Design, synthesis, and evaluation of novel 6-chloro-/fluorochromone derivatives as potential topoisomerase inhibitor anticancer agents

Article abstract of DOI:10.1016/j.bmcl.2005.11.044

6-Chloro-2-pyrrolidino-/morpholino-/piperidino-/N-methylpiperazino-3- formyl-chromones (13-16) and 6-fluoro-2,7-di-morpholino-/piperidino-/N- methylpiperazino-3-formylchromones (17-19) have been synthesized as potential topoisomerase inhibitor anticancer agents, and evaluated, in vitro, against Ehrlich ascites carcinoma (EAC) cells, and also in vivo on EAC bearing mice. The compounds displayed promising anticancer activity under these test systems and shall serve as useful 'leads' for further design.

Full text of DOI:10.1016/j.bmcl.2005.11.044

Bioorganic & Medicinal Chemistry Letters 16 (2006) 1366–1370
Design, synthesis, and evaluation of novel
6-chloro-/fluorochromone derivatives as potential
topoisomerase inhibitor anticancer agents
M. P. S. Ishar,a,* Gurpinder Singh,a Satyajit Singh,b K. K. Sreenivasanb and Gurmit Singha
aDepartment of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143 005, Punjab, India
bDepartment of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal 576 104, Karnataka, India
Received 20 August 2005; revised 30 October 2005; accepted 14 November 2005
Available online 5 December 2005
Abstract—6-Chloro-2-pyrrolidino-/morpholino-/piperidino-/N-methylpiperazino-3-formyl-chromones (13–16) and 6-fluoro-2,7-di-
morpholino-/piperidino-/N-methylpiperazino-3-formylchromones (17–19) have been synthesized as potential topoisomerase inhibi-
tor anticancer agents, and evaluated, in vitro, against Ehrlich ascites carcinoma (EAC) cells, and also in vivo on EAC bearing mice.
The compounds displayed promising anticancer activity under these test systems and shall serve as useful ÔleadsÕ for further design.
ꢀ 2005 Elsevier Ltd. All rights reserved.
DNA topoisomerases are a class of enzymes involved in
regulation of DNA supercoiling and are crucial for rep-
lication and transcription of DNA.1 Consequently, these
enzymes are targets for chemotherapeutic intervention
in antibacterial and anticancer therapies.2,3 Though a
number of classes of compounds are known to inhibit
topoisomerases, their precise target and mode of action
are varied and are still being investigated.2–9 Fluoroqu-
inolone antibacterials such as ciprofloxacin (1a) and
norfloxacin (1b, Fig. 1) are inhibitors of essential bacte-
rial DNA-type-II topoisomerases (DNA gyrase and
Topoisomerase IV found in bacteria).2,3,7 Camptothecin
(2a) and its synthetic analogs such as topotecin (2b,
Fig. 1) are DNA topoisomerase-I poisons used as anti-
cancer agents.6,10 On the other hand, although the nat-
ural product podophyllotoxin is an antimitotic agent,
its semi-synthetic analogs, etoposides, are topoisomer-
ase-II inhibitors with anticancer applications.11 In the
case of psorospermin (3, Fig. 1), a natural antitumor
antibiotic,12 which is apparently an alkylating agent
resembling pluramycin A (4), it has been shown that it
has to intercalate with DNA and its alkylating potential
is significantly increased in the presence of topoisomer-
ase-II.13 Compound A-62176 (5, Fig. 1), a fluoroquino-
lone possessing a quinobenzoxazine moiety, shows good
activity against a number of cancer cell lines and com-
petes with psorospermin for topoisomerase II–DNA
complex;5,13,14 binding of A-62176 has been shown5,14
to involve its two molecules and two Mg2+ ions.
Based on the structural similarities, i.e., presence of a
benzochromone (xanthone) nucleus in psorospermin, a
chromone moiety in pluramycin A, a fluoroquinolone
moiety in A62176 along with known involvement of flu-
orquinolones with topoisomerases, the established
SARs3,7,15 in case of fluoroquinolones, and recent obser-
vation that the ketone moiety plays an important role in
anticancer activity of some 2-fluorinated phenyl-4-
quinolone antimitotic anticancer agents,16 it was reason-
able to infer that N-alkylation in fluoroquinolones is
meant to ensure the keto-tautomer. Therefore, it was
concluded that a chromone moiety can be a replacement
for N-alkyl-4-quinolone nucleus, leading to the design of
novel chloro/fluorochromone analogs (Fig. 2).
2-Anilino-6-chloro-3-formylchromone and 2-anilino-7-
chloro-6-fluoro-3-formylchromone (11a), (11b) were ob-
tained by recently reported thermal rearrangements of
the corresponding nitrones (10a), (10b)17 by refluxing
in dry benzene. Reactions of (11a), (11b) with methyl io-
dide in the presence of anhydrous K2CO3 afforded the
corresponding N-methylanilino derivatives (12a), (12b).
Nucleophilic substitution of N-methylanilino moiety in
12a by heterocyclic amines,18 on refluxing the equimolar
Keywords: Anticancer; Antitumor; DNA topoisomerases; Topoiso-
merase inhibitors; Chromone.
*
Corresponding author. Tel.: +91 183 2258802 09x3321; fax: +91 183
2258820; e-mail: mpsishar@yahoo.com
0960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.11.044

M. P. S. Ishar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1366–1370
1367
O
O
R3 R2
R1
F
COOH
O
N
O
N
N
R
N
N
HO
H
(2)
(1)
Camptothecin (2a) R1 = R2 = R3 = H
Topotecin (2b) R1 = OH, R2 = CH2N(CH3)2, R3 = H
Ciprofloxacin (1a) R =
Norfloxcin (1b) R = -CH2CH3
O
O
O
OCH3
O
O
CH3
OH
O
CH3
O
H3C
O
O
OH
H
N(CH3)2
CH3
O
CH3
CO2CH3
O
Psorospermin (3)
(H3C)2N
H3C
Pluramycin - A, (4)
O
N
O
F
OH
N
O
H2N
H
(5)
A - 62176
Figure 1.
O
O
R1
R2
F/Cl
R
R1
R2
= O ;
R = H
n
X
N
N
/ H
R1
n
= O ;
X
R = OH
n = 1, 2
X = O, N-CH3, NH,CH2
R2
R1 = OH, R2, R = H, Alkyl
Figure 2.
solutions of reactants in acetonitrile under anhydrous
conditions, afforded compounds (13–16, Scheme 1); pro-
gress of the reactions was monitored by TLC and prod-
ucts were isolated by direct crystallization on removal of
solvent and re-crystallized from chloroform–hexane
(2:1). Similar reaction of 12b with two molar equivalents
of heterocyclic amines, under identical conditions, led to
the nucleophilic substitution of both N-methylanilino
moiety as well as 7-chloro, affording compounds (17–
19, Scheme 1), which were isolated similarly and re-crys-
tallized from chloroform–hexane (2:1). All the interme-
diates and the final products have been characterized
different concentrations (125, 250, and 500 lg/ml) of
these compounds. Counting of cells was done with
hemocytometer and the percentage of dead cells was
determined by tryphan blue exclusion method; the re-
sults are summarized in Table 1. For in vivo evaluation
ascites tumors were induced in Swiss Albino mice by
intraperitoneal inoculation of ascitic fluid (containing
estimated 106 cells/200 ll) from donor mice and 24 h
after inoculation, test compounds were administered
intraperitoneally (as 2% suspension with carboxymeth-
yl-cellulose) and continued with a daily dose for nine
days.23 The results of various observations/measure-
ments along with similar measurements on control and
standard22 are summarized in Table 2.
1
by detailed spectroscopic (UV, IR, H and 13C NMR,
and EI-MS) and microanalytical data.19
The obtained compounds (13–19) were evaluated for
cytotoxicity against Ehrlich ascites carcinoma (EAC)
cells and compounds 14, 17, and 18 were also evaluated,
in vivo, against EAC carcinoma bearing mice.20 For
cytotoxicity evaluation, EAC cells were incubated with
The results in Table 1 clearly indicate that compounds
(13–17) show significant cytotoxicity at a concentration
of 250 lg/ml, whereas compound 19 was nontoxic even
at 500 lg/ml. The results of in vivo evaluation (Table
2) indicate significant increase in the life span of ascites

1368
M. P. S. Ishar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1366–1370
OCOCH3
OH
OH
X1
O
O
O
X1
i
COCH3
ii
H
O
iii
X2
X2
X2
X2
X1
(9)
X1
(7)
(8)
a X1 = Cl, X2 = H
b X1 = F, X2 = Cl
(6)
iv
O
O
O
O
O
X1
X2
N
X1
X2
X1
X2
v
vi
H
Ph
H
O
CH3
O
(11)
NH
Ph
O
(12)
N
(10)
Ph
O
O
X1
H
17, X1 = F, X = CH2
18, X1 = F, X = O
19, X1 = F, X = NCH3
HN
X
vii
O
N
N
X1 = F, X2 = Cl
n
X
HN
X
X
vii
(17 -19, 85 -90 %)
X1 = Cl, X2 = H
O
O
13, n = 1, X1 = Cl, X = CH2
14, n = 2, X1 = Cl, X = O
15, n = 2, X1 = Cl, X = CH2
16, n = 2, X1 = Cl, X = NCH3
X1
H
n
X
O
N
(13-16, 90 -95%)
Scheme 1. Reagents and conditions: (i) CH3COCl, D; (ii) anhyd AlCl3, D; (iii) DMF, POCl3; (iv) PhNHOH, anhyd benzene; (v) anhyd benzene, D;
(vi) CH3I, anhyd acetone, D; (vii) anhyd acetonitrile, reflux.
Table 1. Cytotoxicity of compounds (13–19) against Ehrlich ascites
carcinoma (EAC) cells
ro-3-formylchromones (17, 18) have shown promising
anticancer activity and shall serve as useful Ôleads.Õ
Concentration (lg/ml)
Percentage cytotoxicity
(% of dead cells)
Further developments involving oxidation/reduction of
3-formyl group, preparation of 2,7-disubstituted-6-chlo-
ro- and 2-substituted-6-fluoro-analogs, and introduction
of an alkylating function on heterocyclic-amine moieties
are in progress. A substantial increase in anticancer
activity is anticipated after oxidation/reduction of the
formyl function.
13
90
100 100 100 60 100
14
15
16 17
18 19
125
250
500
60 100 50 100
0
0
0
0
100 100 100 60 100 70 20
carcinoma bearing mice treated with compounds 14, 17,
and 18, relative to control. The treated animals also
showed a reduction in body weight as compared to con-
trol and also increased glutathione (GSH) level; the lat-
ter signifying the decreased utilization of GSH due to
suppression of tumors.21,23 In general, 6-chloro-substi-
tuted derivatives gave more consistent results and piper-
idine bearing analogs (15, 17) were more potent.
Acknowledgments
The work was supported by research grant [E-7-14/2003
(FD-III)] from University Grants Commission (UGC),
Government of India. G. Singh also thanks UGC for
Project Fellowship. 300 MHz NMR facility created by
Department of Science and Technology, Government
of India, at Guru Nanak Dev University, Amritsar, is
gratefully acknowledged.
In conclusion, the synthesized 2-substituted-6-chloro-3-
formylchromones (13–16) and 2,7-disubstituted-6-fluo-
Table 2. Median survival time (MST), percent increase in life span (% ILS), percent weight variation, and glutathione level in Ehrlich carcinoma
bearing mice treated with compounds 14, 17, 18, and cisplatin (standard) vis-a-vis blank (untreated)
Sr. No.
Compound
MST (in days)
% ILS
Body weight
% weight variation
GSH level (lg/mg protein)
1
2
3
4
5
Blank (control)
Cisplatin (standard)
9.8 0.17
17.3 0.21
12.0 0.13
11.6 0.15
11.14 0.15
0.5 1.77
75.4 2.21
23.1 1.33
17.9 1.59
16.9 1.59
25.2 0.99
23.0 1.16
19.3 0.77
23.8 1.15
21.7 1.27
10.40
À17.26
À16.81
À9.50
4.17 1.05
9.63 0.09
9.61 0.13
8.17 0.18
5.96 0.04
14
17
18
À15.89

M. P. S. Ishar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1366–1370
1369
17. Ishar, M. P. S.; Kumar, K.; Singh, R. Tetrahedron Lett.
1998, 39, 6547.
References and notes
18. (a) Singh, G.; Singh, R.; Girdhar, N. K.; Ishar, M. P. S.
Tetraherdon 2002, 58, 2471; (b) Singh, G.; Singh, L.; Ishar,
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217; (b) Hsieh, T.-S. In DNA Topology and Its Biolog-
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1990; p 243; (c) Caserta, M.; Amadei, A.; Camilloni, G.;
Di Mauro, E. Biochemistry 1990, 29, 8152; (d) Harrnon,
F. G.; DiGate, R. J.; Kowalczykowski, S. C. Mol. Cell
1999, 3, 611; (e) Nagarajan, M.; Morrell, A.; Fort, B.
C.; Meckley, M. R.; Antony, S.; Kholhagen, G.;
Pommier, Y.; Cushman, M. J. Med. Chem. 2004, 47,
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2. (a) Pommier, Y.; Tanizawa, A. In Cancer Chemotherapy;
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(d) Levine, C.; Hiasa, H.; Marians, K. J. Biochim. Biophys.
Acta 1998, 1400, 29; (e) Potmesil, M., Kohn, K. K (Eds.),
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1989, 41, 223; (g) Spicer, J.; Finlay, G.; Baguley, B.; Velea,
L.; Graves, D.; Denny, W. Anti-Cancer Drug Des. 1999,
14, 37.
19. Spectroscopic and microanalytical data:
6-Chloro-2-pyrrolidin-1-yl-3-formylchromone (13). Pale-
yellow solid, mp 188–189 ꢁC (chloroform–hexane, 1:2);
1
mmax (KBr): 1674, 1638, 1624, 1545, 1440 cmÀ1; H NMR
(300 MHz, CDCl3): d 10.19 (s, 1H, CH@O), 8.18 (br s, 1H,
C5-H), 7.49 (dd, 1H, J = 8.7 and 2.6 Hz, C7-H), 7.19 (d,
1H, J = 8.7 Hz, C8-H), 3.67 (br, 4H, 2· CH2), 2.06 (br,
4H, 2· CH2); 13C NMR (75 MHz, CDCl3): d 187.02
(HC@O), 176.88 (C4), 161.19 (C2), 151.48 (C8a), 133.37
(C7), 129.59 (C6), 125.59 (C5), 120.12 (C4a), 118.04 (C8),
101.5 (C3), 51.27 (N-CH2), 25.16 (CH2); Mass (EI) m/z:
279 (M+ + 2, 12), 278 (M+ + 1, 14), 277 (M+, 21), 249 (65),
241 (41), 221 (100); Anal. Calcd. for C14H12NO3Cl: C,
60.55; H, 4.36; N 5.04. Found: C, 60.39; H, 4.49; N, 4.93.
6-Chloro-2-morpholin-4-yl-3-formylchromone (14). Light-
yellow solid, mp 177–178 ꢁC (chloroform–hexane, 1:2);
1
mmax (KBr): 1672, 1639, 1619, 1542, 1434 cmÀ1; H NMR
(300 MHz, CDCl3): d 10.11 (s, 1H, HC@O), 8.26 (d, 1H,
J = 2.5 Hz, C5-H), 7.55 (dd, 1H, J = 8.8, 2.5 Hz, C7-H),
7.22 (d, 1H, J = 8.8 Hz, C8-H), 3.91 (dist. t, 4H,
J ꢀ 5.1 Hz), 3.69 (dist. t, 4H, J ꢀ 5.1 Hz); 13C NMR
(75 MHz, CDCl3): d 186.59 (HC@O), 177.53 (C4), 162.64
(C2), 151.39 (C8a), 133.64 (C7), 131.44 (C6), 124.04 (C5),
120.17 (C4a), 116.16 (C8), 101.69 (C3), 66.6 (CH2), 49.93
(CH2); Mass (EI) m/z: 295 (M+ + 2, 9), 294 (M+ + 1, 5),
293 (M+, 24), 169 (100), 112 (26); Anal. Calcd for
C14H12NO4Cl: C, 57.28; H, 4.12; N, 4.77. Found: C,
57.45; H, 4.21; N, 4.89.
3. Gootz, T. D.; Birghty, K. E. In The Quinolones;
Andriole, V. T., Ed., 2nd ed.; Academic Press: San
Diego, 1998; p 29.
4. Hooper, D. C. Clin. Infect. Dis. 2001, 32, S9.
5. Fan, J.-Y.; Sun, D.; Yu, H.; Kerwin, S. M.; Hurley, L. H.
J. Med. Chem. 1995, 38, 408.
6-Chloro-2-piperidin-1-yl-3-formylchromone (15). Cream-
colored solid, mp 157–158 ꢁC (chloroform–hexane 1:2);
6. Laco, G. S.; Du, W.; Kohlhagen, G.; Sayer, J. M.; Jerina,
D. M.; Burke, T. G.; Curran, D. P.; Pommier, Y. Biorg.
Med. Chem. 2004, 12, 5225.
1
mmax (KBr): 1670, 1620, 1542, 1443, 1416 cmÀ1; H NMR
(300 MHz, CDCl3): d 10.11 (s, 1H, HC@O), 8.13 (d, 1H,
J = 2.4 Hz, C5-H), 7.54 (dd, 1H, J = 8.8, 2.4 Hz, C7-H),
7.22 (d, 1H, J = 8.8 Hz, C8-H), 3.66–3.63 (br m, 4H),
1.84–1.77 (br m, 6H, 3· CH2); 13C NMR (75 MHz,
CDCl3):d 186.28 (CHO), 177.65 (C4), 162.36 (C2), 151.35
(C8a), 133.53 (C7), 130.92 (C6), 126.61 (C5), 125.53 (C4a),
118.15 (C8), 101.49 (C3), 50.86 (CH2), 26.07 (CH2), 23.65
(CH2); Mass (EI) m/z: 293 (M+ + 2, 11) 292 (30), 291
(M+,30), 167 (25), 149 (79), 71 (58), 70 (47), 58 (100); Anal.
Calcd for C15H14NO3Cl: C, 61.76; H, 4.84; N, 4.80.
Found: C, 61.63; H, 4.96; N, 4.71.
7. Cianchetta, G.; Mannhold, R.; Cruciani, G.; Baroni, M.;
Cecchetti, V. J. Med. Chem. 2004, 47, 3193.
8. Hsiang, Y.-H.; Hertzberg, R.; Hecht, S.; Liu, L. F. J. Biol.
Chem. 1985, 260, 14873.
9. (a) Mhaske, S. B.; Argade, N. P. J. Org. Chem. 2004, 69,
4563; (b) Nagarajan, M.; Xiao, X.; Antony, S.; Kohlha-
gen, G.; Pommier, Y.; Cushman, M. J. Med. Chem. 2003,
46, 5712.
10. (a) Wall, M. E. Med. Res. Rev. 1998, 18, 299; (b) Cragg, G.
M.; Newman, D. J. J. Nat. Prod. 2004, 67, 232; (c)
Osheroff, N.; Zechiedrich, E. L.; Gale, K. C. BioEssays
1991, 13, 269; (d) Rahier, N. J.; Eisenhauer, B. M.; Gao,
R.; Jones, S. H.; Shannon, R. G.; Hecht, S. M. Org. Lett.
2004, 6, 321.
6-Chloro-2-(N-methylpiperazin-1-yl)-3-formylchromone
(16). Yellow solid, mp 155–156 ꢁC (chloroform–hex-
ane, 1:2); mmax (KBr): 1673, 1631, 1615, 1544 cmÀ1 1H
;
NMR (300 MHz, CDCl3): d 10.11 (s, 1H, HC@O), 8.10
(d, 1H, J = 2.5 Hz, C5-H), 7.55 (dd, 1H, J = 8.8, 2.5 Hz,
C7-H), 7.25 (d, 1H, J = 8.8 Hz, C8-H), 3.72 (dist. t, 4H,
J ꢀ 4.9 Hz, 2· CH2), 2.63 (dist. t, 4H, J ꢀ 4.9 Hz, 2·
CH2), 2.37 (s, 3H, N-Me); 13C NMR (75 MHz, CDCl3):
d 186.53 (CHO), 177.72 (C4), 162.51 (C2), 151.43 (C8a),
133.79 (C7), 131.33 (C6), 125.81 (C5), 124.07 (C4a),
118.17 (C8), 101.68 (C3), 54.78 (CH2), 49.57 (CH2),
45.85 (NCH3); Mass (EI) m/z: 307(M+, 4), 283 (15), 169
(94), 112 (26), 111 (46), 71 (100); Anal. Calcd for
11. (a) Arimondo, P.; Boukarim, C.; Bailly, C.; Dauzonne, D.;
Monneret, C. Anti-Cancer Drug Des. 2000, 15, 413; (b)
Xiao, Z.; Vance, J. R.; Bastow, K. F.; Brossi, A.; Wang,
H.-K.; Lee, K.-H. Bioorg. Med. Chem. Lett. 2004, 12,
3363.
12. (a) Cassady, J. M.; Baird, W. M.; Chang, C. J. J. Nat.
Prod. 1990, 53, 23; (b) Kupchan, S. M.; Streelman, D. R.;
Sneden, A. T. J. Nat. Prod. 1980, 43, 296.
13. Kim, M. Y.; Na, Y.; Vankayalapati, H.; Gleason-Guz-
man, M. J. Med. Chem. 2003, 46, 2958.
C15H15N2O3Cl: C, 58.73; H, 4.93; N, 9.13. Found: C,
58.82; H, 5.01; N, 9.36.
14. Kwok, Y.; Sun, D.; Clement, J.; Hurley, L. Anti-Cancer
Drug Des. 1999, 14, 443.
6-Fluoro-2,7-di-piperidin-1-yl-3-formylchromone (17).
Yellow solid, mp 175–176 ꢁC (chloroform–hexane 1:2);
mmax (KBr): 1674, 1627, 1558, 1407, 1365, 1131. 1H
NMR (CDCl3, 200 MHz): d 10.05 (s, 1H, CHO), 7.89
(d, 1H, 2JH,F = 8.26 Hz, C5-H), 7.38 (d, 1H,
3JH,F = 5.50 Hz, C8-H), 3.61 (br, 8H, 4· CH2), 1.78
(br, 12H, 6· CH2). 13C NMR (CDCl3, 75 MHz): d
15. (a) Domagala, J. M. J. Antimicrob. Chemother. 1994, 33,
685; (b) Bryskier, A.; Chantot, J.-F. Drugs 1995, 49(Suppl.
2), 16; (c) Gootz, T. D.; Brighty, K. E. Med. Res. Rev.
1996, 16, 433.
16. Xia, Y.; Yang, Z.-Y.; Xia, P.; Hackl, T.; Hamel, E.;
Mauger, A.; Wu, J.-H.; Lee, K.-H. J. Med. Chem. 2001,
44, 3932.

1370
M. P. S. Ishar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1366–1370
186.26 (CHO), 177.29 (C4), 162.34 (C2), 156.99 (C6),
(C2), 155.05 (C6), 148.55 (C8a), 126.98 (C7), 122.78 (C4a),
118.90 (C5), 112.67 (C8), 101.24 (C3), 54.53 (CH2), 52.93
(CH2), 49.43 (CH2), 45.76 (N-CH3), 45.61 (N-CH3), 43.65
(CH2). MS (ESI) m/z: 389 (M+H+); Anal. Calcd for
C20H25N4O3F: C, 61.84; H, 6.49; N, 14.42. Found: C,
61.69; H, 6.38; N, 14.27.
148.61 (C8a), 126.46 (C7), 122.84 (C4a), 118.99 (C5),
112.69 (C8), 101.22 (C3), 51.06 (CH2), 50.94 (CH2),
26.10 (CH2), 25.76 (CH2), 24.46 (CH2), 23.59 (CH2).
MS (ESI) m/z: 359 (M+H+); Anal. Calcd for
C20H23N2O3F: C, 67.02; H, 6.47; N, 7.82. Found: C,
66.89; H, 6.34; N, 7.68.
6-Fluoro-2,7-di-morpholin-4-yl-3-formylchromone (18).
Pale-yellow solid, mp 178–179 ꢁC (chloroform–hexane
1:2); mmax (KBr): 1676, 1639,1616, 1548, 1440, 1407,
1398. 1H NMR (CDCl3, 200 MHz): d 10.09 (s, 1H,
CHO), 7.90 (d, 1H, 2JH,F = 8.20 Hz, C5-H), 7.39 (d, 1H,
3JH,F = 5.50 Hz, C8-H), 3.90 (br, 4· CH2), 3.68 (br, 4·
CH2). 13C NMR (CDCl3, 75 MHz): d 186.44 (CHO),
177.07 (C4), 162.49 (C2), 155.50 (C6), 148.55 (C8a),
127.29 (C7), 122.80 (C4a), 118.93 (C5), 112.60 (C8),
101.28 (C3), 66.50 and 65.89 (OCH2), 51.15 and 49.89
(N-CH2). MS (ESI) m/z : 363 (M+H+): Anal. Calcd for
20. EAC was obtained from Radiobiology Department,
Kasturba Medical College, Manipal, India, and was
propagated by serial transplantation in Swiss Albino mice
in Central Animal Facility at Manipal Academy of Higher
Education, Manipal, India.
21. (a) Gupta, M.; Mazumder, U. K.; Kumar, R. S.; Kumar, T.
S. Acta Pharmacol. Sin. 2004, 25, 1070; (b) Bhattacharyya,
A.; Choudhuri, T.; Pal, S.; Chattopadhyay, S.; Datta, G. K.;
Sa, G.; Das, T. Carcinogensis 2003, 24, 75.
22. (a) Cisplatin was used as standard at 3.5 mg/kg.; (b)
Percent increase in life span (% ILS) is calculated21a as %
ILS = Median Survival Time (MST) Ä MST of Control
group · 100.; (c) Glutathione level has been determined by
literature protocol [(a) Lowry, O. H.; Roesebrough, N. J.;
Farr, A. L.; Randall, R. J. J. Biol. Chem. 1951, 193, 265.
(b) Moron, M. S.; Depierre, J. W.; Mannervik, B.
Biochim. Biophys. Acta 1979, 5820, 62].; (d) One-way
analysis of variance (ANOVA) with DunnetÕs test was
applied to all data.
C18H19N2O5F: C, 59.66; H, 5.29; N, 7.73. Found: C,
59.52; H, 5.32; N, 7.59.
6-Fluoro-2,7-bis-(N-methylpiperazin-1-yl)-3-formylchromone
(19). Yellow solid, mp 196–197 ꢁC (chloroform–hexane
1:2); mmax (KBr): 1668, 1635, 1618, 1434, 1406, 1363, 1315,
1
1290. H NMR (CDCl3, 200 MHz): d 10.09 (s, 1H, CHO),
7.88 (d, 1H, J = 8.30 Hz, C5-H), 7.39 (d, 1H, J = 5.38 Hz,
C8-H), 3.99 (br, 4H), 3.69 (br, 4H), 3.05 (br, 4H), 2.60 (br,
4H), 2.34 and 2.32 (singlets, 6H, 2· CH3), 13C NMR
(CDCl3, 75 MHz): d 186.36 (CHO), 117.12 (C4), 162.36
23. (a) Yagi, K. Chem. Phys. Lipids 1991, 45, 337; (b) Sinclair,
A. J.; Barnett, A. H.; Lunie, J. Br. J. Hosp. Med. 1990,
43, 334.