Synthesis of analogues of natural antimitotic glaziovianin A based on dill and parsley seed essential oils

Article abstract of DOI:10.1016/j.mencom.2016.07.005

Glaziovianin A and its analogues were synthesized in six steps starting from allylpolyalkoxybenzenes separated from essential oils of dill (Anetum graviolens) and parsley (Petro-selinum sativum) seeds.

Full text of DOI:10.1016/j.mencom.2016.07.005

Mendeleev
Communications
Mendeleev Commun., 2016, 26, 285–287
Synthesis of analogues of natural antimitotic glaziovianin A
based on dill and parsley seed essential oils
Dmitry V. Tsyganov,a Leonid D. Konyushkin,a Marina N. Semenovab and Victor V. Semenov*a
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: + 7 499 135 5328; e-mail: vs@ioc.ac.ru
b N. K. Kol’tsov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow,
Russian Federation
DOI: 10.1016/j.mencom.2016.07.005
OMe
O
O
O
OMe
MeO
MeO
CH2
O
O
Glaziovianin A and its analogues were synthesized in six
steps starting from allylpolyalkoxybenzenes separated from
essential oils of dill (Anetum graviolens) and parsley (Petro-
selinum sativum) seeds.
6 steps
OMe
O
Glaziovianin A
O
Ateleia glazioviana
OMe
OMe
OMe
Apiol
MeO
MeO
O
O
Synthetic
isoflavone
O
Parsley
iso-Glaziovianin A
Natural compounds and their analogues account for ~80% of
anticancer drugs approved between 1981 and 2010.1 A number of
these cytostatic agents contain polymethoxyphenyl moieties.2–6
Plant flavonoids bearing such moieties are widely abundant in
nature.7 However, alkoxyisoflavones with antiproliferative activity
are scarcely presented in scientific literature.
A synthetic method based on Suzuki reaction was developed
for the preparation of glaziovianin A and its analogues modified
at rings A and B.11,12 However, the intermediates, particularly
boron-containing alkoxybenzenes served as the basic structures
for the ring B, are rather difficult to obtain. In the present study
we constructed both rings A and B in isoflavones from allyl-
alkoxybenzenes 1 easily available from essential oils of dill
(Anetum graviolens) and parsley (Petroselinum sativum) seeds
(Scheme 1). These cultivated herbs have a well-developed tech-
nology for planting and harvesting and can be produced on a
large scale.
A potent cytotoxic isoflavone glaziovianin A and its pre-
viously described less toxic analogues I–III (Figure 1) were
extracted from the leaves of Brazilian tree Ateleia glazioviana
Baill (Leguminosae).8 Its leaves are known to cause abortions,
cardiac failure, and the central nervous system injuries in bovines.8
Glaziovianin A and isoflavones I–III inhibited growth of HL-60
human promyelocytic leukemia cells with IC50 values of 0.29,
16, 23, and 8.5 mm, respectively.8 Furthermore, glaziovianin A
displayed high cytotoxicity against a panel of 39 human cancer
cell lines (average IC50 is 0.66 mm),8 disrupted microtubule struc-
ture and dynamics by binding to the colchicine site of tubulin
molecule,9 and blocked cell cycle progression in mitosis due to
the mitotic spindle damage.8–10 Structure–activity relationship
study showed that the number and position of alkoxy substituents
in the rings A and B are essential for antimitotic microtubule-
modulating properties of glaziovianin A and its analogues.10,11
R1
R1
B
R2
R3
R2
R3
CH2
CO2
O
Dill, parsley
seeds
extraction
R4
R4
1a–d
2a–d
a R1 = H, R2 = R3 = R4 = OMe, Elemicin
b R1 = H, R2 + R3 = OCH2O, R4 = OMe, Myristicin
c R1 = R2 = OMe, R3 + R4 = OCH2O, Dillapiol
d R1 = R4 = OMe, R2 + R3 = OCH2O, Apiol
OMe
5'
MeO
O
4'
Scheme 1 Reagents and conditions:14 KOH, 100°C, 40 min; then, O3,
CHCl3–MeOH–pyridine (80:20:3 v/v), 15°C, 1–2 h.
O
O
O
O
6'
O
B
5
3
MeO
MeO
MeO
MeO
6
7
3'
1'
2'
A
2
OMe
Methoxybenzaldehydes 2 were selectively o-brominated and
then converted to o-bromoacetophenones 5 with MeMgI addition
followed by oxidation (Scheme 2). Transformation of aceto-
phenones 5 to chalcones 6, epoxidation, and rearrangement to
keto aldehydes 8 proceeded in high yields (Scheme 3). Intra-
molecular cyclization of keto aldehyde 8 to target isoflavones 9
was performed in the presence of CuI according to literature
procedure.13 Iso-glaziovianin A 9f with swapped rings A and B
was synthesized by the same reactions (Scheme 3).†
O
O
8
Glaziovianin A
OMe
I
OMe
OMe
OMe
MeO
MeO
O
O
O
MeO
MeO
OMe
O
II
III
†
General procedure for the synthesis of chalcones 6. Sodium hydroxide
Figure 1 Structures of alkoxyisoflavones from Ateleia glazioviana.
(1.2 g, 30 mmol) was added to a vigorously stirred solution containing
© 2016 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2016, 26, 285–287
R1
R1
A
The proposed reaction route is shorter and cheaper than that
reported by Japanese researchers,11,12 which includes nine stages
R2
R3
R2
R3
O
O
i
ii
R1
B
Br
O
R4
R4
MeO
MeO
R2
R3
Me
O
i
A
2d,e
3d,e
70–80%
+
Br
R4
2a–e
R1
A
OH
R1
O
5e
R2
R3
R2
Me
Me
iii
O
R1
A
R2
R3
Br
R3
R4
5d,e
Br
MeO
MeO
ii
R4
A
B
4d,e
64–65%
Br
6a–e
R4
65–85%
d R1 = R4 = OMe, R2 + R3 = OCH2O
e R1 = R4 = H, R2 = R3 = OMe
62–89%
O
O
R1
MeO
MeO
Scheme 2 Reagents and conditions: i, NBS, DMF, ~20°C, 8 h; ii, MeMgI,
diethyl ether, ~20°C, 0.5 h; iii, pyridinium chlorochromate, CH2Cl2, ~20°C,
18 h.
R2 iii
R3
A
B
Br
R4
o-bromoacetophenone 5 (10 mmol) and benzaldehyde 2 (10 mmol) in
EtOH (30 ml) at 20°C. The mixture was stirred at room temperature for
6 h, left overnight, then acidified with 10% HCl to pH 3–4 and strirred
for 1 h. The residue was filtered, washed with water (3×20 ml) and crys-
tallized from EtOAc to afford chalcone 6.
General procedure for the synthesis of epoxides 7. Hydrogen peroxide
(30%, 0.6 ml) was added to a vigorously stirred suspension of chalcone
6 (4 mmol) in EtOH (15 ml) and NaOH (1 n, 1.9 ml) at ~20°C. The
mixture was stirred at 30°C for 3 h and left for 24 h at ~20°C, then
additional portions of NaOH (1 n, 1.9 ml) and H2O2 (30%, 0.6 ml) were
added, and stirring was continued for 6 h at ~20°C. Finally, the last
portions of NaOH (1 n, 1.9 ml) and H2O2 (30%, 0.6 ml) were added
followed by strirring for 24 h. The solid was filtered, washed with EtOH,
water and dried at reduced pressure to afford epoxy ketones 7.
General rearrangement procedure for the synthesis of 2,3-diaryl-3-oxo-
propanals 8. Boron trifluoride etherate (0.39 ml, 3 mmol) was added
dropwise to an ice-cooled solution of chalcone epoxide 7 (3 mmol) in
absolute dichloromethane (15 ml) under argon and this was stirred for
3 h at 20°C. The reaction was then quenched with 5% aqueous NaHCO3
solution (15 ml) and extracted with chloroform (2×5 ml). The organic layer
was washed with water (2×15 ml) and dried over anhydrous Na2SO4.
Evaporation of the solvent afforded crude keto aldehydes 8 as oils. The
products were roughly-purified by column chromatography from CH2Cl2
extract [EtOAc–hexane (1:4), Rf 0.6]. Yields: 8a, 86%; 8b, 92%; 8c,
95%; 8d, 21%; 8e, 86%; 8f, 88%. Compounds 8 were used for the next
step without further purification.
General procedure for the synthesis of isoflavones. A mixture of keto
aldehyde 8 (5 mmol), CuI (95 mg , 0.5 mmol), K2CO3 (1.38 g, 10 mmol)
and 2-picolinic acid (123 mg, 1 mmol) in dry DMF (30 ml) in a flask
filled with argon was stirred at 135–140°C for 8 h. The mixture was
diluted with H2O (100 ml) and extracted by AcOEt (3×50 ml). The organic
layer was dried (Na2SO4), filtered, evaporated under vacuum and purified
by column chromatography [hexane–EtOAc (3:1), Rf 0.3–0.4] to afford
the target izoflavones 9.
7a–e
65–89%
R2
B
R1
O
R3
R4
MeO
MeO
iv
A
O
Br
8a–e
21–95%
R2
R1
R3
R4
O
B
MeO
MeO
A
O
9a–e
24–49%
9d Glaziovianin A
MeO
A
O
OMe
OMe
O
O
i
5d + 2e
B
Br
OMe
6f
78%
OMe
OMe
MeO
O
O
B
O
ii–iv
A
6,7-Dimethoxy-3-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one 9a. Yield
0.71 g (38%), yellowish solid, mp 172–174°C. 1H NMR (CDCl3) d: 7.99
(s, 1H, H-2), 7.64 (s, 1H, H-5), 6.90 (s, 1H, H-8), 6.82 (s, 2H, H-2',6'),
4.01, 3.99 (2s, 6H, 2OMe-6,7), 3.91 (s, 6H, 2OMe-3',5'), 3.89 (s, 3H,
OMe-4'). 13C NMR (CDCl3) d: 175.30, 154.44, 153.15, 152.27, 152.16,
147.77, 138.06, 127.55, 124.53, 117.81, 106.26, 104.73, 99.46, 60.80,
56.42, 56.30, 56.16. MS (EI), m/z: 373 [M+1] (25), 372 [M]+ (100), 358
(10), 357 (48), 329 (10), 271 (20), 171 (14), 149 (17), 134 (10). Found
(%): C, 64.51; H, 5.41. Calc. for C20H20O7 (%): C, 64.42; H, 5.36.
6,7-Dimethoxy-3-(4,7-dimethoxy-1,3-benzodioxol-5-yl)-4H-chromen-
4-one (Glaziovianin A) 9d. Yield 0.62 g (32%), yellowish solid, mp 139–
O
OMe
9f iso-Glaziovianin A
32% on 3 steps
Scheme 3 Reagents and conditions: i, EtOH, ~20°C, 6 h; ii, H2O2, EtOH–
NaOH, ~20°C, 54 h; iii, BF3·Et2O, CH2Cl2, ~20°C, 3 h; iv, CuI–K2CO3,
2-picolinic acid, DMF, 135–140°C, 8 h.
121.68, 118.02, 117.79, 110.05, 104.88, 101.80, 99.52, 60.14, 56.83,
56.39, 56.32. MS (EI), m/z: 387 [M+1] (24), 386 [M]+ (100), 371 (7),
357 (7), 356 (12), 355 (49), 313 (10), 206 (12), 205 (15), 181 (50), 137
(10). Found (%): C, 62.18; H, 4.70. Calc. for C20H18O8 (%): C, 62.08;
H, 4.66.
1
141°C. H NMR (CDCl3) d: 7.91 (s, 1H, H-2), 7.62 (s, 1H, H-5), 6.89
(s, 1H, H-8), 6.53 (s, 1H, H-6'), 6.03 (s, 2H, OCH2O), 4.00, 3.99 (2s,
6H, 2OMe-6,7), 3.86, 3.87 (2s, 6H, 2OMe-4',7'). 13C NMR (CDCl3) d:
175.37, 154.27, 153.41, 152.28, 147.60, 139.10, 138.95, 137.04, 136.75,
– 286 –

Mendeleev Commun., 2016, 26, 285–287
5 N.-H. Nam, Curr. Med. Chem., 2003, 10, 1697.
starting from 2,3,4-trimethoxybenzaldehyde15 and quite expensive
2-hydroxy-4,5-dimethoxyacetophenone. Moreover, a great amount
of a costly Pd-catalyst in a proportion of 342 mg per 714 mg
of glaziovianin A was used. The antimitotic microtubule-
destabilizing properties of glaziovianin A and its analogues 9
were confirmed by the phenotypic sea urchin embryo assay.7,16
In conclusion, glaziovianin A and its analogues were syn-
thesized in six steps starting from readily available commercial
2-bromo-4,5-dimethoxybenzaldehyde 3e and polyalkoxy-
benzenes 1, extracted from dill and parsley seeds. The compounds
obtained were found to be promising antimitotic microtubule
destabilizing agents with low toxicity against human non-malignant
cells.
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Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2016.07.005.
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Received: 8th February 2016; Com. 16/4836
– 287 –