 150 and Arg 162. In addition, the fluoro atom substituent
forms a hydrogen bond with Thr 147 (Fig. 3B).
27, 504.
4. Chen, A. Y.; Liu, L. F. Annu. Rev. Pharmacol. Toxicol. 1994, 34, 191.
5. Kellner, U.; Rudolph, P.; Parwaresch, R. Onkologie 2000, 23, 424.
6. Singh, S. K.; Ruchebman, A. L.; Li, T. K.; Liu, A.; Liu, L. F.; Lavoie, E. J. J. Med. Chem.
2003, 46, 2254.
7. Fassberg, J.; Stella, V. J. J. Pharm. Sci. 1992, 81, 676.
8. Fox, B. M.; Xiao, X.; Antony, S.; Kohlhagen, G.; Pommier, Y.; Staker, B. L.;
Stewart, L.; Cushman, M. J. Med. Chem. 2003, 46, 3275.
9. Morrell, A.; Antony, S.; Kohlhagen, G.; Pommier, Y.; Cushman, M. J. Med. Chem.
2006, 49, 7740.
10. Pommier, Y. Nat. Rev. Cancer 2006, 6, 789.
11. Xiao, X.; Antony, S.; Pommier, Y.; Cushman, M. J. Med. Chem. 2006, 49, 1408.
12. You, Q. D.; Li, Z. Y.; Huang, C. H.; Yang, Q.; Wang, X. J.; Guo, Q. L.; Chen, X. G.;
He, X. G.; Li, T. K.; Chen, J. W. J. Med. Chem. 2009, 52, 5649.
The results of molecular docking indicated that the introduction
of electron withdrawing substituents into the benzene ring may
13. General procedure for the synthesis of intermediates 8a–8l: To a solution of the
Boc-protected Lomefloxacin (0.5 g, 1.1 mmol) in CH2Cl2 (20 mL) was added a
catalytic amount of DMAP (54 mg, 0.44 mmol) followed by TEA (0.5 mL,
3.3 mmol) and BOP (1 g, 2.2 mmol). The reaction mixture was allowed to stir
for 1 h at room temperature. After that a solution of amine (0.1 g, 1.1 mmol) in
CH2Cl2 (10 mL) was added dropwise and slowly to the mixture. The reaction
mixture was allowed to stir overnight at room temperature. Saturated
ammonium chloride aqueous solution (30 mL) was added and the reaction
was extracted with CH2Cl2 (3 ꢀ 20 mL). The organic layer was washed with
brine, dried over Na2SO4, filtered and concentrated. The product was then
purified over silica gel eluting with PET/EtOAc (1:1) to give pure 8a (0.29 g) in
50.1% yield. The compounds 8b–8l were similarly produced as 8a.
14. General procedure for the synthesis of the target compounds 9a–9l: A solution of
8a (0.2 g, 0.38 mmol) and CF3COOH (5 mL) in dry CH2Cl2 (20 mL) was stirred at
room temperature for 2 h. Saturated sodium bicarbonate solution (30 mL) was
added and the reaction was extracted with CH2Cl2 (3 ꢀ 10 mL). The organic
layer was washed with brine, dried over Na2SO4, filtered and concentrated. The
crude material was purified over silica gel eluting with CH2Cl2/MeOH (10:1) to
give the pure 9a (0.15 g) in 92.6% yield. The target compounds 9b–9l were
similarly produced as 9a.
anchor in the ATP-binding domain of human topoisomerase II
resulting in increased binding affinity, which lead to a higher topo-
isomerase II inhibitory activity.
In conclusion, we have designed and synthesized a series of
lomefloxacin derivatives and evaluated their pharmacological
activity. Of the compounds prepared compounds 9d, 9e, 9g, 9k,
9i and 9f could selectively impede topoisomerase II function with-
out affecting topoisomerase I catalytic activity. Molecular docking
study revealed compound 9g to have a stable binding pattern to
a
the ATP-binding domain of human topoisomerase IIa. This study
may provide valuable information to researchers working on the
development of novel antitumor agents targeting topoisomerase II.
References and notes
15. The data of selected compound 9d: yield 91.5%; mp 229–232 °C; IR (KBr): 3462,
1. (a) Wang, J. C. Annu. Rev. Biochem. 1996, 65, 635; (b) Berger, J. M. Biochim.
Biophys. Acta 1998, 1400, 3; (c) Kaufmann, S. H. Biochim. Biophys. Acta 1998,
1400, 195.
2969, 2845, 1680, 1605, 1563, 1471, 1376, 1318, 1296, 1022, 796, 649 cmꢁ1
;
EI-MS: 462 (M); 1H NMR (300 MHz, CDCl3): d 12.56 (s, 1H, –NH-CO), 8.59 (s,
1H, Ar-H), 8.24 (d, J = 1.9 Hz, 1H, Ar-H), 8.21 (s, 1H, Ar-H), 7.94 (d,
2. Pommier, Y. Biochimie 1998, 80, 255.

2978
Y. Zhou et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2974–2978
J = 12.0 Hz,1H, Ar-H), 7.59 (dd, J = 11.3 Hz, 1H, Ar-H), 4.38 (m, 2H, N-CH2–CH3),
(d, J = 9 Hz, 1H, 60-H), 8.00 (dd, J = 13.5 Hz, 1H, 5-H), 8.88 (s, 1H, 2-H), 9.36 (dd,
J = 9 Hz, 1H, 50-H), 12.71 (s, 1H, –N-H); Anal. Calcd for C23H22F3N5O4: C, 56.44;
H, 4.53; N, 14.31. Found: C, 56.01; H, 4.54; N, 14.18. Compound 9k: yield 95.8%;
mp 210–214 °C; IR (KBr): 3469, 2955, 2825, 1679, 1626, 1555, 1537, 1473,
1263, 1200, 1022, 799, 656 cmꢁ1; EI-MS: 510(M); 1H NMR (300 MHz, CDCl3): d
12.17 (s, 1H, –NH-CO), 8.73 (s, 1H, Ar-H), 8.04 (d, J = 11.7 Hz, 1H, Ar-H), 7.78 (d,
J = 8.8 Hz, 2H, Ar-H), 7.21 (d, J = 8.3 Hz, 2H, Ar-H), 4.48 (m, 2H, N-CH2–CH3),
3.51 (m, 3H, N-CH2, N-CH), 3.25 (m, 4H, 2 ꢀ N-CH2), 1.57 (t, J = 13.4 Hz, 3H, –
CH2–CH3), 1.33 (d, J = 5.0 Hz, 3H, –CH–CH3); Anal. Calcd for C24H23N4O3F5: C,
55.49; H, 4.66; N, 10.79. Found: C, 55.92; H, 4.74; N, 10.79.
3.24 (m, 3H, N-CH2, N-CH), 2.94 (m, 4H, 2 ꢀ N-CH2), 1.49 (t, J = 13.6 Hz, 3H, –
CH2–CH3), 1.06 (d, J = 6.0 Hz, 3H, –CH–CH3); 13C NMR (75 MHz, CDCl3): 15.8,
18.9, 45.9, 48.8, 50.8, 53.6, 58.0, 107.9, 109.2, 112.8, 114.7, 120.4, 125.7, 128.8,
133.6, 136.9, 146.3, 149.8, 152.8, 156.0, 162.4, 173.6. Anal. Calcd for
C22H22N5O2F2Cl: C, 57.21; H, 4.80; N, 15.16. Found: C, 56.78; H, 5.19; N,
15.12. Compound 9e: yield 91.0%; mp 216–219 °C; IR (KBr): 3469, 2967, 2825,
1681, 1603, 1527, 1351, 1320, 1241, 798, 738 cmꢁ1; EI-MS: 471 (M); 1H NMR
(300 MHz, CDCl3): d 12.51 (s, 1H, –NH-CO), 8.77 (s, 1H, Ar-H), 8.72(s, 1H, Ar-H),
8.00 (d, J = 12.8 Hz, 2H, Ar-H), 7.94 (s, 1H, Ar-H), 7.50 (t, J = 8.0 Hz, 1H, Ar-H),
4.49 (m, 2H, N-CH2–CH3), 3.35 (m, 3H, N-CH2, N-CH), 3.05 (m, 4H, 2 ꢀ N-CH2),
1.59 (t, J = 5.4 Hz, 3H, –CH2–CH3), 1.15 (d, J = 4.1 Hz, 3H, –CH–CH3); Anal. Calcd
for C23H23N5O4F2: C, 58.60; H, 4.92; N, 14.85. Found: C, 58.22; H, 5.17; N, 15.28.
Compound 9g: yield 96.23%; mp 287–289 °C; IR (KBr): 3422, 2979, 1677, 1604,
1560, 1534, 1474, 1384, 1348 cmꢁ1; EI-MS: 489 [M]+; 1H NMR (300 MHz,
DMSO-d6): d 1.05 (d, J = 6 Hz, 3H, –CH–CH3), 1.45 (t, 3H, –CH2–CH3), 2.88 (m,
6H, 3 ꢀ –N-CH2), 4.56 (m, 3H, –N-CH–CH2–N), 7.61 (t, J = 18 Hz, 1H, 30-H), 7.83
16. Carmichael, J.; DeGraff, W. G.; Gazdar, A. F.; Minna, J. D.; Mitchell, J. B. Cancer
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