Synthesis of new anticancer and anti-inflammatory isoxazolines and aziridines from the natural (-)-deltoin

Article abstract of DOI:10.1111/jphp.13013

Objectives: This work describes the synthesis, the bioactivity and the structure–activity relationship of new derivatives from a natural coumarin. Methods: (-)-Deltoin 1 and the corresponding isoxazolines and aziridines were characterized by spectroscopic

Full text of DOI:10.1111/jphp.13013

Research Paper
Synthesis of new anticancer and anti-inflammatory
isoxazolines and aziridines from the natural (-)-deltoin
Mansour Znatia, Meriem Debbabia, Anis Romdhanea , Hichem Ben Janneta
and Jalloul Bouajilab
aLaboratory of Heterocyclic Chemistry, Natural Products and Reactivity (LR11ES39), Team: Medicinal Chemistry and Natural Products, Faculty of
Science of Monastir, University of Monastir, Monastir, Tunisia and bLaboratory of IMRCP UMR CNRS 5623, Faculty of Pharmacy Toulouse,
Paul-Sabatier University, University of Toulouse, Toulouse, France
Keywords
Abstract
(-)-deltoin; anti-5-lipoxygenase; anticancer;
Ferula lutea; heterocycle derivatives
Objectives This work describes the synthesis, the bioactivity and the structure–
activity relationship of new derivatives from a natural coumarin.
Correspondence
Methods (-)-Deltoin 1 and the corresponding isoxazolines and aziridines were
characterized by spectroscopic means. The cytotoxic (HTC-116, IGROV-1 and
OVCAR-3 cancer cell lines) and 5-lipoxygenase activity of (-)-deltoin 1 and its
structural analogues have been evaluated.
Jalloul Bouajila, Laboratory of IMRCP UMR
CNRS 5623, Faculty of Pharmacy Toulouse,
Paul-Sabatier University, University of
Toulouse, 118 route de Narbonne, F-31062
Toulouse, France.
Key findings The phytochemical investigation of the ethyl acetate extract of the
flowers of Ferula lutea (Poir.) Maire has led to the isolation of (-)-deltoin 1. A series
of new isoxazoline 2a,a0–2f,f0 and aziridine 3a,a0–3e,e0 derivatives have been pre-
pared by 1,3-dipolar cycloaddition. It has been found that the derivatives 2a
(IC50 = 3.3 ꢀ 0.1 lM), 3a,a0 (IC50 = 5.9 ꢀ 0.1 lM), 3b,b0 (IC50 = 6.1 ꢀ 0.7 lM)
and 3c,c0 (IC50 = 7.3 ꢀ 0.9 lM) bearing a phenyl isoxazoline, a phenylaziridine, a 4-
methlphenylaziridine and a 4-methoxyphenylaziridine, respectively, are more cyto-
toxic than (-)-deltoin 1 (IC50 = 14.3 ꢀ 0.2 lM). The diastereoisomers in mixture
(2f,f0) with a 6-chloropyridin-2-yl system have shown the best anti-5-lipoxygenase
activity (% inhibition = 53.1 ꢀ 4.8% at 200 lM).
E-mail: jalloul.bouajila@univ-tlse3.fr
and
Hichem Ben Jannet, Laboratory of
Heterocyclic Chemistry, Natural Products
and Reactivity (LR11ES39), Team: Medicinal
Chemistry and Natural Products, Faculty of
Science of Monastir, University of Monastir,
Avenue of Environment, 5019 Monastir,
Tunisia.
E-mail: hich.benjannet@yahoo.fr
Conclusions Some analogues have been found more bioactive than deltoin 1.
Their activity has been related to the nature of the added heterocycles. It would
be interesting to evaluate their in-vivo activity.
Received October 23, 2017
Accepted August 26, 2018
doi: 10.1111/jphp.13013
presents interesting phytochemical features, such as the
occurrence of furanocoumarins and coumarins.[9,10] Ferula
Introduction
Very beneficial to the well-being of humans are bioactive
compounds containing fruits, vegetables and herbs.[1] Cou-
marin is a heterocyclic compound, which plays an impor-
tant role in the domain of natural products and organic
synthetic chemistry.[2] The coumarins are classified as sim-
ple coumarin, pyranocoumarins, furanocoumarins and
coumarins substituted in the pyrone groups.[3] Coumarins
that are found in many plants such as Ferula species are
used in the form of crude drugs in traditional medica-
tion.[4] These natural compounds exhibit many biological
effects.[5] Coumarins, naturally present in many plants,
possess antioxidant, anticoagulant, anti-inflammatory,
antimicrobial, anticancer and antiallergic properties.[6,7]
The genus Ferula, belonging to the Apiaceae family,[8]
lutea (Poir.) Maire (Apiaceae) is also called as Ferulago
lutea (Poir.) Grande.[11,12] The roots of F. lutea were the
subject of previous phytochemical investigation that led to
the isolation of new dihydrofuranocoumarins as two
inseparable isomers, (-)-5-hydroxyprantschimgin and (-)-
5-hydroxydeltoin, together with eight known compounds,
(-)-prantschimgin, (-)-deltoin, psoralen, xanthotoxin,
umbelliferone, caffeic acid, b-sitosterol and stigmasterol.[13]
The same work has indicated the significant cytotoxic activ-
ity of (-)-deltoin towards the human colorectal cancer cell
lines HCT-116 and HT-29 with IC50 values of
0.93 ꢀ 0.11 lM and 7.6 ꢀ 1.05 lM, respectively. The del-
toin has been cited to be a hepatoprotective and a TNF-a
inhibitor.[14]
© 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2018), pp. **–**
1

Bioactivity of (-)-deltoin derivatives
Mansour Znati et al.
Recently, there has been wide interest in compounds
bearing isoxazoline moiety because of their unique chemi-
cal structure and broad spectrum of biological properties
including antibiotic, antithrombolytic, antitumour, anti-
HIV and cytotoxic activity.[15] On the other hand, among
three-membered heterocycles, aziridines constitute a partic-
ular versatile class of molecule, and both physical and
chemical properties of aziridines have been studied (theo-
retical and experimental investigations).[16] The antitu-
mour drug (FR900482) containing aziridine is an
example.[17] Many aziridine alkaloids have been proven to
be anticancer, antibacterial or antimicrobial. This indicates
that the presence of the aziridine ring in natural as well as
synthetic compounds is essential for such activity.[18]
spectrophotometer (4000–400 cmꢁ1) using NaCl pellets.
1H (300 MHz) and 13C (75 MHz) NMR spectra have been
recorded on a Bruker AM300 spectrometer, using CDCl3 as
solvent and none deuterated residual solvent as internal
standard. Chemicals shifts (d) are given in parts per million
(ppm) and coupling constants (J) in Hertz. Melting points
have been determined on a Bu€chi 510 apparatus using cap-
illary tubes and are uncorrected.
Chemistry
Extraction and isolation
The fresh flowers of F. lutea (5.8 kg) have been macerated
with MeOH/H2O (7:3, 25 l) at room temperature for
7 days. The corresponding aqueous extract has been
obtained after filtration and evaporation of the organic sol-
vent (MeOH) under reduced pressure. The aqueous residue
has been extracted successively with ethyl acetate and n-
butanol to obtain, after evaporation of the solvents, the cor-
responding extracts (56 and 220 g, respectively). The ethyl
acetate extract (50 g) was further subjected to silica gel col-
umn chromatography with petroleum ether/ethyl acetate
used as an eluent to obtain six fractions. The precipitation
of the fraction 3 (13.63 g) in MeOH at ꢁ20 °C yielded
3.5 g of compound 1.
For the preparation of isoxazoline and aziridine rings,
intermolecular [3 + 2] cycloaddition reaction of arylnitrile
oxides and azidobenzenes, respectively, with alkenes repre-
sents an efficient and convergent method. It has been the
subject of intense research over the last decade, due to its
great synthetic value, and has been the most effective pro-
cess to the synthesis of five-membered heterocycles, which
are difficult to be prepared with other means.[16,19]
In view of broad biological activity of furanocoumarins,
and as a part of our search for new five-membered hetero-
cyclic compounds, we have suggested to investigate the beha-
viour of the bioactive (-)-deltoin 1 isolated quantitatively
from the flowers of F. lutea towards a series of arylnitrile
oxides and azidobenzenes as a dipole.[20] The reaction has
been regiospecific and has led to a series of new derivatives
with a better biological profile. The evaluation of the anti-
inflammatory (5-lipoxygenase) and anticancer (HTC-116,
IGROV-1 and OVCAR-3 cancer cell lines) activity of all the
synthesized heterocycles has been studied and reported here.
(-)-Deltoin 1
MP: 104 °C, ([a] = ꢁ20.95, cc = 5 mg/ml, CHCl3), 1H
NMR (CDCl3, 300 MHz): 7.65 (1H, d, J = 9.3 Hz, H-4),
7.31 (1H, s, H-5), 6.78 (1H, s, H-8), 6.27 (1H, d,
J = 9.3 Hz, H-3), 6.06 (1H, qq, J1 = 7.2 Hz; J2 = 1.2 Hz,
H-3″), 5.13 (1H, t, J = 9.0 Hz, H-2″), 3.33–3.28 (2H, m,
H-30a,b), 1.94 (3H, d, J = 7.2 Hz, H-5″), 1.72 (3H, d,
J = 1.2 Hz, H-4″), 1.67 (3H, s, H-60), 1.65 (3H, s, H-50).
13C-NMR (CDCl3, 75 MHz, d): 167.2 (C-1″), 163.3 (C-2),
161.3 (C-7), 155.6 (C-8a), 143.6 (C-4), 137.6 (C-3″), 128.5
(C-6), 124.4 (C-5), 123.1 (C-2″), 112.1 (C-4a), 112.5 (C-3),
97.7 (C-8), 89.0 (C-20), 65.8 (C-40), 29.5 (C-30a,b), 22.2 (C-
60), 20.4 (C-50), 15.7 (C-4″), 15.4 (C-5″). ESI-MS m/z 329
[M+H]+. On the basis of these data and the reported data
for deltoin, the compound 1 has been assigned as (-)-Z-del-
toin.
Materials and Methods
Plant material
Ferula lutea flowers were collected from a river valley
located at 15 km from the south side of the city of Beja
(North West Tunisia), on April 2010, and identified by
Professor Fꢀethia Harzallah Skhiri, in the Laboratory of
Vegetal Biology and Botanic, High Institute of Biotechnol-
ogy of Monastir, Tunisia, and a voucher specimen (F.L.F-
10) was deposited in the same laboratory.
Preparation of compounds 2a,a0-2f,f 0
General methods
The nitrile oxides were prepared according to the general
procedure, generated from aldoximes by halogenation fol-
lowed by an in-situ dehydrohalogenation.[20] To compound
1 (0.1 g, 0.32 mmol) in refluxing dichloromethane, the
appropriate nitrile oxide (2 equiv.) has been added in the
presence of triethylamine (2 equiv.) and the mixture has
Desorption chemical ionization–high-resolution mass spec-
trometry (DCI-HRMS) has been run in a GCT 1er Waters,
and the ESI+ experiment has been evaluated by Shimadzu
QP-1000 EX spectrometer. IR spectra have been recorded
on
a
Perkin–Elmer
Fourier
transform
FT-IR
2
© 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2018), pp. **–**

Mansour Znati et al.
Bioactivity of (-)-deltoin derivatives
been refluxed for 48 h. The resulting mixture has been
washed with water to remove salts and then extracted with
CH2Cl2. The organic layer has been dried over anhydrous
Na2SO4. The solvent has been then removed under reduced
pressure. The resulting residue has been purified by flash
chromatography (cyclohexane/EtOAc (60:40)) to give the
corresponding isoxazoline derivatives as separated
diastereoisomers 2a,a0–2e,e0 except 2f,f0.
J = 9.3 Hz, H-4), 7.28 (2H, d, J = 8.1 Hz, H-8″, H-12″),
7.28 (1H, s, H-5), 7.12 (2H, d, J = 8.1 Hz, H-9″, H-11″),
6.25 (1H, s, H-8), 6.25 (1H, d, J = 9.6 Hz, H-3), 4.93 (1H,
dd, J1 = 9.6 Hz, J2 = 7.8 Hz, H-20), 3.41 (1H, q,
J = 7.2 Hz, H-3″), 3.33–3.31 (2H, m, H-30a,b), 2.34 (3H, s,
H-13″), 1.64 (3H, s, H-60), 1.62 (3H, s, H-50), 1.51 (3H, s,
H-4″), 1.23 (3H, d, J = 7.2 Hz, H-5″). 13C-NMR (CDCl3,
75 MHz, d): 169.0 (C-1″), 162.6 (C-2), 160.9 (C-7), 158.8
(C-6″), 155.2 (C-8a), 143.3 (C-4), 139.9 (C-10″), 124.0 (C-
7″), 128.9 (C-8″, C-12″), 125.5 (C-6), 126.2 (C-9″, C-11″),
122.8 (C-5), 112.3 (C-4a), 111.7 (C-3), 97.2 (C-8), 89.1 (C-
20), 88.7 (C-2″), 83.4 (C-3″), 51.3 (C-40), 29.2 (C-30), 29.1,
23.2, 20.9, 21.0, 13.5 (C-50, C-60, C-4″, C-5″, C-13″); DCI-
HRMS [M+H]+ calcd. for (C27H27NO6)+: 461.1838, found:
461.1836.
7-oxo-3,7-dihydro-2H-furo[3,2-g]chromen-2-yl)propan-
2-yl 4,5-dimethyl-3-phenyl-4,5-dihydroisoxazole-4-carbox-
ylate 2a
Yield 40%; MP: 190 °C; IR band (NaCl) cmꢁ1: 1422
(C=N); 1H NMR (CDCl3, 300 MHz, d):7.64 (1H, d,
J = 9.6 Hz, H-4), 7.41–7.30 (5H, m, H-8″, H-9″, H-10″,
H-11″, H-12″), 7.26 (1H, s, H-5), 6.60 (1H, s, H-8), 6.25
(1H, d, J = 9.6 Hz, H-3), 4.94 (1H, dd, J1 = 7.5 Hz,
J2 = 9.3 Hz, H-20), 3.47 (1H, q, J = 7.2 Hz, H-3″), 3.38–
2.95 (2H, m, H-30a,b), 1.66 (3H, s, H-60), 1.61 (3H, s,
H-50), 1.52 (3H, s, H-4″), 1.21 (3H, d, J = 7.2 Hz, H-5″).
13C-NMR (CDCl3, 75 MHz, d): 169.7 (C-1″), 163.3 (C-2),
161.6 (C-7), 159.6 (C-6″), 155.9 (C-8a), 144.0 (C-4), 130.4
(C-7″), 129.0 (C-10″), 128.5 (C-6), 127.1 (C-8″, C-12″),
124.8 (C-9″, C-11″), 123.7 (C-5), 113.1 (C-4a), 112.5 (C-
3), 97.9 (C-8), 90.0 (C-20), 89.4 (C-2″), 84.2 (C-3″), 51.9
(C-40), 29.8 (C-30), 23.9, 22.2, 21.7, 14.1 (C-50,C-60, C-4″,
C-5″); DCI-HRMS [M+H]+ calcd. for (C26H25NO6)+:
447.1682, found: 447.1686.
7-oxo-3,7-dihydro-2H-furo[3,2-g]chromen-2-yl)propan-
2-yl 4,5-dimethyl-3-(p-tolyl)-4,5-dihydroisoxazole-4-car-
boxylate 2b0
Yield 39%; MP: 178 °C; IR band (NaCl) cmꢁ1: 1422
(C=N); 1H NMR (CDCl3, 300 MHz, d): 7.63 (1H, d,
J = 9.3 Hz, H-4), 7.45 (2H, d, J = 8.1 Hz, H-8″, H-12″),
7.24 (2H, d, J = 8.1 Hz, H-9″, H-11″), 7.18 (1H, s, H-5),
6.76 (1H, s, H-8), 6.26 (1H, d, J = 9.6 Hz, H-3), 5.08 (1H,
dd, J1 = 9.6 Hz, J2 = 6.6 Hz, H-20), 3.49–3.24 (2H, m, H-
30a,b), 3.11 (1H, q, J = 7.2 Hz, H-3″), 2.37 (3H, s, H-13″),
1.66 (3H, s, H-60), 1.62 (3H, s, H-50), 1.39 (3H, s, H-4″),
1.16 (3H, d, J = 7.2 Hz, H-5″). 13C-NMR (CDCl3,
75 MHz, d): 169.5 (C-1″), 163.9 (C-2), 160.7 (C-7), 159.2
(C-6″), 156.4 (C-8a), 144.0 (C-4), 141.3 (C-10″), 130.3 (C-
8″, C-12″), 127.5 (C-9″, C-11″), 126.1 (C-7″), 125.1 (C-6),
123.8 (C-5), 113.4 (C-4a), 113.1 (C-3), 98.5 (C-8), 89.9 (C-
20), 89.5 (C-2″), 84.9 (C-3″), 51.7 (C-40), 30.3 (C-3″), 24.3,
22.6, 22.1, 21.9, 14.0 (C-50, C-60, C-4″, C-5″, C-13″); DCI-
HRMS [M+H]+ calcd. for (C27H27NO6)+: 461.1838, found:
461.1836.
7-oxo-3,7-dihydro-2H-furo[3,2-g]chromen-2-yl)propan-2-
yl 4,5-dimethyl-3-phenyl-4,5-dihydroisoxazole-4-carboxy-
late 2a0
Yield 44%; MP: 136 °C; IR band (NaCl) cmꢁ1: 1422
(C=N); 1H NMR (CDCl3, 300 MHz, d): 7.62 (1H, d,
J = 9.6 Hz, H-4), 7.56–7.38 (5H, m, H-8″, H-9″, H-10″,
H-11″, H-12″), 7.26 (1H, s, H-5), 6.75 (1H, s, H-8), 6.25
(1H, d, J = 9.6 Hz, H-3), 5.01 (1H, dd, J1 = 6.9 Hz,
J2 = 9.6 Hz, H-20), 3.48–3.24 (2H, m, H-30a,b), 3.17 (1H,
q, J = 7.5 Hz, H-3″), 1.66 (3H, s, H-60), 1.62 (3H, s, H-50),
1.40 (3H, s, H-4″), 1.19 (3H, d, J = 7.5 Hz, H-5″). 13C-
NMR (CDCl3, 75 MHz, d): 168.6 (C-1″), 163.1 (C-2),
161.1 (C-7), 159.9 (C-6″), 155.6 (C-8a), 143.4 (C-4), 130.1
(C-7″), 128.7 (C-10″), 128.1 (C-8″, C-12″), 127.1 (C-6),
126.7 (C-9″, C-11″), 124.1 (C-5), 112.6 (C-4a), 112.3 (C-
3), 97.6 (C-8), 89.3 (C-20), 88.6 (C-2″), 84.1 (C-3″), 50.8
(C-40), 29.5 (C-30), 23.5, 21.7, 21.1, 13.7 (C-50,C-60, C-4″,
C-5″); DCI-HRMS [M+H]+ calcd. for (C26H25NO6)+:
447.1682, found: 447.1686.
7-oxo-3,7-dihydro-2H-furo[3,2-g]chromen-2-yl)propan-2-
yl
3-(4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroisoxa-
zole-4-carboxylate 2c
Yield 41%; MP: 112 °C; IR band (NaCl) cmꢁ1: 1422
(C=N); 1H NMR (CDCl3, 300 MHz, d): 7.64 (1H, d,
J = 9.6 Hz, H-4), 7.33 (2H, d, J = 9 Hz, H-8″, H-12″),
7.26 (1H, s, H-5), 6.82 (2H, d, J = 9 Hz, H-9″, H-11″),
6.60 (1H, s, H-8), 6.24 (1H, d, J = 9.6 Hz, H-3), 4.93 (1H,
dd, J1 = 9.3 Hz, J2 = 7.5 Hz, H-20), 4.14 (1H, q,
J = 7.2 Hz, H-3″), 3.90–3.76 (2H,m, H-30a,b), 3.81 (3H, s,
H-13″), 1.66 (3H, s, H-60), 1.6 (3H, s, H-50), 1.5 (3H, s, H-
4″), 1.19 (3H, d, J = 7.2 Hz, H-5″). 13C-NMR (CDCl3,
75 MHz, d): 168.9 (C-1″), 162.5 (C-2), 160.4 (C-7), 158.4
(C-6″), 143.2 (C-4), 141.6 (C-10″), 127.6 (C-7″), 123.9 (C-
8″, C-12″), 122.7 (C-9″, C-11″), 121.6 (C-5), 113.5 (C-4a),
111.6 (C-3), 97.0 (C-8), 88.6 (C-20), 83.3 (C-3″), 83.2 (C-
2″), 54.7 (C-40), 54.4 (C-13″), 29.1 (C-30), 23.1, 21.2, 20.8,
7-oxo-3,7-dihydro-2H-furo[3,2-g]chromen-2-yl)propan-
2-yl 4,5-dimethyl-3-(p-tolyl)-4,5-dihydroisoxazole-4-car-
boxylate 2b
Yield 45%; MP: 196 °C; IR band (NaCl) cmꢁ1: 1422
(C=N); 1H NMR (CDCl3, 300 MHz, d): 7.64 (1H, d,
© 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2018), pp. **–**
3

Bioactivity of (-)-deltoin derivatives
Mansour Znati et al.
13.4 (C-50, C-60, C-4″, C-5″); DCI-HRMS [M+H]+ calcd.
dd, J1 = 9 Hz, J2 = 7.5 Hz, H-20), 3.98 (2H, t, J = 6.6 Hz,
H-13″), 3.99 (1H, q, J = 7.2 Hz, H-3″), 3.42–3.32 (2H, m,
H-30a,b), 1.82 (2H, q, J = 6.9 Hz, H-14″), 1.64 (3H, s, H-
60), 1.58 (3H, s, H-50), 1.55 (2H, six, J = 6.6 Hz, H-15″),
1.48 (3H, s, H-4″), 1.31 (3H, d, J = 6.9 Hz, H-5″), 0.98
(3H, t, J = 7.3 Hz, H-16″). 13C-NMR (CDCl3, 75 MHz, d):
170.2 (C-1″), 163.7 (C-2), 162.0 (C-7), 161.3 (C-6″), 159.7
(C-10″), 156.3 (C-8a), 144.4 (C-4), 128.9 (C-7″), 125.1 (C-
8″, C-12″), 124.0 (C-6), 121.0 (C-9″, C-11″), 115.3 (C-5),
113.4 (C-4a), 112.9 (C-3), 98.3 (C-8), 90.0 (C-20), 89.8 (C-
2″), 84.5 (C-3″), 68.4 (C-13″), 52.4 (C-40), 31.8 (C-14″),
30.2 (C-30), 24.3 (C-15″), 22.5, 22.0, 19.8, 14.7, 14.5 (C-50,
C-60, C-4″, C-5″, C-16″); DCI-HRMS [M+H]+ calcd. for
(C30H33NO7)+: 519.2257, found: 519.2249.
for (C27H27NO7)+:477.1788, found: 477.1781.
7-oxo-3,7-dihydro-2H-furo[3,2-g]chromen-2-yl)propan-2-
yl 3-(4-methoxyphenyl)-4,5-dimethyl-4,5-dihydroisoxazole-
4-carboxylate 2c0
Yield 46%; MP: 102 °C; IR band (NaCl) cmꢁ1: 1422
(C=N); 1H NMR (CDCl3, 300 MHz, d): 7.62 (1H, d,
J = 9.6 Hz, H-4), 7.48 (2H, d, J = 8.7 Hz, H-8″, H-12″),
7.23 (1H, s, H-5), 6.9 (2H, d, J = 8.7 Hz, H-9″, H-11″),
6.74 (1H, s, H-8), 6.23 (1H, d, J = 9.6 Hz, H-3), 4.99 (1H,
dd, J1 = 9.6 Hz, J2 = 6.6 Hz, H-20), 4.13 (1H, q,
J = 7.2 Hz, H-3″), 3.81 (3H, s, H-13″), 3.38–2.99 (2H, m,
H-30a,b), 1.65 (3H, s, H-60), 1.60 (3H, s, H-50), 1.23 (3H, s,
H-4″), 1.16 (3H, d, J = 7.2 Hz, H-5″). 13C-NMR (CDCl3,
75 MHz, d): 168.6 (C-1″), 163.1 (C-2), 161.1 (C-7), 159.5
(C-6″), 143.5 (C-10″), 128.2 (C-6), 128.1 (C-7″), 126.4 (C-
8″, C-12″), 123.0 (C-9″, C-11″), 120.5 (C-5), 114.1 (C-4a),
112.1 (C-3), 97.5 (C-8), 88.7 (C-2″), 84.0 (C-3″), 84.0 (C-
20), 55.2 (C-40), 55.2 (C-13″), 29.5 (C-30), 21.7, 21.1, 22.1,
13.7 (C-50, C-60, C-4″, C-5″); DCI-HRMS [M+H]+ calcd.
for (C27H27NO7)+:477.1788, found: 477.1781.
7-oxo-3,7-dihydro-2H-furo[3,2-g]chromen-2-yl)propan-2-
yl 3-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroisoxazole-4-
carboxylate 2e
Yield 34%; MP: 124 °C; IR band (NaCl) cmꢁ1: 1423
(C=N); 1H NMR (CDCl3, 300 MHz, d): 7.66 (1H, d,
J = 9.6 Hz, H-4), 7.55 (2H, d, J = 8.4 Hz, H-8″, H-12″),
7.29 (1H, s, H-5), 7.42 (2H, d, J = 8.4 Hz, H-9″, H-11″),
6.79 (1H, s, H-8), 6.30 (1H, d, J = 9.6 Hz, H-3), 5.05 (1H,
t, J = 6.6 Hz, H-20), 3.69 (1H, q, J = 7.2 Hz, H-3″), 3.36–
3.04 (2H, m, H-30a,b), 1.70 (3H, s,H-60), 1.65 (3H, s, H-50),
1.43 (3H, s, H-4″), 1.24 (3H, d, J = 7.2 Hz, H-5″). 13C-
NMR (CDCl3, 75 MHz, d): 168.8 (C-1″), 163.2 (C-2),
161.2 (C-7), 159.1 (C-6″), 155.8 (C-8a), 143.7 (C-4), 126.3
(C-10″), 129.2 (C-7″), 128.7 (C-8″, C-12″), 128.2 (C-6),
124.3 (C-5), 123.2 (C-9″, C-11″), 112.8 (C-4a), 112.5 (C-
3), 97.8 (C-8), 89.7 (C-20), 88.8 (C-3″), 84.5 (C-2″), 50.9
(C-40), 29.7 (C-30), 22.7, 21.9, 21.3, 14.2 (C-50, C-60, C-4″,
C-5″); DCI-HRMS [M+H]+ calcd. for (C26H24ClNO6)+:
481.1292, found: 481.129.
7-oxo-3,7-dihydro-2H-furo[3,2-g]chromen-2-yl)propan-2-
yl 3-(4-butoxyphenyl)-4,5-dimethyl-4,5-dihydroisoxazole-
4-carboxylate 2d
Yield 39%; MP: 143 °C; IR band (NaCl) cmꢁ1: 1422
(C=N); 1H NMR (CDCl3, 300 MHz, d): 7.63 (1H, d,
J = 9.6 Hz, H-4), 7.48 (2H, d, J = 9 Hz, H-8″, H-12″), 7.24
(1H, s, H-5), 6.90 (2H, d, J = 9 Hz, H-9″, H-11″), 6.76 (1H,
s, H-8), 6.25 (1H, d, J = 9.6 Hz, H-3), 4.97 (1H, dd,
J1 = 9.6 Hz, J2 = 7.5 Hz, H-20), 4.12 (1H, q, J = 6.9 Hz, H-
3″), 3.99 (2H, t, J = 6.6 Hz, H-13″), 3.40–3.12 (2H, m, H-
30a,b), 1.79 (2H, q, J = 6.6 Hz, H-14″), 1.66 (3H, s, H-60),
1.61 (3H, s, H-50), 1.49 (2H, six, J = 7.5 Hz, H-15″), 1.37
(3H, s, H-4″), 1.17 (3H, d, J = 6.6 Hz, H-5″), 0.99 (3H, t,
J = 7.5 Hz, H-16″). 13C-NMR (CDCl3, 75 MHz, d): 169.2
(C-1″), 163.6 (C-2), 161.6 (C-7), 161.1 (C-6″), 160.1 (C-10″),
156.1 (C-8a), 144.0 (C-4), 128.7 (C-7″), 124.8 (C-8″, C-12″),
123.5 (C-6), 120.8 (C-9″, C-11″), 115.2 (C-5), 113.1 (C-4a),
112.8 (C-3), 98.1 (C-8), 89.5 (C-20), 89.2 (C-2″), 84.6 (C-3″),
68.2 (C-13″), 51.4 (C-40), 31.5 (C-14″), 30.0 (C-30), 24.0 (C-
15″), 22.2, 21.6, 19.5, 14.3, 14.2 (C-50, C-60, C-4″, C-5″, C-
16″); DCI-HRMS [M+H]+ calcd. for (C30H33NO7)+:
519.2257, found: 519.2249.
7-oxo-3,7-dihydro-2H-furo[3,2-g]chromen-2-yl)propan-2-
yl 3-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroisoxazole-4-
carboxylate 2e0
Yield 30%; MP: 116 °C; IR band (NaCl) cmꢁ1: 1422
(C=N); 1H NMR (CDCl3, 300 MHz, d): 7.67 (1H, d,
J = 9.6 Hz, H-4), 7.38 (2H, d, J = 7.8 Hz, H-8″, H-12″),
7.37 (1H, s, H-5), 7.31 (2H, d, J = 7.8 Hz, H-9″, H-11″),
6.65 (1H, s, H-8), 6.29 (1H, d, J = 9.6 Hz, H-3), 4.99 (1H,
t, J = 9 Hz, H-20), 3.44 (1H, q, J = 7.2 Hz, H-3″), 3.52–
3.32 (2H, m, H-30a,b), 1.70 (3H, s, H-60), 1.64 (3H, s,
H-50), 1.59 (3H, s, H-4″), 1.23 (3H, d, J = 7.2 Hz, H-5″).
13C-NMR (CDCl3, 75 MHz, d): 169.5 (C-1″), 163.4 (C-2),
161.6 (C-7), 158.9 (C-6″), 156.0 (C-8a), 144.0 (C-4), 126.5
(C-10″), 129.4 (C-7″), 128.3 (C-8″, C-12″), 127.1 (C-6),
124.7 (C-5), 123.7 (C-9″, C-11″), 113.1 (C-4a), 112.7 (C-
3), 98.0 (C-8), 90.3 (C-20), 89.4 (C-3″), 84.5 (C-2″), 51.1
(C-40), 30.1 (C-30), 24.0, 22.2, 21.8, 14.3 (C-50, C-60, C-4″,
C-5″); DCI-HRMS [M+H]+ calcd. for (C26H24ClNO6)+:
481.1292, found: 481.1298.
7-oxo-3,7-dihydro-2H-furo[3,2-g]chromen-2-yl)propan-2-
yl 3-(4-butoxyphenyl)-4,5-dimethyl-4,5-dihydroisoxazole-
4-carboxylate 2d0
Yield 38%; MP: 170 °C; IR band (NaCl) cmꢁ1: 1422
(C=N); 1H NMR (CDCl3, 300 MHz, d): 7.67 (1H, d,
J = 9.6 Hz, H-4), 7.37 (2H, d, J = 9 Hz, H-8″, H-12″),
7.29 (1H, s, H-5), 6.86 (2H, d, J = 9 Hz, H-9″, H-11″),
6.65 (1H, s, H-8), 6.27 (1H, d, J = 9.6 Hz, H-3), 4.98 (1H,
4
© 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2018), pp. **–**

Mansour Znati et al.
Bioactivity of (-)-deltoin derivatives
7-oxo-3,7-dihydro-2H-furo[3,2-g]chromen-2-yl)propan-
2-yl 3-(6-chloropyridin-3-yl)-4,5-dimethyl-4,5-dihydroi-
soxazole-4-carboxylate 2f, f0
mixture has been refluxed for 48 h. The resulting residue
purified by flash chromatography (cyclohexane/EtOAc
(60:40)) has given the corresponding heterocycles 3a,a0-3e,e0.
Yield 71%; MP: 118 °C; IR band (NaCl) cmꢁ1: 1422
7-oxo-3,7-dihydro-2H-furo[3,2-g]chromen-2-yl)propan-
2-yl 2,3-dimethyl-1-phenylaziridine-2-carboxylate 3a,a0
Yield 65%; MP: 115 °C; IR band (NaCl) cmꢁ1: 1265 (C-
N); 1H NMR (CDCl3, 300 MHz, d): 3a: 7.62 (1H, d,
J = 9.6 Hz, H-4), 7.18 (1H, s, H-5), 7.16 (2H, dd,
J1 = 8.7 Hz, J2 = 1.2 Hz, H-7″, H-11″), 6.74 (1H, dd,
J1 = 8.4 Hz, J2 = 2.7 Hz, H-9″), 6.73 (1H, s, H-8), 6.55
(2H, dd, J1 = 8.1 Hz, J2 = 1.2 Hz, H-8″, H-10″), 6.24 (1H,
d, J = 9.6 Hz, H-3), 4.02 (1H, dd, J1 = 9.6 Hz, J2 = 7.2 Hz,
H-20), 3.98 (1H, q, J = 6.9 Hz, H-3″), 3.96 (2H, m, H-30a,
b), 1.62(3H, d, J = 6.9 Hz, H-5″), 1.47 (3H, s, H-60), 1.41
(3H, s, H-50), 1.39 (3H, s, H-4″). 13C-NMR (CDCl3,
75 MHz, d): 173.9 (C-1″), 163.4 (C-2), 161.6 (C-7), 155.9
(C-8a), 146.8 (C-6″), 143.8 (C-4), 129.5 (C-7″, C-11″), 124.6
(C-6), 123.4 (C-5), 123.4 (C-8″, C-10″), 118.6 (C-9″), 112.9
(C-4a), 112.6 (C-3), 98.1 C-8), 88.8 (C-20), 88.6 (C-2″), 83.4
(C-3″), 52.8 (C-40), 29.9 (C-30) 21.6, 21.3, 19.6, 19.0 (C-50,
C-60, C-4″, C-5″). 1H NMR (CDCl3, 300 MHz, d): 3a0: 7.61
(1H, d, J = 9.3 Hz, H-4), 7.18 (1H, s, H-5), 7.16 (2H, dd,
J1 = 8.7 Hz, J2 = 1.2 Hz, H-7″, H-11″), 6.74 (1H, dd,
J1 = 8.4 Hz, J2 = 2.7 Hz, H-9″), 6.71 (1H, s, H-8), 6.55
(2H, dd, J1 = 8.1 Hz, J2 = 1.2 Hz, H-8″, H-10″), 6.25 (1H,
d, J = 9.3 Hz, H-3), 4.02 (2H, dd, J1 = 9.6 Hz, J2 = 7.2 Hz,
H-20), 3.98 (1H, q, J = 6.9 Hz, H-3″), 3.96 (4H, m, H-30a,
b), 1.62(6H, d, J = 6.9 Hz, H-5″), 1.47 (3H, s, H-60), 1.41
(3H, s, H-50), 1.39 (3H, s, H-4″). 13C-NMR (CDCl3,
75 MHz, d): 173.8 (C-1″), 163.4 (C-2), 161.6 (C-7), 155.9
(C-8a), 146.8 (C-6″), 143.8 (C-4), 129.5 (C-7″, C-11″), 124.5
(C-6), 123.4 (C-5), 123.4 (C-8″, C-10″), 118.6 (C-9″), 112.9
(C-4a), 112.6 (C-3), 98.0 (C-8), 88.8 (C-20), 88.6 (C-2″),
83.2 (C-3″), 52.8 (C-40), 29.7 (C-30) 21.6, 21.3, 19.6, 19.0 (C-
50, C-60, C-4″, C-5″); DCI-HRMS [M+H]+ calcd. for
(C25H25NO5)+: 419.1733, found: 419.1738.
1
(C=N); H NMR (CDCl3, 300 MHz, d): 2f: 8.60 (1H, d,
J = 2.4 Hz, H-8″), 7.94 (1H, dd, J1 = 8.4 Hz, J2 = 2.4 Hz,
H-12″), 7.76 (1H, d, J = 8.4 Hz, H-11″), 7.66 (1H, d,
J = 9.6 Hz, H-4), 7.41 (1H, s, H-5), 6.75 (1H, s, H-8), 6.27
(1H, d, J = 9.6 Hz, H-3), 4.96 (1H, t, J = 8.4 Hz, H-20),
3.49–3.21 (2H, m, H-30a,b), 3.43 (1H, q, J = 7.2 Hz, H-3″),
1.66 (3H, s, H-60), 1.63 (3H, s, H-50), 1.46 (3H, s, H-40), 1.24
(3H, d, J = 7.2 Hz, H-5″). 13C-NMR (CDCl3, 75 MHz, d):
d:168.5 (C-1″), 163.0 (C-2), 158.1 (C-6″), 157.9 (C-8″),
155.9 (C-8a), 152.6 (C-10″), 147.4 (C-4), 144.9 (C-12″),
136.5 (C-7″), 124.3 (C-6), 123.7 (C-11″), 123.1 (C-5), 112.6
(C-4a), 112.1 (C-3), 97.6 (C-8), 90.2 (C-20), 89.9 (C-2″), 84.4
(C-3″), 50.7 (C-40), 31.7 (C-30), 23.3, 21.6, 21.3, 13.9 (C-50,
1
C-60, C-4″, C-5″). H NMR (CDCl3, 300 MHz, d): 2f0:8.58
(1H, d, J = 2.4 Hz, H-8″), 7.94 (1H, dd, J1 = 8.4 Hz,
J2 = 2.4 Hz, H-12″), 7.76 (1H, d, J = 8.4 Hz, H-11″), 7.64
(1H, d, J = 9.3 Hz, H-4), 7.38 (1H, s, H-5), 6.61 (1H, s, H-
8), 6.26 (1H, d, J = 9.3 Hz, H-3), 4.96 (1H, t, J = 8.4 Hz,
H-20), 3.49–3.21 (2H, m, H-30a,b), 3.43 (1H, q, J = 7.2 Hz,
H-3″), 1.66 (3H, s, H-60), 1.63 (3H, s, H-50), 1.46 (3H, s, H-
4″), 1.24 (3H, d, J = 7.2 Hz, H-5″). 13C-NMR (CDCl3,
75 MHz, d): 168.1 (C-1″), 162.8 (C-2), 158.1 (C-6″), 157.9
(C-8″), 155.5 (C-8a), 152.6 (C-10″), 147.4 (C-4), 143.5 (C-
12″), 136.2 (C-7″), 124.1 (C-6), 123.3 (C-11″), 123.0 (C-5),
112.6 (C-4a), 112.1 (C-3), 97.6 (C-8), 90.2 (C-20), 88.9 (C-
2″), 84.1 (C-3″), 50.7 (C-40), 31.7 (C-30), 22.4, 21.5, 21.0,
13.6 (C-50, C-60, C-4″, C-5″); DCI-HRMS [M+H]+ calcd. for
(C25H23ClN2O6)+: 482.1245, found: 482.1243.
Synthesis of substituted azidobenzenes
The azidobenzenes have been prepared according to the
general procedure.[21] Substituted aniline (0.018 mol) was
dissolved in 9.4 ml 1 : 1 ratio of HCl : H2O and put in a
round-bottom flask equipped with a stirrer. The reaction
has been agitated at 0–5 °C; sodium nitrite (0.018 mol)
was dissolved in 5.13 ml of ice-cold water and added drop-
wise; sodium azide (0.018 mol) was dissolved in 11.3 ml of
water and added dropwise; and then, the reaction has been
made to continue for 30 min. The resultant precipitate has
been extracted with chloroform and washed successively
with water. The organic layer has been dried over anhy-
drous sodium sulfate, and the solvent stripped out in a
rotary evaporator to get azidobenzenes.
7-oxo-3,7-dihydro-2H-furo[3,2-g]chromen-2-yl)propan-
2-yl 1-(4-chlorophenyl)-2,3-dimethylaziridine-2-carboxy-
late 3b,b0
Yield 78%; MP: 95 °C; IR band (NaCl) cmꢁ1: 1267 (C-
1
N), 749 (C-Cl); H NMR (CDCl3, 300 MHz, d): 3b: 7.62
(1H, d, J = 9.6 Hz, H-4), 7.25 (1H, s, H-5), 7.11 (2H, d,
J = 8.4 Hz, H-7″, H-11″), 6.72 (1H, s, H-8), 6.47 (2H, d,
J = 9 Hz, H-8″, H-10″), 6.24 (1H, d, J = 9.6 Hz, H-3),
5.01 (1H, dd, J1 = 9.6 Hz, J2 = 7 Hz, H-20), 3.96 (1H, q,
J = 6.9 Hz, H-3″), 3.10–2.93 (2H, m, H-30a,b), 1.53 (3H,
d, J = 6.9 Hz, H-5″), 1.48 (3H, s, H-60), 1.41 (3H, s, H-50),
1.38 (3H, s, H-4″). 13C-NMR (CDCl3, 75 MHz, d): 173.1
(C-1″), 163.0 (C-2), 161.1 (C-7), 155.5 (C-8a), 146.4 (C-4),
143.4, (C-6″), 129.0 (C-9″), 128.9 (C-7″, C-11″), 123.0 (C-
6), 122.7 (C-5), 114.3 (C-8″, C-10″), 112.6 (C-4a), 112.2
(C-3), 97.7 (C-8), 88.4 (C-20), 88.2 (C-3″), 83.2 (C-2″),
Preparation of compounds 3a,a0-3e,e0
To compound 1 (0.1 g, 0.32 mmol) in refluxing toluene, the
appropriate azidobenzene (2 equiv.) has been added and the
© 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2018), pp. **–**
5

Bioactivity of (-)-deltoin derivatives
Mansour Znati et al.
52.7 (C-40), 29.5 (C-30), 21.8, 21.2, 18.5, 15,0 (C-50, C-60,
J = 9.6 Hz, H-4), 7.19 (1H, s, H-5), 6.73 (1H, s, H-8), 6.55
(2H, d, J = 8.4 Hz, H-7″, H-11″), 6.51 (2H, d, J = 8.4 Hz,
H-8″, H-10″), 6.25 (1H, d, J = 9.6 Hz, H-3), 5.02 (1H, dd,
J1 = 9.6 Hz, J2 = 7.2 Hz, H-20), 4.15 (1H, q, J = 7.2 Hz,
H-3″), 3.23 (2H, m, H-30a,b), 1.74 (3H, d, J = 7.2 Hz, H-
5″), 1.59 (3H, s, H-60), 1.52 (3H, s, H-50), 1.42 (3H, s, H-
4″). 13C-NMR (CDCl3, 75 MHz, d): 173.1 (C-1″), 163.3
(C-2), 161.5 (C-7), 156.0 (C-8a), 149.3 (C-6″), 143.8 (C-4),
126.8 (C-6), 124.4 (C-7″, C-11″), 124.3 (C-12″), 123.5 (C-
5), 120.2 (C-9″), 112.9 (C-4a), 112.6 (C-8″, C-10″), 112.5
(C-3), 98.1 (C-8), 88.9 (C-20), 88.8 (C-3″), 83.8 (C-2″),
52.5 (C-40), 29.9 (C-30), 22.2, 21.7, 18.8, 14.0 (C-50, C-60,
C-4″, C-5″). 1H NMR (CDCl3, 300 MHz, d): 3d0: 7.61 (1H,
d, J = 9.6 Hz, H-4), 7.13 (1H, s, H-5), 6.71 (1H, s, H-8),
6.54 (2H, d, J = 8.4 Hz, H-7″, H-11″), 6.51 (2H, d,
J = 8.4 Hz, H-8″, H-10″), 6.23 (1H, d, J = 9.6 Hz, H-3),
4.99 (1H, dd, J1 = 9.6 Hz, J2 = 7.2 Hz, H-20), 4.15 (1H, q,
J = 7.2 Hz, H-3″), 3.08 (2H, m, H-30a,b), 1.54 (3H, d,
J = 7.0 Hz, H-5″), 1.59 (3H, s, H-60), 1.52 (3H, s, H-50),
1.42 (3H, s, H-4″). 13C-NMR (CDCl3, 75 MHz, d): 173.1
(C-1″), 163.3 (C-2), 161.5 (C-7), 156.0 (C-8a), 149.2 (C-
6″), 143.8 (C-4), 126.8 (C-6), 124.4 (C-7″, C-11″), 124.3
(C-12″), 123.5 (C-5), 120.2 (C-9″), 112.7 (C-4a), 112.6 (C-
8″, C-10″), 112.5 (C-3), 98.0 (C-8), 88.9 (C-20), 88.6 (C-
3″), 83.7 (C-2″), 52.2 (C-40), 29.9 (C-30), 21.9, 21.4, 18.7,
14.0 (C-50, C-60, C-4″, C-5″); DCI-HRMS [M+H]+ calcd.
for (C26H24F3NO5)+: 487.1607, found: 487.1604.
1
C-4″, C-5″). H NMR (CDCl3, 300 MHz, d): 3b0:7.61 (1H,
d, J = 9.3 Hz, H-4), 7.19 (1H, s, H-5), 7.10 (2H, d,
J = 8.4 Hz, H-7″, H-11″), 6.70 (1H, s, H-8), 6.44(2H, d,
J = 9 Hz, H-8″, H-10″), 6.24 (1H, d, J = 9.6 Hz, H-3),
4.96 (1H, dd, J1 = 9.6 Hz, J2 = 7.0 Hz, H-20), 3.96 (1H, q,
J = 6.9 Hz, H-3″), 3.10–2.93 (2H, m, H-30a,b), 1.53 (3H,
d, J = 6.9 Hz, H-5″), 1.48 (3H, s, H-60), 1.41 (3H, s, H-50),
1.38 (3H, s, H-4″). 13C-NMR (CDCl3, 75 MHz, d): 173.1
(C-1″), 162.9 (C-2), 161.1 (C-7), 155.5 (C-8a), 145.0 (C-4),
143.4, (C-6″), 129.0 (C-9″), 128.9 (C-7″, C-11″), 123.0 (C-
6), 122.7 (C-5), 114.1 (C-8″, C-10″), 112.6 (C-4a), 112.2
(C-3), 97.6 (C-8), 88.4 (C-20), 88.2 (C-3″), 83.0 (C-2″),
52.5 (C-40), 29.5 (C-30), 21.5, 20.8, 18.4, 15,0 (C-50, C-60,
C-4″,
C-5″)
DCI-HRMS
[M+H]+
calcd.
for
(C25H24ClNO5)+: 453.1343, found: 453.1429.
7-oxo-3,7-dihydro-2H-furo[3,2-g]chromen-2-yl)propan-
2-yl 2,3-dimethyl-1-(p-tolyl)aziridine-2-carboxylate 3c,c0
Yield 72%; MP: 110 °C; IR band (NaCl) cmꢁ1: 1265 (C-
N); 1H NMR (CDCl3, 300 MHz, d): 3c: 7.62 (1H, d,
J = 9.3 Hz, H-4), 7.18 (1H, s, H-5), 6.97 (2H, d,
J = 8.1 Hz, H-7″, H-11″), 6.73 (1H, s, H-8), 6.45 (2H, d,
J = 8.1 Hz, H-8″, H-10″), 6.24 (1H, d, J = 9.3 Hz, H-3),
5.03–4.99 (1H, m, H-20), 3.98 (1H, q, J = 6.9 Hz, H-3″),
3.22–2.88 (2H, m, H-30a,b), 2.88 (3H, s, H-12″), 1.53 (3H,
d, J = 6.9 Hz, H-5″), 1.47 (3H, s, H-60), 1.37 (3H, s, H-50),
1.34 (3H, s, H-4″). 13C-NMR (CDCl3, 75 MHz, d): 174.1
(C-1″), 163.5 (C-2), 161.6 (C-7), 155.9 (C-8a), 144.5 (C-
6″), 143.8 (C-4), 130.0 (C-9″), 129.0 (C-7″, C-11″), 124.6
(C-6), 123.4 (C-5), 113.8 (C-4a), 112.9 (C-8″, C-10″),
112.9 (C-3), 98.1 (C-8), 88.8 (C-20), 88.6 (C-3″), 83.3 (C-
2″), 53.4 (C-40), 32.1 (C-30), 29.6, 21.6, 20.6, 19.0, 14.7 (C-
7-oxo-3,7-dihydro-2H-furo[3,2-g]chromen-2-yl)propan-
2-yl 1-(3,5-dichlorophenyl)-2,3-dimethylaziridine-2-car-
boxylate 3e,e0
Yield 82%; MP: 100 °C; IR band (NaCl) cmꢁ1: 1266 (C-
N); 1H NMR (CDCl3, 300 MHz, d): 3e:7.64 (1H, d,
J = 9.6 Hz, H-4), 7.22 (1H, s, H-5), 6.74 (1H, s, H-8), 6.71
(1H, dd, J1 = 1.5 Hz, J2 = 3.3 Hz, H-9″), 6.39 (1H, d,
J = 1.5 Hz, H-7″), 6.32 (1H, d, J = 1.5 Hz, H-11″), 6.25
(1H, d, J = 9.3 Hz, H-3), 5.06 (1H, dd, J1 = 9.6 Hz,
J2 = 7.5 Hz, H-20), 4.15 (1H, q, J = 6.9 Hz, H-3″), 3.35
(2H, m, H-30a,b), 1.57 (3H, d, J = 6.9 Hz, H-5″), 1.52 (3H,
s, H-60), 1.40 (3H, s, H-50), 1.25 (3H, s, H-4″). 13C-NMR
(CDCl3, 75 MHz, d): 172.8 (C-1″), 163.2 (C-2), 161.1 (C-
7), 155.8 (C-8a), 148.3 (C-8″), 148.2 (C-6″), 143.7 (C-4),
135.6 (C-10″), 124.2 (C-6), 123.8 (C-9″), 123.4 (C-5), 112.5
(C-7″), 111.3 (C-4a), 111.5 (C-3), 98.0 (C-8), 88.7 (C-20),
88.4 (C-3″), 83.7 (C-2″), 52.2 (C-40), 29.8 (C-30), 22.4,
1
50, C-60, C-4″, C-5″, C-12″). H NMR (CDCl3, 300 MHz,
d): 3c0: 7.61 (1H, d, J = 9.6 Hz, H-4), 7.16 (1H, s, H-5),
6.97 (2H, d, J = 8.1 Hz, H-7″, H-11″), 6.71 (1H, s, H-8),
6.45 (2H, d, J = 8.1 Hz, H-8″, H-10″), 6.24 (1H, d,
J = 9.3 Hz, H-3), 5.03–4.99 (1H, m, H-20), 3.98 (1H, q,
J = 6.9 Hz, H-3″), 3.22–2.88 (2H, m, H-30a,b), 2.88 (3H, s,
H-12″), 1.53 (3H, d, J = 6.9 Hz, H-5″), 1.47 (3H, s, H-60),
1.37 (3H, s, H-50), 1.34 (3H, s, H-4″). 13C-NMR (CDCl3,
75 MHz, d): 174.0 (C-1″), 163.4 (C-2), 161.6 (C-7), 155.9
(C-8a), 144.4 (C-6″), 143.8 (C-4), 130.0 (C-9″), 129.0 (C-
7″, C-11″), 124.5 (C-6), 123.4 (C-5), 113.8 (C-4a), 112.9
(C-8″, C-10″), 112.6 (C-3), 98.0 (C-8), 88.8 (C-20), 88.6
(C-3″), 83.2 (C-2″), 53.2 (C-40), 32.1 (C-30), 29.5, 21.2,
19.0, 19.0, 14.7 (C-500, C-60, C-4″, C-5″, C-12″); DCI-
HRMS [M+H]+ calcd. for (C26H27NO5)+: 433.1889, found:
433.1887.
1
18.6, 14.3, 14.2 (C-50, C-60, C-4″, C-5″). H NMR (CDCl3,
300 MHz, d): 3e0:7.62 (1H, d, J = 9.3 Hz, H-4), 7.17 (1H,
s, H-5), 6.72 (1H, s, H-8), 6.71 (1H, dd, J1 = 1.5 Hz,
J2 = 3.3 Hz, H-9″), 6.39 (1H, d, J = 1.5 Hz, H-7″), 6.32
(1H, d, J = 1.5 Hz, H-11″), 6.24 (1H, d, J = 9.6 Hz, H-3),
4.96 (1H, dd, J1 = 9.6 Hz, J2 = 7.5 Hz, H-20), 4.15 (1H, q,
J = 6.9 Hz, H-3″), 3.14 (2H, m, H-30a,b), 1.57 (3H, d,
J = 6.9 Hz, H-5″), 1.52 (3H, s, H-60), 1.40 (3H, s, H-50),
1.25 (3H, s, H-4″). 13C-NMR (CDCl3, 75 MHz, d): 172.8
7-oxo-3,7-dihydro-2H-furo[3,2-g]chromen-2-yl)propan-
2-yl 2,3-dimethyl-1-(4-(trifluoromethyl)phenyl)aziridine-
2-carboxylate 3d,d0
Yield 79%; MP: 120 °C; IR band (NaCl) cmꢁ1: 1265 (C-
N); 1H NMR (CDCl3, 300 MHz, d): 3d: 7.61 (1H, d,
6
© 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2018), pp. **–**

Mansour Znati et al.
Bioactivity of (-)-deltoin derivatives
(C-1″), 163.2 (C-2), 161.1 (C-7), 155.5 (C-8a), 148.3 (C-
8″), 148.2 (C-6″), 143.7 (C-4), 135.6 (C-10″), 124.2 (C-6),
123.8 (C-9″), 123.3 (C-5), 112.5 (C-7″), 111.3 (C-4a), 111.5
(C-3), 97.9 (C-8), 88.7 (C-20), 88.4 (C-3″), 83.5 (C-2″),
52.2 (C-40), 29.7 (C-30), 21.5, 18.6, 14.3, 14.2 (C-50, C-60,
cancer chemotherapy, have been used as positive control
against HCT-116, and IGROV-1 and OVCAR-3, respec-
tively.[23] Cytotoxic activity has been expressed as IC50, and
defined as the concentration of the sample required to
cause a 50% decrease signal. The calculation of the IC50 was
performed by logarithmic regression.
C-4″,
C-5″);
DCI-HRMS
[M+H]+
calcd.
for
(C25H23Cl2NO5)+: 487.0953, found: 487.0960.
Statistical analysis
Biological evaluation
Data from the experiments were subjected to analysis of vari-
ance (ANOVA) using SPSS 16.0 for Windows (SPSS Inc. Chi-
cago, IL, USA). The inhibition data relative to 5-lipoxygenase
inhibition and cytotoxic activity have been transformed using
arcsin-square root (arcsin √x) transformation before ANOVA.
Means were separated at the 5% significance level by a least
significant difference test (Student’s t-test).
5-lipoxygenase inhibitory
The 5-lipoxygenase enzyme has long been known to be an
important modulator of inflammation in other disease
states. The anti-5-lipoxygenase activity of deltoin 1 and its
derivatives (2a,a0–2f,f0, 3a,a0–3e,e0) has been determined on
soya bean lipoxygenase with modifications.[22] One concen-
tration (20 ll) of each compound has been mixed individ-
ually with 150 ll sodium phosphate buffer (pH 7.4)
containing (20 ll) of 5-lipoxygenase and 60 ll of linoleic
acid (3.5 mM), yielding a final volume of 250 ll. However,
the blank does not contain the substrate, but will be added
30 ll of buffer solution. All compounds are resuspended in
the DMSO followed by dilution in the buffer so that the
DMSO does not exceed 1%. The mixture has been incu-
bated at 25 °C for 10 min, and the absorbance has been
determined at 234 nm. The absorption change with the
conversion of linoleic acid to 13-hydroperoxyoctadeca-
9,11-dienoate (characterized by the appearance of the con-
jugated diene at 234 nm) has been flowed for 10 min at
25 °C. Nordihydroguaiaretic acid (NDGA), a phenolic
anti-5-lipoxygenase, was used as a positive control.[22] The
percentages of enzyme activity were obtained at 200 lM. All
measurements were performed in triplicate.
Results and Discussion
Chemistry
(-)-Deltoin 1 was isolated from the ethyl acetate extract of
the flowers of F. lutea, showing on TLC a spot featuring a
characteristic blue fluorescence under UV light. ES-MS of
compound 1 gave a pseudomolecular ion peak [M+H]+ at
m/z 329, which is consistent with the molecular formula
C19H20O5. Its structure was elucidated on the basis of the
1H and 13C NMR spectral data and by comparison with lit-
1
erature.[10] The H NMR spectrum has shown two signals
at dH 6.27 (1H, d, J = 9.3 Hz) and dH 7.65 (1H, d,
J = 9.3 Hz) as AB-type signals, attributable to H-3 and H-
1
4. The same H NMR spectrum displayed an ABX system
at dH 5.13 (1H, t, J = 9.0 Hz, H-20), dH 3.33–3.28 (2H, m,
H-30a,b). These data suggested the presence of the dihydro-
furanocoumarin skeleton in 1. The presence of two closed
singlets at dH 6.78 and 7.31 is attributable to the aromatic
protons H-8 and H-5, respectively. The other signals on the
same spectrum coincide with the spectral data of an ange-
loyl moiety in 1.[13,24]
Cytotoxic activity
The human cancer cell lines (HCT-116, IGROV-1 and
OVCAR-3) have been used for cytotoxic assay.[23] The cells
were grown in RPMI-1640 medium supplemented with
10% fetal calf serum (Gibco, Gaithersburg Maryland,
USA), air and 5% CO2. The isolate was added to a medium
containing 1 9 106 cells/ml, L-glutamine (2 mM) and gen-
tamicin (50 lg/ml), and kept at 37 °C in a fully humidified
atmosphere. After 18 h of incubation at 37 °C in 5% CO2
incubator, the tubes have been centrifuged at 8000g for
10 min. The supernatant has been decanted, and the pellets
have been washed with 20 mM of phosphate-buffered saline
solution. Each pellet has been dissolved in 100 ll (2 mg/
ml) MTT solution in a tube, incubated at 22 °C for 4 h
and centrifuged at 8000g for 10 min. All the pellets have
been dissolved in 500 ll DMSO and read spectrophoto-
metrically at 500 nm. Doxorubicin and tamoxifen, drugs in
The 13C NMR spectrum of compound 1 reinforces the
above spectral data by showing 19 signals including 11
attributed to the dihydrofuranocoumarin system. The
angeloyl fragment was also identified by the observation of
the corresponding carbon atoms at dC 167.2, 123.1, 137.6,
15.7 and 15.4 ppm attributable to C-1″, C-2″, C-3″, C-4″
and C-5″, respectively.[13] Compound 1 has been identified
as (-)-deltoin by its optical rotation power ([a]D = ꢁ20.95,
c = 0.5 mg/ml, CHCl3).
(-)-Deltoin 1 used as a dipolarophile has been treated
with various arylnitrile oxides generated in situ from aro-
matic oxime precursors, in refluxing dichloromethane for
48 h, to give the desired new isoxazolines 2a,a0–2f,f0 in 30–
71% yield. The undertaken reaction proceeded with
© 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2018), pp. **–**
7

Bioactivity of (-)-deltoin derivatives
Mansour Znati et al.
complete regiospecificity to provide two separable
diastereoisomers except 2f,f0 (Scheme 1).
is consistent with the molecular formula C27H27NO6. Fur-
1
thermore, the H NMR spectrum of this compound was
The ratio of diastereoisomers in mixture (2f,f0) has been
compatible with the proposed structure. In addition to the
signals corresponding to the protons introduced by the
dihydofuranocoumarin moiety of (-)-deltoin 1, we have
observed the presence of new signals consequent to a char-
acteristic AA0BB0 pattern for aromatic hydrogens. Examina-
tion at 300 MHz offered excellent resolution with two
doublets at dH 7.45 (2H, d, J = 8.1 Hz, H-8″, H-12″) and
at dH 7.24 (2H, d, J = 8.1 Hz, H-9″, H-11″). The same 1H-
NMR spectrum revealed the presence of characteristic
1
determined from quantitative H NMR spectrum, by the
integration of the peaks. Indeed, it has been found that the
diastereoisomers of the above case were formed in 50 : 50
ratio.
The structures of these compounds have been confirmed
according to their spectral data. Compound 2b0, as an
example, was obtained as a white solid. Its DCI-HRMS gave
pseudomolecular ion peak [M+H]+ at m/z 462.1836, which
Scheme 1 Synthesis of (-)-deltoin derivatives 2a,a0–f,f0.
8
© 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2018), pp. **–**

Mansour Znati et al.
Bioactivity of (-)-deltoin derivatives
signals at dH 3.11 (1H, q, J = 7.2 Hz, H-3″), 1.39 (3H, s,
H-4″) and 1.16 (3H, d, J = 7.2 Hz, H-5″) attributable to
H-3″, (CH3)-4″ and (CH3)-5″ of the isoxazoline ring,
respectively. The 13C-NMR spectrum confirmed the above
spectral data by the observation of signals at dC 130.3
(C-8″, C-12″), 127.5 (C-9″, C-11″), 126.1 (C-7″) and 141.3
(C-10″) relative to carbons of the tolyl ring. The same spec-
trum showed a signal at dC 159.2 attributable to the quater-
nary carbon of the iminic function C-6″.
Following the same way, (-)-deltoin 1 has been treated
according to the 1,3-dipolar cycloaddition with various azi-
dobenzenes as a dipole in refluxing anhydrous toluene for
Scheme 2 Synthesis of (-)-deltoin derivatives 3a,a0–e,e0.
© 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2018), pp. **–**
9

Bioactivity of (-)-deltoin derivatives
Mansour Znati et al.
Table 1 5-lipoxygenase inhibition capacity (per cent inhibition (%)) and cytotoxicity (HCT-116, IGROV-1 and OVCAR-3 cells lines) (IC50 (lM)) of
(-)-deltoin 1 and its derivatives 2a,a0–f,f0 and 3a,a0–e,e0
Cytotoxic activity† (IC50 lM)
Compound
5-lipoxygenase inhibition (%) at 200 lM
HCT-116
IGROV-1
OVCAR-3
1
12.2 ꢀ 1.2f
27.6 ꢀ 6.1d
23.8 ꢀ 5.3e
–
14.3 ꢀ 0.2c
3.3 ꢀ 0.1b*
49.0 ꢀ 2.1f
49.0 ꢀ 1.8e
63.0 ꢀ 5.3f
89.0 ꢀ 3.7
56.0 ꢀ 3.2f
71.0 ꢀ 4.3
65.0 ꢀ 5.1f
63.0 ꢀ 1.6f
31.6 ꢀ 1.7c
>100k
2a
2a0
>100i
g
h
h
g
>100
98.0 ꢀ 3.5
50.0 ꢀ 5.0f
>100i
2b
2b0
21.6 ꢀ 1.1d
g
–
>100
2c
2c0
13.5 ꢀ 6.1f
69.1 ꢀ 1.7f
62.8 ꢀ 1.9f
17.3 ꢀ 0.8c
63.0 ꢀ 3.0f
–
>100i
2d
2d0
23.1 ꢀ 4.6e
26.0 ꢀ 4.1d
23.8 ꢀ 5.3e
>100i
g
>100
>100i
2e
2e0
14.3 ꢀ 0.3c
37.3 ꢀ 0.9e
4.3 ꢀ 0.1b
5.9 ꢀ 0.1b
6.1 ꢀ 0.7b
7.3 ꢀ 0.9b
16.2 ꢀ 0.5c
13.3 ꢀ 0.0c
0.2 ꢀ 0.0a
42.7 ꢀ 4.2d
57.0 ꢀ 2.1f
98.0 ꢀ 6.2j
>100k
h
3.3 ꢀ 1.2
>100i
2f+2f0
3a+3a0
3b+3b0
3c+3c0
3d+3d0
3e+3e0
Doxorubicin
Tamoxifen
NDGA
53.1 ꢀ 4.8b
>100i
g
8.3 ꢀ 0.4
39.8 ꢀ 3.0d
31.6 ꢀ 2.1c
6.3 ꢀ 0.5b
31 ꢀ 2.0c
62 ꢀ 5.1e
71.0 ꢀ 2.6i
g
7.0 ꢀ 0.3
56.0 ꢀ 2.9f
–
18.0 ꢀ 0.7b
40.0 ꢀ 1.9d
56.0 ꢀ 2.4f
g
8.9 ꢀ 0.4
36.2 ꢀ 1.8c
2.0 ꢀ 0.1a
1.3 ꢀ 0.1a
98.0 ꢀ 0.1a
–, not active. Different letters in columns indicate significant differences among fractions at P < 0.05 (LSD test). †Cytotoxicity as IC50 for each cell
line is the concentration of the compound that inhibits 50% of the cell multiplication after 48 h of treatment. *Bold type indicates relatively sig-
nificant activity.
48 h, provided with complete regiospecificity the expected
1,2,3-triazoles, which lose a molecule of nitrogen to yield
the corresponding aziridines 3a,a0–e,e0 (Scheme 2).
The ratio (50 : 50) of diastereoisomers in mixture has
been determined from quantitative 1H-NMR spectra, by
integration of the peaks.
(C-7″, C-11″), 114.3, 114.1 (C-8″, C-10″) and 129.0 (C-9″)
relative to carbons of the introduced aromatic system. The
disappearance of C-2″ and C-3″ signals (dC 123.1 and
137.6, respectively) in the angeloyl system of (-)-deltoin 1
was in accordance with the obtained structures.
The diastereoselectivity of the reaction was ascertained by
the duplication of the most of the signals indicated above.
The structures of these compounds were confirmed
according to their spectral data. Compounds 3b + 3b0 (also
noted 3b,b0), as an example, were obtained as a yellow oil
as a mixture of diastereoisomers. Their common DCI-
HRMS gave pseudomolecular peak [M+H]+ at m/z
454.1429, which is consistent with the molecular formula
C25H24NO5Cl. The 1H-NMR spectrum showed the appear-
ance of a new signal at dH 3.96 attributable to H-3″ of the
aziridine ring in addition to the characteristic signals of the
protons introduced by the dihydrofuranocoumarin system.
The disappearance of the ethylenic proton signal at dH 6.06
(1H, qq, J1 = 7.2 Hz; J2 = 1.2 Hz) of the angeloyl fragment
in (-)-deltoin 1 was in agreement with the undertaken
cycloaddition reaction. The same spectrum also has shown
four doublets at dH 6.47 (2H, d, J = 9 Hz, H-8″, H-10″),
6.44 (2H, d, J = 9 Hz, H-8″, H-10″) and at dH 7.11 (2H, d,
J = 8.4 Hz, H-7″, H-11″), 7.10 (2H, d, J = 8.4 Hz, H-7″,
H-11″) as AA0BB0-type signals characteristic of the aromatic
hydrogens introduced by the azido-p-chlorobenzene. The
13C-NMR spectrum confirmed the above spectral data by
the observation of new signals at dC 143.4 (C-6″), 128.9
Biological activity
5-lipoxygenase inhibitory
All compounds have been evaluated for their 5-lipoxygenase
inhibition effect (Table 1). There is no report in literature
indicating that (-)-deltoin 1 and its derivatives were tested
against this enzyme. The results have shown that (-)-deltoin
1 did not exhibit any considerable inhibition (% inhibi-
tion = 12.2 ꢀ 1.2%) of 5-lipoxygenase at the used concen-
tration (200 lM). The prepared derivatives have been shown
to be inactive to moderately active and the noted per cent
inhibitions of most of them ranged from 3.3 ꢀ 1.2% (com-
pound 2e0) to 53.1 ꢀ 4.8% (mixture 2f+f0) at 200 lM. These
results were in agreement with one of our earlier works that
described the anti-5-lipoxygenase activity of certain isoxazo-
lines prepared from harmine.[25] The results of the above
work have shown that cycloadducts with isoxazolines
bearing a phenyl, a 4-methylphenyl, a 4-methoxyphenyl and
10
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Mansour Znati et al.
Bioactivity of (-)-deltoin derivatives
a 4-chlorophenyl have been found to be inactive.[23] For
aziridines, our findings have shown that the mixture of
diastereoisomers 3e,e0 displayed the best activity against 5-
lipoxygenase with a per cent inhibition value of 36.2 ꢀ 1.8%
at 200 lM. No previous work dealt with the description of
the anti-5-lipoxygenase of aziridine derivatives.
systems used to improve the cytotoxic activity of (-)-deltoin
1. On the other hand, taking into account the importance of
stereochemistry in the case of the activity of the stereoisomer
2a compared to 2b against the same cancer cell line, it is very
likely that the stereochemistry of one of the stereoisomers in
mixture (2f,f0) also has an effect on this activity, as it can be
from a synergistic effect. In addition, except of the couple of
the diastereoisomers 2c and 2c0, the cytotoxic activity is
reversed with the inversion of the absolute configuration of
the introduced asymmetric centres (case of the couples 2a,
2a0, 2b, 2b0, 2d, 2d0 and 2e, 2e0).
Cytotoxic activity
Cytotoxic activity of the various products (1, 2a,a0–2f,f0 and
3a,a0–e,e0) tested against the human cell lines HCT-116,
IGROV-1 and OVCAR-3 (Table 1) has been assessed using
MTT assay, which is reliable to detect the proliferation of
the cells. The results showed that (-)-deltoin 1 exhibited a
good cytotoxic activity against the colon cell line HCT-116
(IC50 = 14.3 ꢀ 0.2 lM) and a moderate cytotoxic activity
against the ovary cell lines IGROV-1 and OVCAR-3 with
IC50 values of 49.0 ꢀ 2.1 and 49.0 ꢀ 1.8 lM, respectively.
It has been found that one of the two diastereoisomers
named 2a was found to be the most active against the
human colon cell line HCT-116 (IC50 = 3.3 ꢀ 0.1 lM), and
it was four and thirty-seven times more active than (-)-del-
toin 1 (IC50 = 14.3 ꢀ 0.2 lM) and its stereoisomer 2a0
(IC50 = 122.9 ꢀ 2.5 lM), respectively. This finding showed
the importance of the stereochemistry of the stereogenic cen-
tres (C-2″ and C-3″) when the isoxazoline system bears an
unsubstituted phenyl. The determination of the stereochem-
istry of the formed diastereoisomers was not possible by the
NOESY experiment, which led to the same conclusion (a
nOe between H-3″ and H-4″ in both structures). Moreover,
after several attempts of recrystallization of all compounds
prepared, it was difficult to determine the stereochemistry of
each diastereoisomer using the X-ray diffraction.
The introduction of the isoxazoline system with a variety of
aromatic rings does not seem to improve the activity of (-)-
deltoin 1 against the ovary cell line IGROV-1 and OVCAR-3
except in limited cases (2d (IC50 = 31.6 ꢀ 1.7 lM) and 2e
(IC50 = 42.7 ꢀ 4.2 lM) against OVCAR-3 and IGROV-1,
respectively). This result is certainly due to the selectivity of
the products tested towards these cancer cell lines.[29]
The results have shown that the mixture of diastereoiso-
mers 3a,a0, 3b,b0 was more than twice of the cytotoxic than
(-)-deltoin 1 (IC50 = 14.3 ꢀ 0.2 lM) against HCT-116,
and they exhibited IC50 values of 5.9 ꢀ 0.1 and
6.1 ꢀ 0.7 lM, respectively. Our findings were supported by
results from the literature describing the cytotoxic potential
of some aziridine derivatives against Hep2, CT-50 and BC-
M1 cells, with LD50 values ranging from 4 to 12 lM.[30]
The increase in the activity of compounds 3a,a0 compared
to that of (-)-deltoin 1 was due to the simple phenyl aziri-
dine moiety introduced by the cycloaddition reaction. The
mono-chlorination in para-position of the aromatic ring as
compared to the compounds 3e,e0 (IC50 = 13.3 ꢀ 0.0 lM)
supported the activity of the mixture 3b,b0 against HCT-
116. It has been found that the substitution of the 4-position
in the phenyl group attached to the nitrogen of the aziridine
ring in compounds 3a,a0 by a methyl group (3c,c0) or a
chlorine atom (3b,b0) did not influence considerably this
activity, whereas the trifluoromethyl group in 3d,d0
(IC50 = 16.2 ꢀ 0.5 lM) and the two chlorine atoms in 3,5-
positions in 3e,e0 (IC50 = 13.3 ꢀ 0.9 lM) can be the origin
of the loss in activity by comparison with that of the com-
pounds 3a,a0. It has been shown that independently of the
stereochemistry of the two asymmetric centres introduced
by the aziridine system, the nature of the substitute in the
aromatic ring seemed to influence the activity against HCT-
116. The three cancer cell lines used (HCT-116, IGROV-1
and OVCAR-3) showed a particular sensitivity to the mix-
ture 3c,c0 (IC50 = 7.3 ꢀ 0.9, 6.3 ꢀ 0.5 and 18.0 ꢀ 0.7 lM,
respectively) compared to the remaining of the synthesized
derivatives. This finding can be explained by the nature of
the aromatic ring (para-methylphenyl), in addition to the
stereochemistry of the introduced stereogenic centres (C-2″
and C-3″), as it can be interpreted by a possible synergistic
effect still retaining the first two cited factors.[31]
The relatively high activity of the derivative 2a compared
to those of (-)-deltoin 1 and to the rest of derivatives 2
showed the contribution of the isoxazoline moiety to this
activity. This result was supported by some anterior studies
showing the cytotoxic activity, towards various cancer cell
lines, of several isoxazoline derivatives. However, the man-
ner of attachment of this ring in the molecule certainly
affects the cytotoxic activity.[26–28]
The absence of any significant improvement in activity
of (-)-deltoin 1 by incorporating an isoxazoline system
bearing an aromatic ring at C-6″ with a chlorine, a methyl,
a methoxy and a butoxy all in para-position has shown the
importance of the nature of the aromatic moiety used,[25]
in addition to the stereochemistry of the asymmetric cen-
tres introduced.
The mixture of diastereoisomers 2f,f0 was more active
against HCT-116 cell line than (-)-deltoin 1 with an IC50
value of 4.3 ꢀ 0.1 lM. This result has shown clearly the con-
tribution of the 2-chloropyridin group attached to the isoxa-
zoline at C-6″ by comparison with the other aromatic
© 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ** (2018), pp. **–**
11

Bioactivity of (-)-deltoin derivatives
Mansour Znati et al.
The aziridine derivatives, except 3c,c0, have shown a mod-
erate cytotoxic activity against the ovary cell lines IGROV-1
and OVCAR-3 with IC50 values ranging from 31.0 ꢀ 2.0 to
71.0 ꢀ 2.6 lM. This difference is due to the selectivity of the
products tested against these cancer cell lines.[29]
flowers of F. lutea, has been subjected to a [3 + 2]
cycloaddition reaction towards a series of arylnitrile oxi-
des and azidobenzenes as a dipole. The reactions were
regiospecific and led to a series of new isoxazoline and
aziridine derivatives. Cytotoxic activity evaluated against
three cancer cell lines (HCT-116, IGROV-1 and OVCAR-
3) has shown that compound 2a from the series of the
isoxazoline derivatives and 3a,a0, 3b,b0 and 3c,c0 from
that of the aziridine derivatives have been the best cyto-
toxic effect. The isoxazoline derivative (mixture 2f+f0)
has shown the best result against 5-lipoxygenase com-
pared to NDGA.
A review of the literature showed that the fura-
nocoumarin moiety exists in a cytotoxic natural extract.
Prantschimgin, an analogous of deltoin, isolated from the
same plant (F. lutea), is an example that it has showed
cytotoxic activity against HT-29 and HCT-116 with IC50
values of 5.20 ꢀ 1.02 and 14.95 ꢀ 4.9 lM, respectively.
Furthermore, imperatorin, a natural furanocoumarin iso-
lated from Angelica dahurica, was also found to be able to
function as a cancer suppressor by inducing apoptosis in
HepG2 cells through both death receptor- and mitochon-
dria-mediated pathways.[32] These findings do not exclude
the involvement of the furanocoumarin moiety in the cyto-
toxic activity of all compounds tested.[13]
Declaration
Conflict of interest
The authors declare that there are no conflict of interests
regarding the publication of this article.
All synthesis compounds are new and have not been
investigated for cytotoxic activity.
Acknowledgement
Conclusion
The authors like to acknowledge Ministry of Higher Educa-
tion and Scientific Research of Tunisia for financial support
(LR11ES39).
The natural hepatoprotective, TNF-a inhibitor and
cytotoxic (-)-deltoin 1 isolated quantitatively from the
6. Wu L et al. The structure and phar-
macological functions of coumarins
vꢀegꢀetation tunisienne, Tunisie, pre-
miꢁere partie, 1979b: 608.
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