1-Oxo-2-hydroxy-1,2-dihydroacronycine: A useful synthon in the acronycine series for the introduction of amino substituents at 6-position and for the conversion into isopropylfuroacridones

Article abstract of DOI:10.1248/cpb.49.1304

Thermic aromatic nucleophilic displacement of the methoxy group at C-6 of (±)-1-oxo-2-hydroxy-1,2-dihydroacronycine (2) by an amine is a reaction that gives a facile entry to acronycine derivatives bearing an amino substituent at this position. The introduction of the amino substituents was confirmed with a long-range ¹H-¹⁵N correlation NMR spectrum at natural abundance. Under basic conditions, compound 2 can also be rearranged to the corresponding isopropylfuroacridone 12, in 80% yield.

Full text of DOI:10.1248/cpb.49.1304

1304
Chem. Pharm. Bull. 49(10) 1304—1307 (2001)
Vol. 49, No. 10
1-Oxo-2-hydroxy-1,2-dihydroacronycine: A Useful Synthon in the
Acronycine Series for the Introduction of Amino Substituents at 6-Position
and for the Conversion into Isopropylfuroacridones
a
a
b
Prokopios MAGIATIS, Sofia MITAKU, Alexios-Leandros SKALTSOUNIS, ,a and François TILLEQUIN
*
Laboratory of Pharmacognosy, University of Athens,a Panepistimiopolis, Zografou, GR-15771 Athens, Greece and
Laboratoire de Pharmacognosie de l’Université René Descartes,b UMR/CNRS N0 8638, Faculté des Sciences
Pharmaceutiques et Biologiques, 4 avenue de l’Observatoire, F-75006 Paris, France.
Received May 21, 2001; accepted July 24, 2001
Thermic aromatic nucleophilic displacement of the methoxy group at C-6 of (؎)-1-oxo-2-hydroxy-1,2-dihy-
droacronycine (2) by an amine is a reaction that gives a facile entry to acronycine derivatives bearing an amino
substituent at this position. The introduction of the amino substituents was confirmed with a long-range 1H–15N
correlation NMR spectrum at natural abundance. Under basic conditions, compound 2 can also be rearranged
to the corresponding isopropylfuroacridone 12, in 80% yield.
Key words acronycine; furanoacridone; alkaloid; cytotoxicity; 15N-NMR
The pyranoacridone alkaloid acronycine (1), first isolated carbonyl group at C-1 of 2.
from Acronychia baueri SCHOTT (Rutaceae) in 1948 was later
When ammonia is used as the nucleophile agent, the ex-
found to be a potent anticancer agent.1—5) Its main interest pected 6-amino derivative 8 is only obtained in small yield
lies in its broad spectrum of activity, which includes numer- (10%) when the reaction is carried out under pressure in a
ous solid tumors.2—8) Nevertheless, clinical trials have been sealed tube. Under those conditions the major product 9 re-
so far severely hampered by its very low water solubility and sults from a degradation of the pyrano ring of the starting
have therefore given only poor results.7) In this context, the material. A similar byproduct 10 was also observed in the
development of new acronycine derivatives bearing amino case of methylamine, but only in 5% yield.
groups and able to give water-soluble salts appears highly de-
When 2 is treated by the more bulky ethylamine, ethyl-
amino substitution product 11 is only obtained in 10% yield
sirable.10—13)
Among the various oxidation products of acronycine at the and 2-hydroxy-2-isopropyl-5-methoxy-11-methyl-1,2-dihy-
dimethylpyran ring, (Ϯ)-1-oxo-2-hydroxy-1,2-dihydroacro- drofurano[2,3-c]acridin-1,6(11H)dione (12) is the major
nycine (2) (2-hydroxy-6-methoxy-3,3,12-trimethyl-1,2,3,12- product of the reaction, isolated in 50% yield. This re-
tetrahydro-7H-pyrano[2,3-c]acridin-1,7-dione) is particularly arrangement compound most probably arises through an al-
easy to obtain by simple permanganate oxidation of the kaline-catalyzed mechanism (Fig. 2), previously described
parent alkaloid.14) This compound presents two electron for the isomerization of ketohydroxypyranocoumarins into
withdrawing carbonyl groups at C-1 and C-7, respectively their furocoumarin isomers under basic conditions.17) In good
in positions para and ortho to the methoxy group at C-6. agreement with this statement, 12 is the only product, iso-
Consequently, a thermic aromatic nucleophilic displacement lated in 80% yield when 2 is treated by propylamine, butyl-
of the methoxy group by an amine can be envisaged at this amine, dimethylamine or sodium methoxide in methanol. It
latter position.15,16) Such a reaction should give a facile entry must be noted that compound 12 is a useful synthon for the
to acronycine derivatives bearing an amino substituent at preparation of acronycine analogues with a D-furano ring.
C-6, which could not be efficiently obtained so far, either by
The study of the cytotoxic properties of the new
acronycine derivatives 3, 4, 6 and 12 was carried out in vitro
conversion of acronycine itself, or by total synthesis.5)
Indeed, treatment of 2 by methylamine or hydrazine led in on L-1210 leukemia cells.18) The results (IC50) are summa-
60—90% yield to the nucleophilic substitution product 3 and rized in Table 1. The new compounds exhibited moderate cy-
4, respectively (Chart 1). The introduction of the amino sub- totoxic activity, which is in agreement with our previous hy-
stituent at position 6 was directly confirmed by a gradient in- pothesis that cytotoxicity in this series is correlated with the
1
verse-detected long-range H–15N correlation experiment at presence of a good leaving group at the benzylic position,
natural abundance. In each case a clear 3J correlation was ob- able to ensure sufficient reactivity toward nucleophilic
served between H-5 and N-1 of the amino substituent. For agents.7) However, the comparison with the cytotoxicity of 2
example, in the case of compound 4 proton H-5 (d 6.33) was shows that either the amino substitution at position 6 or the
correlated with N-1 (d 114.5) (Fig. 1).
rearrangement of the D-ring from pyrano to furano are two
It should be noted that hydrazine does not react on the car- promising modifications which must be further explored in
bonyl group at C-1 of 2 under these conditions, probably due the acronycine series. Additionally, the potential formation of
to steric hindrance. In contrast, hydrazine reacts with the less water-soluble salts of the synthesized amino derivatives is of
hindered 2-oxo-1,2-dihydroacronycine (5) to give the ex- great importance because they are some of the very few ex-
pected hydrazone 6, and with acronycine itself to afford the amples of amino substituted acronycine analogues.
well known 1,2-dihydroacronycine (7),2) emphasizing the
lack of reactivity of the methoxy group at C-6 of acronycine
General Experimental Procedures Melting points were measured with
towards nucleophilic substitution and the crucial role of the a Büchi apparatus and are uncorrected. Spectra were recorded on the follow-
Experimental
To whom correspondence should be addressed. e-mail: skaltsounis@pharm.uoa.gr © 2001 Pharmaceutical Society of Japan

October 2001
1305
Chart 1
ents, gt1—gt3, had durations of 0.8 ms. Gradient pairs were optimized as
70 : 30 : 50 for 15N. Column chromatographies were conducted using flash
Silica gel 60 Merck (40—63 mm), with an overpressure of 300 mbars. All
new compounds gave satisfactory combustion analyses (C, H, N, withinϮ
0.4% of calculated values).
(؎)-6-Demethoxy-6-hydrazino-2-hydroxy-1-oxo-1,2-dihydroacronycine
(4) To a solution of (Ϯ)-2-hydroxy-1-oxo-1,2-dihydroacronycine (2) (150
mg, 0.42 mmol) in EtOH (4 ml) was added 0.4 ml hydrazine hydrate. The re-
action mixture was refluxed for 4 h. Then the reagents were removed under
reduced pressure and the residue was submitted to flash chromatography on
silica gel with Chex : EtOAc (60 : 40 to 40 : 60) to give 4 (130 mg, 88%). mp
Fig. 1. Characteristic Long-range 1H–15N Correlation for 4
1
213 °C. H-NMR (DMSO, 200 MHz) d: 11.63 (1H, s, NH-NH2), 8.22 (1H,
ing apparatus: MS, Nermag R10-10C in desorption-chemical ionization, d, Jϭ8 Hz, H-8), 7.74 (2H, m, H-10, 11), 7.38 (1H, t, Jϭ8 Hz, H-9), 6.33
using NH3 as reagent gas. NMR, Bruker AC 200, 1H-NMR (200 MHz), 13C- (1H, s, H-5), 5.55 (1H, d, Jϭ2 Hz, OH-2), 4.81 (2H, s, NH-NH2), 3.96 (1H,
NMR (50 MHz) and a Bruker DRX400, 1H-NMR (400 MHz). Chemical d, Jϭ2 Hz, H-2), 3.62 (3H, s, NCH3), 1.50 (3H, s, CH3), 1.35 (3H, s, CH3).
shifts are given in d with tetramethylsilane (TMS) as an internal standard. 13C-NMR (DMSO, 50 MHz) d: 186.51 (C-1), 176.91 (C-7), 165.19 (C-4a),
1
Coupling constants (J) are given in Hz. The signals of H and 13C spectra 158.43 (C-6), 148.73 (C-12a), 142.77 (C-11a), 133.32 (C-10), 125.43 (C-8),
were unambiguously assigned by using 2D NMR techniques: correlation 123.44 (C-7a), 122.95 (C-9), 117.93 (C-11), 103.81 (C-6a), 97.79 (C-12b),
1
spectroscopy (COSY), H-detected heteronuclear multiple quantum coher- 88.51 (C-5), 81.32 (C-3), 75.32 (C-2), 44.94 (NCH3), 25.77 (CH3), 19.59
ence (HMQC) and heteronuclear multiple bond correlation (HMBC). These (CH3). C 64.6%, H 5.4%, N 11.8%, MS-DCI m/z: 354 (MϩH)ϩ.
2D experiments were performed using standard Bruker microprograms. For
(؎)-6-Demethoxy-2-hydroxy-6-methylamino-1-oxo-1,2-dihydroacro-
the 1H–15N GHMQC spectrum, data were acquired as 3072ϫ400 data points nycine (3) and 2,N-Dimethyl-2-(10-methyl-1-methylamino-9-oxo-9,10-di-
with a total of 290 transients accumulated/t1 increment. Pulse widths were hydroacridin-3-yloxy)propanamide (10) Treatment of 2 (100 mg, 0.28
8.55 ms for 1H and 27.7 ms for the 15N at powers of 0 dB and Ϫ3 dB. The F1 mmol) for 24 h with 0.4 ml of a water solution of methylamine (40%) in
spectral window employed was set from 100—400 ppm. Pulsed field gradi- conditions essentially similar to those described for the preparation of 4

1306
Vol. 49, No. 10
Fig. 2. Proposed Mechanism for the Rearrangement of Pyranoacridone 2 to Furanoacridone 12
Table 1. Cytotoxic Activitya)
34.45 (NCH3), 25.04 (2ϫCH3). C 66.6%, H 5.7%, N 12.8%, MS-DCI m/z:
326 (MϩH)ϩ.
Compound
3
4
6
12
1
2
(؎)-6-Ethylamino-6-demethoxy-2-hydroxy-1-oxo-1,2-dihydroacro-
nycine (11) Treatment of 2 (100 mg, 0.28 mmol) for 24 h with 0.3 ml of a
water solution of ethylamine (70% w/v) and in conditions essentially similar
to those described for the preparation of 4 afforded 11 (13 mg, 13%) and 12
IC50 (mM)
52.8
33.3
38.1
23
25
75.1
1
a) Inhibition of L1210 cell proliferation measured by the MMT assay (mean of 2 val-
ues obtained in independent experiments).
(50 mg, 50%). Compound 11: mp 208 °C. H-NMR (DMSO, 200 MHz) d:
11.00 (1H, s, NH-CH2), 8.26 (1H, d, Jϭ8 Hz, H-8), 7.80 (2H, m, H-10, 11),
7.44 (1H, t, Jϭ8 Hz, H-9), 5.88 (1H, s, H-5), 5.84 (1H, d, Jϭ2 Hz, OH-2),
3.99 (1H, d, Jϭ2 Hz, H-2), 3.63 (3H, s, NCH3), 3.30 (2H, quintet, Jϭ7 Hz,
NH-CH2CH3), 1.52 (3H, s, CH3), 1.39 (3H, s, CH3), 1.30 (3H, t, Jϭ7 Hz,
NH-CH2CH3). C 68.7%, H 6.0%, N 7.5%, MS-DCI m/z: 367 (MϩH)ϩ.
(؎)-2-Hydroxy-2-isopropyl-5-methoxy-11-methyl-1,2-dihydrofurano-
[2,3-c]acridin-1,6(11H) dione (12) To a solution of 2 (400 mg, 1.13
mmol) in MeOH (30 ml) was added 4 ml of NaOH 1 N. The reaction mixture
was refluxed for 1.5 h and then it was neutralized with acetic acid. The sol-
vents were removed under reduced pressure, the residue was extracted with
CH2Cl2/H2O and the organic layer was collected. Compound 12 (315 mg,
78%) was purified by crystallization with MeOH. mp 280 °C (dec.). 1H-
NMR (DMSO, 200 MHz) d: 8.14 (1H, dd, Jϭ8, 1.5 Hz, H-7), 7.83 (1H, s,
OH-2), 7.73 (2H, m, H-9, 10), 7.36 (1H, td, Jϭ8, 1.5 Hz, H-8), 6.64 (1H, s,
H-4), 3.98 (3H, s, OCH3), 3.86 (3H, s, NCH3), 2.15 (1H, sept, Jϭ7 Hz, H-
1Ј), 1.05 (3H, d, Jϭ7 Hz, CH3), 0.82 (3H, d, Jϭ7 Hz, CH3). 13C-NMR
(DMSO, 50 MHz) d: 192.58 (C-1), 175.86 (C-6), 174.40 (C-3a), 170.57
(C-5), 145.24 (C-11a), 142.46 (C-10a), 133.28 (C-9), 125.98 (C-7), 125.25
(C-6a), 123.13 (C-8), 117.28 (C-10), 108.02 (C-5a,2), 101.43 (C-11b), 89.67
(C-4), 57.15 (OCH3), 43.22 (NCH3), 33.42 (C-1Ј), 16.08 (CH3), 15.56
(CH3). C 67.8%, H 5.4%, N 3.8%, MS-DCI m/z: 354 (MϩH)ϩ.
2-Hydrazo-1,2-dihydroacronycine (6) Treatment of 2-oxo-1,2-dihy-
droacronycine (5) (50 mg, 0.15 mmol) for 15 min with 0.15 ml of hydrazine
hydrate in conditions essentially similar to those described for the prepara-
tion of 4 afforded after crystallization with EtOH compound 6 (28 mg,
53%). mp 185 °C. 1H-NMR (CDCl3, 200 MHz) d: 8.24 (1H, dd, Jϭ8,
1.5 Hz, H-8), 7.55 (1H, td, Jϭ8, 1.5 Hz, H-10), 7.28 (1H, d, Jϭ8 Hz, H-11),
7.19 (1H, t, Jϭ8 Hz, H-9), 6.28 (1H, s, H-5), 5.25 (2H, br, NH2), 3.91 (3H,
s, OCH3), 3.77 (3H, s, NCH3), 3.54 (2H, s, H-1), 1.53 (6H, s, 2ϫCH3). 13C-
NMR (CDCl3, 50 MHz) d: 177.84 (C-7), 160.95 (C-6), 158.93 (C-4a),
149.55 (C-12a), 149.17 (C-2), 145.81 (C-11a), 132.57 (C-10), 126.77 (C-8),
125.82 (C-7a), 121.91 (C-9), 116.43 (C-11), 111.61 (C-6a), 100.00 (C-12b),
96.04 (C-5), 78.10 (C-3), 56.19 (OCH3), 44.74 (NCH3), 25.17 (2ϫCH3),
23.11 (C-1). C 68.3%, H 6.2%, N 11.6%, MS-DCI m/z: 352 (MϩH)ϩ.
Cell Culture and Cytotoxicity L1210 cells were cultivated in RPMI
1640 medium (Gibco) supplemented with 10% fetal calf serum, 2 mM L-glu-
tamine, 100 units/ml penicillin, 100 mg/ml streptomycin, and 10 mM HEPES
buffer (pHϭ7.4). Cytotoxicity was measured by the microculture tetra-
zolium assay as described.18) Cells were exposed to graded concentrations of
drug (nine serial dilutions in triplicate) for 48 h. Results are expressed as
IC50, the concentration needed to reduce by 50% the optical density of
treated cells with respect to the optical density of untreated controls.
afforded compound 3 (60 mg, 61%) and 10 (6 mg, 5%). Compound 3: mp
205 °C. H-NMR (CDCl3, 200 MHz) d: 11.26 (1H, q, Jϭ5 Hz, NH-CH3),
1
8.38 (1H, dd, Jϭ8, 1.5 Hz, H-8), 7.71 (1H, td, Jϭ8, 1.5 Hz, H-10), 7.58 (1H,
d, Jϭ8 Hz, H-11), 7.37 (1H, t, Jϭ8 Hz, H-9), 5.82 (1H, s, H-5), 4.19 (1H, d,
Jϭ2 Hz, OH-2), 4.09 (1H, d, Jϭ2 Hz, H-2), 3.70 (3H, s, NCH3), 2.99 (3H, d,
Jϭ5 Hz, NH-CH3), 1.56 (6H, s, 2ϫCH3). 13C-NMR (CDCl3, 50 MHz) d:
186.17 (C-1), 178.51 (C-7), 166.05 (C-4a), 158.86 (C-6), 149.46 (C-12a),
143.28 (C-11a), 133.05 (C-10), 126.03 (C-8), 124.39 (C-7a), 123.09 (C-9),
117.35 (C-11), 105.59 (C-6a), 96.79 (C-12b), 89.63 (C-5), 82.32 (C-3),
75.76 (C-2), 45.21 (NCH3), 29.59 (6-NHCH3), 27.09 (CH3), 17.91 (CH3). C
68.3%, H 5.7%, N 7.9%, MS-DCI m/z: 353 (MϩH)ϩ. Compound 10: mp
1
153 °C. H-NMR (CDCl3, 200 MHz) d: 10.34 (1H, q, Jϭ5 Hz, 1-NH-CH3),
8.40 (1H, dd, Jϭ8, 1.5 Hz, H-8Ј), 7.62 (1H, td, Jϭ8, 1.5 Hz, H-6Ј), 7.36
(1H, d, Jϭ8 Hz, H-5Ј), 7.22 (1H, t, Jϭ8 Hz, H-7Ј), 6.50 (1H, q, Jϭ5 Hz,
CONHCH3), 5.94 (1H, d, Jϭ1.5 Hz, H-4Ј), 5.75 (1H, d, Jϭ1.5 Hz, H-2Ј),
3.68 (3H, s, NCH3), 2.88 (3H, d, Jϭ5 Hz, 1-NH-CH3), 2.85 (3H, d, Jϭ5 Hz,
CONHCH3), 1.64 (6H, s, 2ϫCH3). 13C-NMR (CDCl3, 50 MHz) d: 178.95
(C-1), 175.12 (C-9Ј), 166.52 (C-3Ј), 155.02 (C-1Ј), 146.53 (C-4aЈ), 141.90
(C-10aЈ), 132.88 (C-6Ј), 126.92 (C-8Ј), 123.30 (C-8aЈ), 121.04 (C-7Ј),
114.11 (C-5Ј), 104.56 (C-9aЈ), 91.72 (C-4Ј), 90.57 (C-2Ј), 81.47 (C-2Ј),
34.43 (NCH3), 29.52 (1Ј-NHCH3), 26.28 (CONHCH3), 25.54 (2ϫCH3). C
67.8%, H 6.6%, N 11.8%, MS-DCI m/z: 354 (MϩH)ϩ.
(؎)-6-Amino-6-demethoxy-2-hydroxy-1-oxo-1,2-dihydroacronycine
(8) and 2-(1-Amino-10-methyl-9-oxo-9,10-dihydroacridin-3-yloxy)-2-
methyl-propanamide (9) Treatment of 2 (55 mg, 0.15 mmol) for 24 h with
1 ml of a water solution of ammonia (28% w/v) in a sealed tube and in con-
ditions essentially similar to those described for the preparation of 4 af-
forded compound 8 (5 mg, 10%) and 9 (27 mg, 51%). Compound 8: mp
1
200 °C. H-NMR (DMSO, 200 MHz) d: 9.95 (2H, s, NH2), 8.25 (1H, dd,
Jϭ8, 1.5 Hz, H-8), 7.79 (2H, m, H-10,11), 7.41 (1H, td, Jϭ8, 1.5 Hz, H-9),
5.91 (1H, s, H-5), 5.74 (1H, d, Jϭ2 Hz, OH-2), 4.00 (1H, d, Jϭ2 Hz, H-2),
3.62 (3H, s, NCH3), 1.49 (3H, s, CH3), 1.36 (3H, s, CH3). 13C-NMR
(DMSO, 50 MHz) d: 186.77 (C-1), 177.01 (C-7), 164.40 (C-4a), 158.07
(C-6), 149.16 (C-12a), 143.07 (C-11a), 133.44 (C-10), 125.46 (C-8), 123.60
(C-7a), 122.87 (C-9), 117.93 (C-11), 107.41 (C-6a), 98.59 (C-12b), 93.14
(C-5), 81.32 (C-3), 76.90 (C-2), 44.92 (NCH3), 25.70 (CH3), 19.58 (CH3). C
67.6%, H 5.5%, N 8.2%, MS-DCI m/z: 339 (MϩH)ϩ. Compound 9: mp
1
120 °C. H-NMR (CDCl3, 200 MHz) d: 8.46 (1H, dd, Jϭ8, 1.5 Hz, H-8Ј),
7.67 (1H, td, Jϭ8, 1.5 Hz, H-6Ј), 7.42 (1H, d, Jϭ8 Hz, H-5Ј), 7.22 (1H, t,
Jϭ8 Hz, H-7Ј), 6.12 (1H, d, Jϭ1.5 Hz, H-4Ј), 5.91 (1H, d, Jϭ1.5 Hz, H-2Ј),
3.68 (3H, s, NCH3), 1.66 (6H, s, 2ϫCH3). 13C-NMR (CDCl3, 50 MHz) d:
178.04 (C-1), 174.99 (C-9Ј), 165.82 (C-3Ј), 156.42 (C-1Ј), 147.23 (C-4aЈ),
142.98 (C-10aЈ), 133.45 (C-6Ј), 127.02 (C-8Ј), 122.80 (C-8aЈ), 121.08 (C-
7Ј), 114.19 (C-5Ј), 105.06 (C-9aЈ), 96.22 (C-4Ј), 91.67 (C-2Ј), 81.37 (C-2Ј),
Acknowledgments Dr. A. Pierré and Dr. Gh. Atassi (Institut de
Recherches SERVIER, France) are gratefully acknowledged for the cytotoxi-
city tests and their kind interest in this work.

October 2001
1307
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