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Abstract: Synthesis of C-8 fluoroaryl substituted pyrimidine linked-PBD conjugates are described. The
compounds are prepared with varying degrees of linker length in order to probe the structural requirements for
optimal in vitro antitumour activity. These compounds have been tested against a panel of 60 human cancer cell
lines, and it is demonstrated that compound 5b with four carbon spacer exhibited promising in vitro anticancer
activity in comparison to the other analogues (5a and 5c).
Keywords: Pyrrolobenzodiazepines, pyrimidines, cytotoxicity, antitumour activity.
10
9 N 11
HO
H1
8 11a
H3CO 7 N 2
6 5 4
O 3
DC-81
O H
N O (CH2) n O N
H H
N OCH3 H3CO N
O O
n = 3-5, 8
Imine-aimde dimers (2)
NH2
N
R1 N N
HN N NH
NH
X
OH R3
R2
Me 2N O
3 X= H, F, Cl, CF 3 4
CH3
N N
O (CH2) n O N
H
F
H3CO N
n = 3-5 O
5a-c
compared with the control was calculated. The GI50 values CEM and MOLT-4 are 0.01, 0.08 and 0.08 µM
concentration for killing 50% of the cells) for compounds 5a- respectively. In repeated testing of compound 5b (Fig. 2) the
c against the 60 different cell lines are given in Table 1. cytotoxic activity is further confirmed in most of the cell
lines particularly GI50 value is 0.002 µM in case of colon
Compounds 5a-c possess cytotoxic potency against
cancer HCC-2998. Compounds 5a and 5c exhibit cytotoxic
many cell lines. Compound 5b exhibits a wide spectrum of
potency against number of cell lines in the nine panels, with
activity against 60 human cancer cell lines in nine cell line
the GI50 value range of <20 µM. Compound 5c exhibits
panel with GI50 value of <1 µM. The average GI50 value of
cytotoxic potency in the leukemia which CCRF-CEM,
compound 5b against leukemia cancer RFMI-8226, CCRF-
CH3 CH3
N N N N
i
OH O (CH2) n Br
F 6 F 7a-c n = 3-5
Scheme 1. Teagents and conditions: (i) dibromoalkanes, K2 CO 3 , acetone, 48h, reflux, 92-95%.
Synthesis and Biological Activity of C-8 Fluoroaryl Substituted Pyrimidine Letters in Drug Design & Discovery, 2005, Vol. 2, No. 1 57
N
H3 CO N
H3 CO
O O
8 9
CH3 ii
N N
F N
H3CO
10a-c n = 3-5
O
CH3 iii
N N
F N
H3CO
11a-c n = 3-5
O
iv
5a-c
Scheme 2. Reagents and condition: (i) EtSH-BF3 OEt 2 , CH 2 Cl 2 , 12 h , rt, 75%; (ii) 7a-c, K2 CO 3 , acetone 48 h, reflux, 93-95%; (iii)
SnCl 2 . 2H 2 O, MeOH, reflux, 4 h 80-85%; (iv) HgCl2 -CaCO 3 , CH3 CN-H2 O, 12 h, rt, 68-70%.
EPMI-8226 and SR cell lines are 2.86, 2.21 and 2.98 µM binding has the potential to inhibit the BamH1 cleavage
respectively. In the non-small cell lung cancer, the growth of activity. The study has been carried out to determine the
HOP-92 cell line is affected by compound 5c with GI 50 value ability of 5a-c, which inhibits the DNA linearization by
0.37 µM. The in vitro cytotoxicity (IC50) for the naturally BamH1. It is observed that for the compound 5b the
occurring DC-81 [18] is 0.38, 0.33 and 0.1 µM in L1210, inhibition of BamH1 cleavage is in agreement with the DNA
PC6 and CH1 cell lines respectively. binding affinity as determined by thermal denaturation.
Table 1. In Vitro Anticancer Activity of Compound 5a-c in Selected Cancer Cell Lines
5a 5b 5b (repeated) 5c
Leukemia
CCRF-CEM 15.8 0.08 0.20 2.8
HL-60 (TB) 24.9 0.32 0.24 -
K-562 - 0.24 0.29 4.67
MOLT-4 14.3 0.08 0.13 3.23
RPMI-8226 26.0 0.01 0.19 2.21
SR 10.3 0.16 - 2.98
Colon
COLO 205 29.1 0.53 0.22 18.6
HCT-116 16.9 0.64 - 28.0
HCT-15 12.6 0.55 0.89 17.6
HT29 23.1 0.38 0.51 20.4
KM12 19.3 0.66 0.79 23.3
SW-620 22.8 0.85 0.85 10.3
HCC-2998 - - 0.002 -
CNS
SF-268 17.2 0.56 - 10.5
SF-295 16.4 037 0.24 25.9
SF-539 16.6 0.94 0.91 -
SNB-19 20.1 0.86 0.55 21.4
SNB-75 19.1 0.45 - -
U251 14.8 0.19 0.20 12.1
Melanoma
LOX EMVI 13.6 0.09 0.27 11.1
MALME-3M 12.8 0.67 1.00 23.3
M14 15.5 0.74 0.61 20.7
SK-MEL-2 17.2 0.76 0.94 23.4
SK-MEL-5 15.9 0.62 0.56 1.24
UACC-257 17.2 0.68 0.69 -
UACC-62 14.5 0.21 0.67 14.5
Ovarian
IGROVI 19.2 0.29 - 7.74
OVCAR-3 15.2 0.43 0.26 14.6
OVCAR-4 33.5 0.59 0.11 16.5
OVCAR-5 24.5 0.17 0.42 -
OVCAR-8 24.6 0.86 0.11 13.9
Renal
786-0 16.8 0.27 0.86 20.1
ACHN 16.1 0.17 0.21 14.2
CAKI-1 17.5 0.25 0.38 17.4
RXF393 20.2 0.36 0.50 10.8
SN12C 16.5 0.37 - 19.6
TK-10 18.1 0.14 0.34 24.9
UO-31 17.7 0.26 0.94 8.0
Prostate
PC-3 - 0.62 0.91 11.1
DU-145 9.0 0.20 0.25 15.9
Breast
MCF7 29.4 0.33 0.75 5.58
MDA-MB-231/ATCC 13.8 0.66 - 15.6
HS 57BT
MDA-MB-435 24.7 0.84 0.67 22.6
BT-549 15.2 0.63 0.54 20.5
T-47D - 0.61 0.28 10.8
25.8 0.30 - 6.27
Synthesis and Biological Activity of C-8 Fluoroaryl Substituted Pyrimidine Letters in Drug Design & Discovery, 2005, Vol. 2, No. 1 59
Fig. (2). Log 10 GI50 data from the NCI 60 cell line screen for compound 5b and its repeat testing data.
1H NMR spectra were recorded on Varian Gemini 200 mL) was refluxed for 48 h. After the completion of reaction
MHz spectrometer using tetramethyl silane (TMS) as an as indicated by TLC, ethyl acetate-hexane (2:8), the reaction
internal standard. Chemical shifts are reported in parts per mixture was poured on to the water and then extracted with
million (ppm) down field from tetramethyl silane. Spin ethyl acetate. Evaporation of the organic layer gave the crude
multiplicities are described as s (singlet), d (doublet), t product, which was further purified by column
(triplet), q (quartet), m (multiplet). Coupling constants are chromatography on silica gel eluting with ethyl acetate-
reported in Hertz (Hz). Low resolution mass spectra were hexane (5:95) gave the pure 7a (1.465g, 92%): 1H NMR
recorded on VG-7070H Micromass mass spectrometer at 200 (CDCl 3) δ 2.20-2.35 (m, 2H), 2.65 (s, 3H), 4.25 (t, 2H, J =
oC, 70 eV with trap current of 200 A and 4 KV 4.8 Hz), 4.50 (t, 2H, J = 4.5 Hz), 6.70 (s, 1H), 7.08-7.16
acceleration voltage. Optical rotations are measured on (m, 2H), 7.90-8.05 (m, 2H); MS (EI) m/z 325. Anal. calcd
Horiba, High Sensitive Polarimeter, SEPA-300. for C14H14BrFN2O: C, 51.71; H, 4.33; N, 8.61. Found: C,
51.67; H, 4.23; N, 8.49.
3-Bromopropyl-6-(4-fluorophenyl)-2-methyl-4-pyrimidyl
ether (7a) 4-Bromobutyl-6-(4-fluorophenyl)-2-methyl-4-pyrimidyl
ether (7b)
A solution of 6-(4-fluorophenyl)-2-methyl-4-pyridinol (6)
(1.0 g, 4.90 mmol), 1,3-dibromopropane (2.475 g, 12.25 The compound 7b was prepared according to the method
mmol) and K2CO3 (2.03 g, 14.7 mmol) in dry acetone (40 described for the compound 7a employing compound 6 (1.0
60 Letters in Drug Design & Discovery, 2005, Vol. 2, No. 1 Kamal et al.
g, 4.90 mmol), 1,4-dibromobutane (2.65 g, 12.25 mmol) 6.78 (s, 1H), 6.82 (s, 1H), 7.10-7.20 (m, 2H), 7.65 (s, 1H),
and K2CO3 (2.03 g, 14.70 mmol) to afford the crude 7.95-8.10 ( m, 2H); FABMS 659 (M+H)+. . Anal. calcd for
product, which was purified by column chromatography (4% C 32H39FN4O6S 2: C, 58.34; H, 5.97; N, 8.50. Found: C,
ethyl acetate-hexane) to afford the compound 7b (1.578g, 58.23; H, 5.69; N, 8.49.
95%): 1H NMR (CDCl 3) δ 1.90-2.15 (m, 4H), 2.65 (s, 3H),
3.50 (t, 2H, J = 4.7 Hz), 4.5 (t, 2H, J = 4.9 Hz), 6.85 (s,
(2S)-N-[{4[6'-(4" -Fluorophenyl)-2'-methylpyrimidine-4'-
1H), 7.1-7.2 (m, 2H), 8.0-8.1 (m, 2H); MS (EI) m/z 339.
yloxy]pentoxy}-5-methoxy-2'-nitrobenzoyl]pyrrolidine-2-
Anal. calcd for C15H16BrFN2O: C, 53.11; H, 4.75; N, 8.26.
carboxaldehydediethylthioacetal (10c)
Found: C, 53.02; H, 4.65; N, 8.07.
The compound 10c was prepared according to the
method described for the compound 10a employing
5-Bromopentyl-6-(4-fluorophenyl)-2-methyl-4-pyrimidyl compound 9 (1.59 g, 3. 97 mmol), 7c (1.4 g, 3.97 mmol)
ether (7c) and K2CO3 (1.64 g, 11.898 mmol) to afford the crude
The compound 7c was prepared according to the method product, which was purified by column chromatography
described for the compound 7a employing compound 6 (1.0 (27% ethyl acetate-hexane) to afford the compound 10c
g, 4.90 mmol), 1,5-dibromopentane (2.82 g, 12.25 mmol) (2.507g, 94%): 1H NMR (CDCl3) δ 1.20-1.50 (m, 6H),
and K2CO3 (2.03 g, 14.70 mmol) to afford the crude 1.60-2.40 (m, 10H), 2.64 (s, 3H), 2.70-2.90 (m, 4H), 3.20-
product, which was purified by column chromatography (3% 3.30 (m, 2H), 3.95 (s, 3H), 4.50 (t, 2H, J = 6.25 Hz), 4.45
ethyl acetate-hexane) to afford the compound 7c (1.608 g, (t, 2H, J = 6.5 Hz), 4.62-4.75 (m, H), 4.85 (d, 1H, J = 4.2
93%): 1H NMR (CDCl3) δ 1.50-1.60 (m, 2H), 1.70-1.80 Hz), 6.78 (s, 1H), 6.82 (s, 1H), 7.05-7.20 (m, 2H), 7.65 (s,
(m, 2H), 1.90-2.00 (m, 2H), 2.60 (s, 3H), 3.40 (t, 2H, J = 1H), 7.95-8.1 (m, 2H); FABMS 939 (M+H)+. . Anal. calcd
5.1 Hz), 4.40 (t, 3H, J = 5.5 Hz), 6.7 (s, 1H), 7.10-7.12 (m, for C33H41FN4O6S 2: C, 58.91; H, 6.14; N, 8.32. Found: C,
2H), 7.95-8.05 (m, 2H); MS (EI) m/z 353. Anal. calcd for 58.83; H, 5.98; N, 8.22.
C 16H18BrFN2O: C, 54.40; H, 5.14; N, 7.93. Found: C,
54.22; H, 5.05; N, 7.67.
(2S)-N-[{4-[6'-(4" -Fluorophenyl)-2'-methylpyrimidine-4'-
yloxy]propoxy}-5-methoxy-2-aminobenzoyl]pyrrolidine
(2S)-N-[{4-[6'-(4" -Fluorophenyl)-2'-methylpyrimidine-4'- -2-carboxaldehyde diethyl thioacetal (11a)
yloxy]-propoxy}-5-methoxy-2-nitrobenzoyl]pyrrolidine- The 10a (0.5 g, 0.78 mmol) was dissolved in methanol
2-carboxaldehyde diethyl thioacetal (10a) (10 mL) and added SnCl2.2H2O (0.873 g, 3.88 mmol) was
A solution of 7a (1.2 g, 3.69 mmol), A solution of (2S)- refluxed for 1.5 h. The reaction mixture was then carefully
N-(4-hydroxy-5-methoxy-2-nitrobenzoyl)pyrrolidine-2- adjusted to pH 8 with saturated NaHCO3 solution and then
carboxaldehydediethylthioacetal (9) (1.472 g, 3.69 mmol) extracted with ethyl acetate (3x30 mL). The combined
and K 2CO3 (1.53 g, 11.07 mmol) in dry acetone (20 mL) organic phase was dried over Na2SO4 and evaporated under
was refluxed for 48 h. After the completion of reaction as vacuum to afford the crude 11a
indicated by TLC, ethyl acetate, the reaction mixture was
poured on to the water and then extracted with ethyl acetate.
(2S)-N-[{4-[6'-(4" -Fluorophenyl)-2'-methylpyrimidine-4'-
Evaporation of the organic layer gave the crude product,
yloxy]butoxy}-5-methoxy-2-aminobenzoyl]pyrrolidine-2-
which was further purified by column chromatography on
carboxaldehyde diethyl thioacetal (11b)
silica gel eluting with ethyl acetate-hexane (1:3) gave the
pure 10a (2.186g, 92%): 1H NMR (CDCl3) δ 1.20-1.40 (m, The compound 11b was prepared according to the
6H), 1.70-2.42 (m, 6H), 2.65 (s, 3H), 2.68-2.90 (m, 4H), method described for the compound 11a employing the
3.15- 3.30 (m, 2H), 3.95 (s, 3H), 4.25-4.35 (m, 2H), 4.58- compound 10b (0.5 g, 0.76 mmol) and SnCl2.2H2O (0.855
4.78 (m, 2H), 4.65-4.80 (m, 1H), 4.85 (d, 1H, J = 4.2 Hz), g, 3.80 mmol) to afford the amino diethyl thioacetal 11b.
6.78 (s, 1H), 6.90 (s, 1H), 7.10-7.20 (m, 2H), 7.70 (s, 1H),
8.00-8.10 (m, 2H); FABMS 645 (M+H)+. . Anal. calcd for
(2S)-N-[{4-[6'-(4" -Fluorophenyl)-2'-methylpyrimidine-4'-
C 31H37FN4O6S 2: C, 57.75; H, 5.78; N, 8.69. Found: C,
yloxy]pentoxy}-5-methoxy-2-aminobenzoyl]pyrrolidine-
57.63; H, 5.65; N, 8.48.
2-carboxaldehyde diethyl thioacetal (11c)
The compound 11c was prepared according to the
(2S)-N-[{4-[6'-(4" -Fluorophenyl)-2'-methylpyrimidine-4'- method described for the compound 11a employing the
yloxy]butoxy}-5-methoxy-2-nitrobenzoyl]pyrrolidine-2- compound 10c (0.5 g, 0.74 mmol) and SnCl2.2H2O (0.84
carboxaldehyde diethyl thioacetal (10b) g, 3.72 mmol) to afford the amino diethyl thioacetal 11c.
The compound 10b was prepared according to the
method described for the compound 10a employing
7-Methoxy-8-[6'-(4" -fluorophenyl)-2 '-methylpyrimidine-
compound 9 (1.532 g, 3.83 mmol), 7b (1.3 g, 3.83 mmol)
4'-yloxy]propoxy-(11aS)-1,2,3,11a-tetrahydro-5H-
and K2CO3 (1.585 g, 11.47 mmol) to afford the crude
pyrrolo[2,1-c][1,4]benzodiazepin-5-one (5a)
product, which was purified by column chromatography
(30% ethyl acetate-hexane) to afford the compound 10b A solution of 11a (0.3 g, 0.50 mmol), HgCl2 (0.3 g,
(2.394g, 95%): 1H NMR (CDCl3) δ 1.20-1.50 (m, 8H), 1.10 mmol) and CaCO3 (0.12 g, 1.20 mmol) in
1.90-2.30 (m, 8H), 2.65 (s, 3H), 2.70-2.90(m, 4H), 3.20- CH3CN/H2O (3:1, 15 mL) was stirred at room temperature
3.35 (m, 2H). 3.92 (s, 3H), 4.05-4.25 (m, 4H), 4.45-4.55 for 12 h until TLC (ethyl acetate), indicates complete loss of
(m, 2H), 4.65-4.75 (m, 1H), 4.85 (d, 1H. J = 4.85 Hz), starting material. Then organic layer is evaporated in
Synthesis and Biological Activity of C-8 Fluoroaryl Substituted Pyrimidine Letters in Drug Design & Discovery, 2005, Vol. 2, No. 1 61
vacuum and the residue is diluted with ethyl acetate. To this [5] Kopka, M.L.; Goodsell, D.S.; Baikalov, I.; Grzeskowiak, K.;
Cascio, D.; Dickerson, R.E. Biochemistry 1994, 33, 13593.
saturated NaHCO 3 was added slowly at room temperature [6] (a) Thurston, D.E.; Morris, S.J.; Hartley, J.A. Chem. Commun.
and the mixture is filtered through celite and washed with 1996, 563. (b) Wilson, S.C.; Howard, P.W.; Forrow, S.M.; Hartley,
ethyl acetate. The filterate is evaporated in vacuum to get J.A.; Adams, L.J.; Jenkins, T.C.; Kelland, L.R.; Thurston, D.E. J.
crude 5a, which was further purified by column Med. Chem. 1999, 42, 4028. (c) Reddy, B.S.P.; Damayanthi, Y.;
chromatography on silica gel eluting first with ethyl acetate Reddy, B.S.N.; Lown, W.J. Anti-Cancer Drug Design 2000, 15,
225. (d) Baraldi, P.G.; Balboni, G.; Cacciari, B.; Guiotto, A.;
to remove traces of mercuric salts and further eluted with Manfredini, S.; Romagnoli, R.; Spalluto, G.; Thurston, D.E.;
ethyl acetate-methanol (9:1) (0.166g, 68%):1H NMR Howard, P.W.; Bianchi, N.; Rutigiiano, C.; Mischiati, C.; Gambari,
(CDCl 3) δ 1.90-2.15 (m, 4H), 2.25-2.4 (m, 2H), 2.65 (s, R. J. Med. Chem. 1999, 42, 5131.
3H), 3.5-3.8 (m, 3H), 3.95 (s, 3H), 4.00-4.20 (m, 2H), [7] (a) Thurston, D.E.; Bose, D.S.; Thompson, A.S.; Howard, P.W.;
Leoni, A.; Crocker, S.J.; Jenkins, T.C.; Neidle, S.; Hartley, J.A.;
4.45-4.55 (m, 2H), 6.78 (s, 1H), 6.8 (s, 1H), 7.10-7.20 (m, Hurley, L.H. J. Org. Chem. 1996, 61, 8141. (b) Gregson, S.J.;
2H), 7.50 (s, 1H), 7.50 (d, 1H, J = 4.3 Hz), 7.95-8.20 (m, Howard, P.W.; Hartley, J.A.; Brooks, N.A.; Adams, L.J.; Jenkins,
2H); FABMS: 491 (M+H)+. . Anal. calcd for C 27H27FN4O4: T.C.; Kelland, L.R.; Thurston, D.E. J. Med. Chem. 2001, 44, 737.
C, 66.11; H, 5.55; N, 11.42. Found: C, 65.94; H, 5.38; N, (b) Gregson, S.J.; Howard, P.W.; Corcoran, K.E.; Jenkins, T.C.;
11.34.; [α]26D +213 (c 0.0075, MeOH) Kelland, L.R.; Thurston, D.E. Bioorg. Med. Chem. Lett. 2001, 11,
2859.
[8] Kamal, A.; Ramesh, G.; Laxman, N.; Ramulu, P.; Srinivas, O.;
7-Methoxy-8-[6'-(4" -fluorophenyl)-2 '-methylpyrimidine- Neelima, K.; Kondapi, A.K.; Srinu, V.B.; Nagarajaram, H.M. J.
Med. Chem. 2002, 45, 4679.
4'-yloxy]butoxy-(11aS)-1,2,3,11a-tetrahydro-5H- [9] (a)Wright, G.E.; Gombino, J.J. J. Med. Chem. 1984, 27, 181. (b)
pyrrolo[2,1-c][1,4]benzodiazepin-5-one (5b) Ban, M.; Taquchi, H.; Katsushima, T.; Akoki, S.; Wantanabe, A.
Bioorg. Med. Chem. 1998, 6, 1057. (c) Jalander, L.F.; Longquist,
The compound 5b was prepared according to the method J.E. Heterocycles 1998, 48, 343. (d) Shivastava, S.K.; Agarwal,
described for the compound 5a employing 11b (0.3 g, 0.50 A.; Chauhan, P.M.S.; Agarwal, S.K.; Bhaduri, A.P.; Singh, S.N.;
mmol), HgCl2 (0.3 g, 1.10 mmol) and CaCO3 (0.12 g, 1.20 Fatima, N.; Chatterjee, R.K. J. Med. Chem. 1999, 42, 1667. (e)
mmol) to afford 5b (0.176g, 70%): 1HNMR (CDCl3) δ Kadu, V.B.; Doshi, A.G. Res. J. Chem. Env. 1998, 2, 207.
[10] (a) John, F.B.; Gloria, A.B.; Rebecca, P.A.E.; Stephen, G.; Philip,
1.92-2.42 (m, 8H), 2.63 (s, 3H), 3.502-3.80 (m, 2H), 3.92 J.J.; Catherine, J.M.; Russell, T.N.; Claire, A.M.; Richard, A.P.;
(s, 3H), 4.14-4.28 (m, 3H), 4.45-4.55 (m, 2H), 6.76 (s, Julie, A.T.; Pease, J.E. Bioorg. Med. Chem. Lett. 2003, 13, 2955.
1H), 6.80 (s, 1H) 7.10-7.30 (m, 2H), 7.58 (s, 1H), 7.65 (d, (b) Gloria, A.B.; Rebecca, P.A.E.; Stephen, G.; James, A.R.;
1H), 7.95-8.10 (m, 2H); FABMS: 505 (M+H)+. . Anal. Philip, J.J.; Catherine, J.M.; Richard, A.P.; Claire, A.M.; Julie,
A.T.; Pease, J.E. Bioorg. Med. Chem. Lett. 2003, 13, 2961.
calcd for C28H29FN4O4: C, 66.65; H, 5.79; N, 11.10. [11] Gong, B.; Hong, F.; Kohm, C.; Jenkins, S.; Tulinsky, J.; Bhatt, R.;
Found: C, 66.54; H, 5.67; N, 11.08.; [α]26D +86 (c 0.001, Vries, P.D.; Singer, J.W.; Klein, P. Bioorg. Med. Chem. Lett. 2004,
MeOH) 14, 2303.
[12] (a) Lim, M.H.; Kim, H.O.; Moon, H.R.; Chun, M.H.; Jeong, L.S.
Org. Lett. 2002, 4, 529. (b) Ming Pu, Y.; Torok, D.S.; Ziffer, H. J.
7-Methoxy-8-[6'-(4" -fluorophenyl)-2 '-methylpyrimidine- Med. Chem. 1995, 38, 4120. (c) Mayers A.G.; Barbay, J.K.;
4'-yloxy]pentoxy-(11aS)-1,2,3,11a-tetrahydro-5H- Zhong, B. J. Am. Chem. Soc. 2001, 123, 7207.
[13] (a) Kamal, A.; Laxman, N.; Ramesh, G.; Srinivas, O.; Ramulu, P.
pyrrolo[2,1-c][1,4]benzodiazepin-5-one (5c) Bioorg. Med. Chem. Lett. 2002, 12, 1917. (b) Kamal, A.; Reddy,
The compound 5c was prepared according to the method B.S.N.; Reddy, G.S.K.; Ramesh, G. Bioorg. Med. Chem. Lett.
2002, 12, 1933. (c) Kamal, A.; Ramesh, G.; Ramulu, P.; Srinivas,
described for the compound 5a employing 11b (0.3 g, 0.47 O.; Rehana, T.; Sheelu, G. Bioorg. Med. Chem. Lett. 2003, 13,
mmol), HgCl2 (0.280 g, 1.03 mmol) and CaCO3 (0.11 g, 3451. (d) Kamal, A.; Ramulu, P.; Srinivas, O.; Ramesh, G. Bioorg.
1.10 mmol) to afford 5c (0.170g, 70%): 1HNMR (CDCl3) δ Med. Chem. Lett. 2003, 13, 3517. (e) Kamal, A.; Srinivas, O.;
1.6-1.76 (m, 3H), 1.82.2.20 (m, 5H), 2.30-2.40 (m, 2H), Ramulu, P.; Ramesh, G.; Kumar, P.P. Bioorg. Med. Chem. Lett.
2.65 (s, 3H), 3.60-3.80 (m, 3H), 3.97 (s, 3H), 4.10-4.20 2003, 13, 3577.
[14] (a) Kamal, A.; Rao, M.V.; Laxman, N.; Ramesh, G.; Reddy,
(m, 3H) 4.40-4.50 (m, 2H), 6.84 (s, 1H), 6.86 (s, H), 7.10- G.S.K. Current Medicinal Chemistry – Anti-Cancer Agents 2002,
7.25 (m, 2H), 7.55 (s, 1H), 7.70 (d, 1H, J = 4.4 Hz), 8.0- 2, 215. (b) Kamal, A.; Reddy, G.S.K.; Reddy, K.L.; Raghavan, S.
8.1 (m, 2H); FABMS: 519 (M+H)+. .; Anal. calcd for Tetrahedron Lett. 2002, 43, 2103. (c) Kamal, A.; Reddy, P.S.M.M.;
C 29H31FN4O4: C, 67.17; H, 6.03; N, 9.26. Found: C, Reddy, D.R. Tetrahedron Lett. 2002, 43, 6629. (d) Kamal, A.;
Reddy, K. L.; Devaiah, V; Reddy, G.S.K. Tetrahedron Lett. 2003,
67.05; H, 5.59; N, 9.09.; [α]26D +259 (c 0.07, MeOH). 44, 4741.
[15] Kamal, A.; Reddy, K. L. US Patent, 6, 683, 073, 2004.
ACKNOWLEDGEMENTS [16] Thurston, D.E.; Murty, V.S.; Langley, D.R.; Jones, G.B. Synthesis
1990, 81.
We thank the National Cancer Institute, Maryland for the [17] Aoki, T.; Ukai, Y.; Chokai, S.; Ideguchi, K. WO Pat,
in vitro anticancer assay in human cancer cell lines. We are 9607641.Supplementary Material
[18] Bose, D.S.; Thompson, A.S.; Ching, J.; Hartley, J.A.; Berardini,
also grateful to CSIR, New Delhi for the award of research M.D.; Jenkins, T.C.; Neidle, S.; Hurley, L.H.; Thruston, D.E. J.
fellowships to K. L. R., V. D., N. S. and G. S. K. R. Am. Chem. Soc. 1992, 114, 4939.
[19] (a) Balcarova, Z.; Mrazek, J.; Kleinwachter, V.; Brabec, V. Gen.
physiol. Biophys. 1992, 11, 579. (b) Brabec, V.; Balcarova, Z.
REFERENCES Eur. J. Biochem. 1993, 216, 183. (c) Collier, D.A.; Thuong, N.T.;
[1] Hurley, L.H. J. Med. Chem. 1989, 32, 2027. Helene, C. J. Amer. Chem. Soc. 1991, 113, 1457. (d) Sumner, W.;
[2] Dervan, P.B. Science 1989, 232, 464. Bennett, G.N. Nucleic Acids Res. 1981, 9, 2105.
[3] Thurston, D.E.; Thompson, A.S. Chem. Br. 1990, 26, 767. [20] Puvvada. M.S.; Hartley, J.A.; Jenkins. T.C.; Thurston D.E. Nucleic
[4] Thurston, D.E. In Molecular Aspects of Anticancer Drug-DNA Acids Res. 1993, 21, 3671.
Interactions; The Macmillan Press Ltd.; London, U.K., 1993; Vol.
1, p 54.