Synthesis of 1,11-dihydro-2H-[1,3]oxazolo[4′,5′:5,6]indeno[1,2- b]quinolin-2-ones with potential topoisomerase I inhibitory activity

Article abstract of DOI:10.1055/s-0029-1217007

A series of 1,11-dihydro-2,11-[1,3]oxazolo[4′,5′:5,6]indeno[1, 2-b]quinolin-2-ones were prepared by means of Friedlaender condensations. The starting materials for the preparations were commercial substituted-2- aminoacetophenones and various 5,6-dihydro-2H-indeno[5,6-d][l,3]oxazole-2,7(3H)- diones that were synthesized from 2(3H)-benzoxazolones or their N-methyl analogues. Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217007

PAPER
3819
Synthesis of 1,11-Dihydro-2H-[1,3]oxazolo[4¢,5¢:5,6]indeno[1,2-b]quinolin-2-
ones with Potential Topoisomerase I Inhibitory Activity
1
, 11-Dihydro-2
H
-[1,3]
a
oxazolo[4
¢
,
r
5
¢
:5,6]in
c
deno[1,2-
b
]
quino
D
lin-2-ones elot,a Pascal Carato,*a Christophe Furman,*b Amélie Lemoine,b Nicolas Lebegue,a Pascal Berthelot,a
Saïd Yousa
a
Faculté de Pharmacie, Laboratoire de Chimie Thérapeutique (EA 1043), Université Lille Nord de France, 3 rue du Professeur Laguesse,
BP 83, 59006 Lille Cedex, France
Institut de Chimie Pharmaceutique Albert Lespagnol (EA 2692), IFR 114, Université Lille Nord de France, 3 rue du Professeur Laguesse,
b
BP 83, 59006 Lille Cedex, France
Fax +3(33)20964913; E-mail: pascal.carato@univ-lille2.fr
Received 24 June 2009; revised 6 July 2009
groups, and a 5,6-dihydro-3H-indeno[5,6-d]oxazole-2,7-
Abstract: A series of 1,11-dihydro-2H-[1,3]oxazolo[4¢,5¢:5,6]in-
dione substituted with methyl and/or aryl groups (Figure
deno[1,2-b]quinolin-2-ones were prepared by means of Friedländer
1). These intermediates were synthesized from 2(3H)-
benzoxazolone (1) or its N-methyl derivative 2, both of
condensations. The starting materials for the preparations were
commercial substituted-2-aminoacetophenones and various 5,6-di-
hydro-2H-indeno[5,6-d][1,3]oxazole-2,7(3H)-diones that were which are commercially available.
synthesized from 2(3H)-benzoxazolones or their N-methyl ana-
logues.
The final products 18a–h (Figure 1) were synthesized
from the intermediates 5–6, 9, and 15–17 (Scheme 1).
These compounds were synthesized by three routes, start-
ing from 2(3H)-benzoxazolone 1 or its N-methyl deriva-
tive 2 (Scheme 1). Route A, which gave intermediates 5
and 6, involved two steps. The 2(3H)-benzoxazolone 1 or
2 was acylated with 4-chlorobutanoic acid in polyphos-
phoric acid (PPA)9 to give oxo alcohols 3 and 4, which
were then cyclized in a mixture of aluminum trichloride
and N,N-dimethylformamide to give the intermediates 510
and 6.11 In route B, 3-methyl-2(3H)-benzoxazolone (2)
was acylated in a mixture of aluminum trichloride, N,N-
dimethylformamide, and 3-chloropropanoyl chloride to
give chloro ketone 7,12 which was dehydrohalogenated
with potassium acetate in N,N-dimethylformamide to give
the enone 8; cyclization of this compound in sulfuric acid
gave the indenofurandione 9. The final route C gave the
intermediates compounds 15–17. The first step involved
the acylation of 2(3H)-benzoxazolone 1 or 2 by acetic
acid in a mixture of aluminum trichloride and N,N-di-
methylformamide to give products 1013 and 11.14 Crotoni-
zation of 10 and 11 with a suitably substituted
benzaldehyde was achieved by treatment with potassium
hydroxide in ethanol to give the corresponding products
12–14.11,15–16 These adducts were cyclized in polyphos-
phoric acid to give intermediates 15–17.11,15,17
Key words: alkaloids, heterocycles, cyclizations, condensation,
fused-ring systems
The natural pentacyclic alkaloid camptothecin (CPT; Fig-
ure 1),1 first isolated from the Chinese tree Camptotheca
acuminata,2 acts as a selective poison of the nuclear en-
zyme topoisomerase I by forming a ternary complex with
topoisomerase I and DNA.3 Stabilization of this complex
results in breakdown of DNA by preventing DNA re-liga-
tion.4 Therapeutic applications of CPT have been hin-
dered by its poor aqueous solubility, and by the severe and
unpredictable toxicities identified in early clinical studies
performed in the 1970s.5 Since then, academic and indus-
trial research groups have focussed their attention on the
synthesis of the alkaloids of the camptothecin family and
their analogues as promising agents for the treatment of
human cancers.6–8
R2
R3
O
N
R1
R3
N
N
N
O
18a–h
O
O
OH
The Friedländer reaction of one of the intermediates 5–6,
9, and 15–17 with a commercially available aminoace-
tophenone, optionally substituted by methoxy groups,
gave the corresponding 1,11-dihydro-2H-[1,3]oxazo-
lo[4¢,5¢:5,6]indeno[1,2-b]quinolin-2-ones 18a–h. Two
methods were tested: cyclization in acetic acid or cycliza-
tion in butanol containing pyridinium 4-toluenesulfonate
(Scheme 2).18 In acetic acid, compounds 18a and 18e were
obtained in low yields (45 and 55%, respectively), where-
as higher yields of these compounds were obtained in bu-
tanol (70 and 80%, respectively). The reaction in butanol
was therefore used to synthesize the final products 18a–h.
O
R1 = H, Me
camptothecin, CPT
R
2 = H, Me, Ph, 4-ClC6H4
R3 = H, OMe
Figure 1 Structures of camptothecin and its analogues 18a–h
We report the synthesis of a series of new condensed quin-
olines obtained by a Friedländer-type reaction between an
aminoacetophenone, optionally substituted with methoxy
SYNTHESIS 2009, No. 22, pp 3819–3822
Advanced online publication: 23.09.2009
DOI: 10.1055/s-0029-1217007; Art ID: Z13909SS
x
x.
x
x
.
2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

3820
M. Delot et al.
PAPER
R1
N
R1
N
Me
O
AlCl3
DMF
O
O
O
O
OH
5: R1 = H
6: R1 = Me
3: R1 = H
Cl
CO2H
O
4: R1 = Me
PPA
R1
N
Me
N
Me
Cl
N
KOAc
DMF
COCl
O
O
O
AlCl3, DMF
Cl
O
O
O
1: R1 = H
7
8
O
O
2: R1 = Me
H2SO4
AcCl
R1
AlCl3, DMF
Me
N
10: R1 = H
N
O
11: R1 = Me
O
O
O
9
O
R2
O
R2
CHO
KOH, EtOH
R2
R1
N
R1
N
PPA
O
O
O
O
O
O
15: R1 = H R2 = H
16: R1 = H R2 = Cl
17: R1 = Me R2 = H
12: R1 = H R2 = H
13: R1 = H R2 = Cl
14: R1 = Me R2 = H
Scheme 1 Synthesis of intermediates 5–6, 9, and 15–17
O
R3
R1
N
R2
R2
R1
H2N
R3
N
O
O
BuOH
O
O
O
N
R3
R1 = H, Me
R
2 = H, Me, Ph, 4-ClC6H4
18a–h
R3
R3 = H, OMe
Scheme 2 Synthesis of final compounds 1,11-dihydro-2H-[1,3]oxazolo[4¢,5¢:5,6]indeno[1,2-b]quinolin-2-ones 18a–h
bation time of 72 h. Compounds 18a, 18f, and 18d and
showed a weak activity, with an inhibition of proliferation
of 5% at 10 M, whereas compounds 18b, 18c, 18e, 18g,
and 18h showed no activity with these resistant cells at
this concentration. These results could be the result of sev-
eral factors, such as the poor solubility of the compounds
tested and their poor cellular uptake, which is related to
their high values of logP, which were calculated theoreti-
cally to be between 3.7 0.4 and 5.6 0.4.
Table 1 1,11-Dihydro-2H-[1,3]oxazolo[4¢,5¢:5,6]indeno[1,2-
b]quinolin-2-ones 18a–h
18
a
b
c
R1
H
R2
R3
Me
OMe
OMe
OMe
H
Me
Me
H
Me
H
d
e
Ph
In conclusion, we synthesized a series of 1,11-dihydro-
2H-[1,3]oxazolo[4¢,5¢:5,6]indeno[1,2-b]quinolin-2-ones
18a–h by a Friedländer-type reaction. The antiprolifera-
tive activities of these compounds were examined, and
these studies merit further investigation in a solvent other
than dimethyl sulfoxide, for example, N,N-dimethylacet-
amide. Studies to improve the potential cytotoxic activity
of compounds 18a–h are underway. Furthermore, modifi-
cations of the structures of the compounds by adding an
ionizable moiety, such as an alkylamine chain or cy-
cloalkylamine, are in progress.
H
Ph
OMe
H
f
H
4-ClC6H4
4-ClC6H4
Ph
g
h
H
OMe
OMe
Me
The effects of compounds 18a–h on the proliferation of
DU145 human androgen-independent prostate cancer
cells were assayed in triplicate by using a standard incu-
Synthesis 2009, No. 22, 3819–3822 © Thieme Stuttgart · New York

PAPER
1,11-Dihydro-2H-[1,3]oxazolo[4¢,5¢:5,6]indeno[1,2-b]quinolin-2-ones
3821
Compounds were purified on a glass column by using Merck silica
gel 60 (230–400 mesh). Melting points were determined on a Büchi
510 capillary apparatus and are uncorrected. IR spectra were re-
corded in KBr disks over the range 500–4000 cm–1 on a Nicolet
550-FT spectrometer. 1H and 13C NMR proton spectra were record-
ed on a Bruker AVANCE 300 spectrometer, and chemical shifts are
reported in ppm relative to TMS as an internal standard. Mass spec-
tra were recorded on a quadrupolar Finnigan MAT SSQ 710 instru-
ment.
H, CH, J = 6.9 Hz), 7.55 (m, 2 H, HAr), 7.69 (s, 1 H, HAr), 8.23 (s, 1
H, HAr).
13C NMR (300 MHz, TFA-d6): d = 15, 16.7, 27.6, 41.1, 55.6, 56,
99.3, 103.6, 104.4, 105.8, 108.8, 120.1, 123.3, 125.9, 133.7, 136.7,
138.4, 143.2, 150.3, 151.5, 155.4, 157.23.
MS (EI, 70 eV): m/z (%) = 377.2 [M+ + 1].
7,8-Dimethoxy-1,10-dimethyl-1,11-dihydro-2H-[1,3]oxazo-
lo[4¢,5¢:5,6]indeno[1,2-b]quinolin-2-one (18c)
Yellow crystals (MeOH–DMF, 3:1); yield: 60%; mp > 250 °C.
IR (KBr): 1766, 1643 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.47 (s, 3 H, CH3), 3.10 (s, 3
H, CH3), 3.66 (s, 6 H, OCH3), 3.78 (s, 2 H, CH2), 7.02 (s, 1 H, HAr),
7.05 (s, 1 H, HAr), 7.12 (s, 1 H, HAr), 7.68 (s, 1 H, HAr).
13C NMR (300 MHz, TFA-d6): d = 14.9, 27.5, 33.7, 55.6, 56, 99.4,
103.5, 104.5, 106.7, 108.8, 120.1, 122.9, 127.6, 133.9, 136.6, 143.2,
145, 150.7, 151.3, 155.6, 157.2.
6-Acryloyl-3-methyl-2(3H)-benzoxazolone (8)
KOAc (3.9 g, 37.5 mmol) was added to a soln of benzoxazolone 7
(9.0 g, 37.5 mmol) in DMF (150 mL), and the mixture was warmed
to 75–80 °C for 1 h. The mixture was hydrolyzed with cold H2O
(250 mL) and then stirred for 30 min. The precipitate was filtered
off, washed with H2O, and recrystallized (toluene); yield: 64%; mp
148–149 °C
IR (KBr): 1777, 1655 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.48 (s, 3 H, CH3), 5.96 (dd, J =
10.5, 1.8 Hz, 1 H, CH), 6.49 (dd, J = 16.9 Hz, 1.8 Hz, 1 H, CH), 7.08
(d, J = 8.2 Hz, 1 H, H4), 7.19 (dd, J = 16.9, 10.5 Hz, 1 H, CH), 7.85
(d, J = 1.5 Hz, 1 H, H7), 7;87 (d, J = 8.2 Hz, J = 1.5 Hz, 1 H, H5).
MS (EI, 70 eV): m/z (%) = 363.3 [M+ + 1].
1-Methyl-11-phenyl-1,11-dihydro-2H-[1,3]oxazolo[4¢,5¢:5,6]in-
deno[1,2-b]quinolin-2-one (18d)
Yellow crystals (MeOH–DMF, 3:1); yield: 50%; mp > 250 °C.
MS (EI, 70 eV): m/z (%) = 204.4 [M+ + 1].
IR (KBr): 3256, 1778, 1648 cm–1.
3-Methyl-5,6-dihydro-2H-indeno[5,6-d][1,3]oxazole-2,7(3H)-
dione (9)
Benzoxazolone 8 (2.6 g, 13 mmol) was added to a soln of concd
H2SO4 (96%; 50 mL) and the soln was warmed to 60 °C for 3 h. The
mixture was carefully hydrolyzed with cold H2O (100 mL) and
stirred for 1 h. The precipitate was filtered off, washed with H2O,
and recrystallized (toluene); yield: 25%; mp 225–226 °C.
1H NMR (300 MHz, DMSO-d6): d = 3.16 (s, 3 H, CH3), 5.48 (s, 1
H, CH), 6.93 (s, 1 H, HAr), 7.12 (d, J = 6.4 Hz, 2 H, HAr), 7.32 (m,
3 H, HAr), 7.57 (dd, J = 7.0, 1.2 Hz, 1 H, HAr), 7.74 (dd, J = 8.5, 1.2
Hz, 1 H, HAr), 7.92 (s, 1 H, HAr), 8.11 (m, 2 H, HAr), 11.83 (br s, 1
H, NH).
13C NMR (300 MHz, DMSO-d6): d = 14.9, 50.7, 102.8, 106.9,
124.5, 126, 127.4, 127.8, 128.1, 128.7, 129.4, 129.8, 130.5, 133.1,
133.5, 137.1, 137.5, 139.2, 141.4, 143.9, 147, 148.5, 154.8, 160.4.
IR (KBr): 1778, 1696 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.65 (t, J = 5.6 Hz, 2 H, CH2),
3.12 (t, J = 5.6 Hz, 2 H, CH2), 3.34 (s, 3 H, CH3), 7.43 (s, 1 H, HAr),
7.49 (s, 1 H, HAr).
MS (EI, 70 eV): m/z (%) = 365.5 [M+ + 1].
7,8-Dimethoxy-10-methyl-11-phenyl-1,11-dihydro-2H-[1,3]ox-
azolo[4¢,5¢:5,6]indeno[1,2-b]quinolin-2-one (18e)
MS (EI, 70 eV): m/z (%) = 204.1 [M+ + 1].
Yellow crystals (MeOH–DMF, 3:1); yield: 80%; mp > 250 °C.
Compounds 18a–h; General Procedure
IR (KBr): 3300, 1785, 1644 cm–1.
A mixture of the appropriate intermediate (3.8 mmol), a 2-amino-
acetophenone (5.6 mmol), and PPTS (1.42 g, 5.6 mmol) in BuOH
(10 mL) was refluxed in a Dean–Stark apparatus for 4 h and then
cooled to r.t. The precipitate was filtered off, washed with H2O and
Et2O, and recrystallized.
1H NMR (300 MHz, DMSO-d6): d = 2.31 (s, 3 H, CH3), 3.91 (s, 3
H, OCH3), 3.96 (s, 3 H, OCH3), 5.38 (s, 1 H, CH), 6.90 (s, 1 H, HAr),
7.10 (d, J = 7.1 Hz, 2 H, HAr), 7.29 (m, 4 H, HAr), 7.46 (s, 1 H, HAr),
7.80 (s, 1 H, HAr), 11.75 (br s, 1 H, NH).
13C NMR (300 MHz, TFA-d6): d = 15.1, 52.5, 55.7, 56.1, 99.5,
103.6, 104.6, 108.9, 109.3, 120.1, 123.6, 126.1, 127.3, 128.5, 129.7,
134.3, 134.5, 136.1, 137.5, 144.4, 150.1, 150.9, 151.8, 151.9, 155.9,
158.
7,8-Dimethoxy-10,11-dimethyl-1,11-dihydro-2H-[1,3]oxazo-
lo[4¢,5¢:5,6]indeno[1,2-b]quinolin-2-one (18a)
Yellow crystals (MeOH–DMF, 3:1); yield: 70%; mp > 250 °C.
IR (KBr): 3210, 1784, 1641 cm–1.
MS (EI, 70 eV): m/z (%) = 425.6 [M+ + 1].
1H NMR (300 MHz, DMSO-d6): d = 1.79 (d, J = 6.9 Hz, 3 H, CH3),
3.10 (s, 3 H, CH3), 4.24 (s, 6 H, OCH3), 4.54 (d, J = 6.9 Hz, 1 H,
CH), 7.60 (s, 1 H, HAr), 7.69 (s, 1 H, HAr), 7.79 (s, 1 H, HAr), 8.25
(s, 1 H, HAr), 11.60 (s, 1 H, NH).
13C NMR (300 MHz, DMSO-d6): d = 15.1, 19.6, 39.7, 55.5, 56, 102,
103, 106.5, 108.5, 122.2, 132.4, 133.8, 136.5, 137.5, 143.7, 144.6,
147.3, 148.9, 151.7, 155, 157.3.
11-(4-Chlorophenyl)-10-methyl-1,11-dihydro-2H-[1,3]oxazo-
lo[4¢,5¢:5,6]indeno[1,2-b]quinolin-2-one (18f)
Yellow crystals (DMF); yield: 50%; mp > 250 °C.
IR (KBr): 3332, 1748, 1652 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.38 (s, 3 H, CH3), 5.53 (s, 1
H, CH), 6.95 (s, 1 H, HAr), 7.15 (d, J = 8.5 Hz, 2 H, HAr), 7.35 (d,
J = 8.5 Hz, 2 H, HAr), 7.57 (dd, J = 7.0, 1.2 Hz, 1 H, HAr), 7.75 (dd,
J = 8.5, 1.2 Hz, 1 H, HAr), 7.92 (s, 1 H, HAr), 8.05 (m, 2 H, HAr),
11.74 (br s, 1 H, NH).
13C NMR (300 MHz, DMSO-d6): d = 14.9, 49.8, 102.7, 106.8,
124.4, 125.9, 127.3, 129.4, 129.7, 130.1, 130.6, 131.2, 131.9, 133.2,
133.4, 136.7, 136.9, 139.6, 140.5, 143.9, 146.4, 148.2, 154.8, 160.3.
MS (EI, 70 eV): m/z (%) = 363.6 [M+ + 1].
7,8-Dimethoxy-1,10,11-trimethyl-1,11-dihydro-2H-[1,3]oxazo-
lo[4¢,5¢:5,6]indeno[1,2-b]quinolin-2-one (18b)
Yellow crystals (MeOH–DMF, 3:1); yield: 45%; mp > 250 °C.
IR (KBr): 1765, 1646 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.80 (d, J = 6.9 Hz, 3 H, H3),
3.11 (s, 3 H, CH3), 3.68 (s, 3 H, CH3), 4.24 (s, 6 H, CH3), 4.56 (d, 1
MS (EI, 70 eV): m/z (%) = 399.7 [M+ + 1].
Synthesis 2009, No. 22, 3819–3822 © Thieme Stuttgart · New York

3822
M. Delot et al.
PAPER
11-(4-Chlorophenyl)-7,8-dimethoxy-10-methyl-1,11-dihydro-
2H-[1,3]oxazolo[4¢,5¢:5,6]indeno[1,2-b]quinolin-2-one (18g)
Yellow crystals (DMF); yield: 70%; mp > 250 °C.
IR (KBr): 3095, 1763, 1647 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.53 (s, 3 H, CH3), 4.43 (s, 3
H, OCH3), 4.52 (s, 3 H, OCH3), 5.32 (s, 1 H, CH), 6.91 (d, 2 H, HAr,
J = 8.4 Hz), 7.20 (d, 2 H, HAr, J = 8.4 Hz), 7.31 (s, 1 H, HAr), 7.42
(s, 1 H, HAr), 7.45 (s, 1 H, HAr), 8.11 (s, 1 H, HAr), 11.53 (br s, 1 H,
NH).
13C NMR (300 MHz, TFA-d6): d = 15.1, 51.6, 55.7, 56.1, 99.5,
103.6, 104.7, 108.8, 109.1, 120.1, 123.6, 126.1, 128.6, 129.8, 134.3,
134.6, 134.8, 134.9, 136.8, 144.4, 150.1, 150.9, 151.6, 151.7, 155.9,
157.8.
Acknowledgment
The 300-MHz NMR facilities were funded by the Région Nord-
Pas de Calais (France), the Ministère de la Jeunesse, de l’Education
Nationale et de la Recherche (MJENR), and the Fonds Européens
de Développement Régional (FEDER).
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MS (EI, 70 eV): m/z (%) = 459.8 [M+ + 1].
7,8-Dimethoxy-1,10-dimethyl-11-phenyl-1,11-dihydro-2H-
[1,3]oxazolo[4¢,5¢:5,6]indeno[1,2-b]quinolin-2-one (18h)
Yellow crystals (MeOH–DMF, 3:1); yield 40%; mp > 250 °C.
IR (KBr): 1782, 1645 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.71 (s, 3 H, CH3), 3.55 (s, 3
H, CH3), 4.19 (s, 3 H, OCH3), 4.24 (s, 3 H, OCH3), 5.54 (s, 1 H,
CH), 7.15 (m, 2 H, HAr), 7.28 (s, 1 H, HAr), 7.38 (m, 3 H, HAr), 7.62
(d, J = 7.1 Hz, 2 H, HAr), 8.27 (s, 1 H, HAr).
13C NMR (300 MHz, DMSO-d6): d = 14.9, 27.5, 52.5, 55.6, 56,
99.4, 103.6, 104.3, 106.9, 108.8, 112.6, 116.3, 120, 123.5, 126,
127.4, 128.5, 129.6, 134.1, 136.2, 136.9, 137.5, 143.4, 150.8, 151.8,
155.8, 157.2.
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MS (EI, 70 eV): m/z (%) = 438.3 [M+ + 1].
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Cell Culture and Cell Proliferation Assay
Human prostate DU145 cancer cells were grown at 37 °C in RPMI
1640 medium supplemented with 10% fetal calf serum, in a humid-
ified incubator under 5% CO2. In the cell-proliferation assay, cells
were plated (3200 cells/well) on 96-well plates. After 3 days, the
cell medium was changed to serum-free medium, and the cells were
starved for 24 h for culture synchronization. Cells were then incu-
bated in a culture medium that contained 10 M of the test compound
dissolved in less than 0.1% DMSO. After incubation for 72 h, cell
growth was estimated by means of the colorimetric MTT [3-(4,5-
Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] test.
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