A new family of 1,2,3-oxathiazolidine-2,2-dioxide phosphonate derivatives: Synthesis, characterization and anticancer evaluation

Article abstract of DOI:10.1080/10426507.2016.1274992

An efficient synthesis of a new series of organophosphorus compounds having a cyclic sulfamidates moiety is described. The cyclic sulfamidate precursors were prepared from α-amino acids after four steps (Reduction, N-Boc protection, cyclization and cleavage). The novel organophosphonates were synthesized within two steps starting from the cyclic sulfamidate (chloroacetylation following by phosphorylation via Arbuzov reaction). A particular compound 7-a (diethyl phosphonate {2-[(4S)-4-benzyl-1,2,3-oxathiazolidin-3-yl-2,2-dioxyde]-2-oxoethyl}) was essayed for their in vitro cytotoxic activities against a panel of four cell lines (Jurkat, K562, U266, and A431). For all of these cells, the synthesized compound showed low cytotoxicity, even at high concentration levels (4?mM).

Full text of DOI:10.1080/10426507.2016.1274992

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A New Family of 1,2,3-Oxathiazolidine-2,2-dioxide Phosphonate Derivatives: Synthesis,
Characterization and Anticancer Evaluation.
Hacène K’tira, Zineb Aoufa, Tan Otea Soukb, Rachida Zerroukib, Malika Berredjem,a and Nour-
Eddine Aouf*a
a
Laboratory of Applied Organic Chemistry, Bioorganic Chemistry Group, Sciences Faculty,
Chemistry Department, Badji Mokhtar-Annaba University, Box 12, 23000 Annaba, Algeria.
b
Laboratoroire de Chimie des Substances Naturelles, Faculté des Sciences et Techniques,
Université de Limoges.
Nour-Eddine Aouf - Email: noureddineaouf@yahoo.fr, noureddine.aouf@univ-annaba.dz
Abstract
An efficient synthesis of a new series of organophosphorus compounds having a cyclic
sulfamidates moiety is described. The cyclic sulfamidate precursors were prepared from -amino
acids after four steps (Reduction, N-Boc protection, cyclisation and cleavage). The novel
organophosphonates were synthesized within two steps starting from the cyclic sulfamidate
(chloroacetylation following by phosphorylation via Arbuzov reaction). A particular compound
7-a (diethyl phosphonate {2-[(4S)-4-benzyl-1,2,3-oxathiazolidin-3-yl-2,2-dioxyde]-2-oxoethyl})
was essayed for their in vitro cytotoxic activities against a panel of four cell lines (Jurkat, K562,
U266, and A431). For all of these cells, the synthesized compound showed low cytotoxicity,
even at high concentration levels (4 mM).
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Keywords
Organophosphorus, Cyclic sulfamidates, Arbuzov reaction, anticancer activity.
Introduction
The past decades have seen many advances in the development of new and effective
biomolecules for the treatment of various diseases. The chemistry of organophosphorus
compounds has received considerable attention owing to their diverse biological activities.1
Organophosphonate are analogs of phosphate esters with a non-hydrolysable C-P bond instead of
a fragile O-P bond, which present the possibility of antimetabolic activity.2
The (α,β)-amidophosphonates constitute an important class of organophosphorus compounds
with diverse biological activities, they can be used as antiviral agents,4 anticancer agents,5
antithrombotic agents,6 antibiotic agents,7 antibacterial agents,8 potential antioxydants,9 haptens
of catalytic antibodies,10 enzymes inhibitors,11 anti-inflammatory agents,12 antihypertensive
agents13 and carriers of hydrophilic organic molecules across phospholipid membrane,14 they are
also employed as insecticides and herbicides.15
In the literature several synthetic methods have been developed for the preparation of (α,β)-
amidophosphonates.16 Generally, the phosphonates derivative were prepared via Arbuzov
reaction using trialkyphosphite under a variety of conditions.17
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In recent years, cyclic sulfamidates have been utilized as a relevant precursor for the synthesis of
potentially valuable new building-blocks in medicinal chemistry18 and chiral auxiliaries in
asymmetric synthesis.19 Typically, these heterocyclic compounds is prepared from chiral and
achiral amino alcohols and diols in several steps.20
21
22
In the spite of their importance, only few examples by Dolence et al and Das et al. are
reported in the literature describing the use of the sulfamidates as precursors for the synthesis of
phosphonates derivatives. In continuation of our interest towards development of new class of
phosphonates derivative,23 we report herein the synthesis of new amidophosphonates (figure1)
using cyclic sulfamidates (1,2,3-oxathiazolidin-2,2-dioxide) as chiral precursors, which were
prepared starting from commercially available -amino acids.
Results and Discussion
Chemistry
The five membered cyclic sulfamidates 5 (a-c) (1,2,3-oxathiazolidin-2,2-dioxide) is typically
prepared, this heterocyclic compounds were synthetized from different chiral-amino acids 1
(a-c) as shown in scheme 1.
In first steps the -amino acids were converted into the corresponding -amino alcohols 2 (a-c)
by reduction reaction24 with NaBH4, I2 in THF, in the second steps, the green chemistry
conditions were respected where we converted the -amino alcohols to their corresponding N-
Boc derivatives 3(a-c) using (Boc)2O under ultrasound irradiation.25 The Cyclisation of the N-
Boc protected -aminoalcohols 3(a-c) to form cyclic sulfamidates 4 (a-c) was the key step of this
synthesis, considering that we had to block the nucleophilicity of the nitrogen group by
introducing the Boc group to allow the second nucleophilic attack on the sulfuryl chloride by
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hydroxyl group. The second obstacle was to optimise the reaction conditions. We tried different
temperatures, the best result was obtained at -20 °C, affording the cyclic product in good yield
within 15 minute achieved the standard one-step cyclisation protocol. In all case the duration of
the cyclisation step kept short (15 min) to obtain a good yield (Table 3).
In the last step, and in continuation of our previous interest on the use of catalyst free, we herein
use an efficient protocol for N-Boc deprotection under catalyst free conditions, finding that
heating water (100°C) could efficiently catalyse the deprotection of N-Boc amino alcohols in
good to excellent yields within 10-25 min proving the advantages of this method.26
In our study, the simplest and most typical reactions were used for the synthesis a new class of -
amidophosphonates 7(a-c) using the cyclic sulfamidates 5(a-c) as relevant precursor. This
strategy involves two steps as shown in Scheme 2.
The starting chiral N-chloroacetyl (1,2,3)-oxathiazolidin-2,2-ones 6(a-c) were easily prepared in
good yields by treatment of the corresponding cyclic sulfamidates with K2CO3 in H2O followed
by chloroacetylation using chloroacetyl chloride27. The results are shown in Table 1.
The introduction of the phosphonate moiety was realised by a greener and efficient method
developed by our group.28 The corresponding amidophosphonates 7(a-c) were obtained in good
yields by phosphorylation of N-chloroacetyl cyclic sulfamidates derivatives under ultrasound
irradiation (Table 2). This protocol at a frequency of 40 KHz, strongly accelerates the process of
formation of P-C bonds compared to the classic Arbuzov reaction.
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Biological evaluation
Cell cytotoxicity
The cytotoxicity of this new amidophosphonate was evaluated toward four cancer cell lines
(Jurkat, K562, U266, and A431) using an MTT reduction assay (Table S ). For all of these cells,
synthesized compound (7a) showed low cytotoxicity, even at high concentration levels (4 mM).
Experimental
Chemistry
General
All reagents and solvents were of commercial quality and used without further purification.
Melting points were determined in open capillary tubes on an electro-thermal apparatus and
uncorrected. IR spectra were recorded on a Perkin-Elmer FT-600 spectrometer. Proton nuclear
magnetic resonance was recorded with an AC 250 and 400 MHz Brüker spectrometer using
CDCl3 or DMSO-d6 as a solvent and TMS as an internal standard. Chemical shifts are reported
in δ units (ppm). All coupling constants (J) are reported in Hertz. Multiplicity is indicated as s
(singlet), d (doublet), t (triplet), m (multiplet) or combination of these signals. Elemental
analysis was performed on a Euro-Vector 3000 C, H, N analyzer and. All reaction were
monitored by TLC on Silica Merck 60 F254 (Art. 5554) precoated aluminum plates and were
developed by spraying with ninhydrin and molybdenum bleu solution. Column chromatography
was performed on Merck Silica gel (230-400 mesh). The Supplemental Materials contains
complete characterization data for products 7a-c (Figures S 1 – S 13).
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General procedure for reduction of -amino acids 2(a-c)
To a stirred solution of -amino acids (1 equiv, 5 g) in THF (100 ml) at 0 °C, was added NaBH4
(2.4 equiv.). A solution of iodine I2 (1.1 equiv.) dissolved in THF was added dropwise at 0 °C.
The resulting mixture was stirred under reflux for 18 h. The reaction was quenched by addition
of methanol (20 mL). After evaporation of the solvent, a solution of KOH (20%, 100 mL) was
added and the mixture was stirred for 4h. The crude products were extracted with AcOEt (3×100
mL), dried over MgSO4, filtered, concentred under vacuum and recrystallized in diethyl ether.
General procedure for N-tert-butoxycarbonylation of -amino alcohols 3(a-c)
(S)-amino alcohols (1mmol) and di-tert-butyl dicarbonate [(Boc)2O, 1.1 mmol] were placed in a
glass tube under neat conditions and were sonicated for a suitable time. After completion of the
reaction (as indicated by TLC), 5 mL of diethyl ether was added to the mixture, the resulting
tert-butanol was freely soluble in diethyl ether and the N-Boc product was crystallized.
General procedure fort the cyclisation of N-Boc derivatives -amino alcohols 4(a-c)
A solution of -amino alcohols (1 mmol) in dry dichloromethane (5mL) and triethylamine (5
mmol) were taken in 50 mL round bottom flask under nitrogen and the solution was cooled to
0°C over 5 min. A solution of sulfuryl chloride (2 mmol) was added dropwise at -20°C over 15
min. After completion of the reaction, the organic layer was extracted with ethyl acetate
(3×5mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The
crude product is purified over silica gel column chromatography eluted with (DCM-MeOH-
9.5:0.5) to give yellow oil.
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General procedure for the N-Boc deprotection of cyclic sulfamidates 5(a-c)
One millimoles of N-Boc cyclic sulfamidates and freshly double distilled water (10 mL) were
loaded into 50 mL round bottomed flask related with depressurized system. The reaction mixture
was heated in reflux for particular time and conducted under an argon atmosphere. After
completion, the mixture was extracted with ethyl acetate (3×5mL) and concentrated in vacuum,
all products were obtained pure.
General procedure for the choroacetylation of cyclic sulfamidates 6(a-c)
To a solution of (1,2,3)-oxathizolidin-2,2-dioxide (1 mmol) in H2O (5mL) and K2CO3 (2 mmol)
was added at 0°C chloroacetyl chloride (1.1 mmol). The reaction mixture was stirred for
overnight at room temperature. The resulting mixture was then extracted with ethyl acetate (3 x
25mL). The organic layer was combined and dried over anhydrous sodium sulfate and
concentrated. The crude product was crystallized in diethyl ether or purified by chromatography
(CH2Cl2) to afford 6(a-c).
General procedure for the phosphorylation of N-Acyl-(1,2,3)-oxathiazolidin-2,2-dioxide
7(a-c)
In a 10 mL round bottom flask taken a mixture of N-acylsulfamidate (1 mmol) with
triethylphosphite (1mmol) was added. Then reaction mixture was subjected to the ultrasonication
for appropriate time. After completion of the reaction, as indicated by TLC, silica gel, surplus
reactants were removed by column chromatography eluted with AcOEt.
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Diethyl phosphonate {2-[(4S)-4-benzyl-1,2,3-oxathiazolidin-3-yl-2,2-dioxide]-2-oxoethyl} (7-
a)
Yield :91%, White oil, Rf: 0.60 (AcOEt), IR (KBr: ν cm-1): 1657 (C=O), 1131 & 1312 (SO2).
1H NMR (CDCl3, δ ppm: 1.35 (t, 6H, CH3-CH2, J1-2= 5.3 Hz), 2.76 (2dd, 1H, J1-2=7.3 Hz), 3.33
(2dd, 1H, J1-2=3.5 Hz), 3.70-3.91 (2dd, 2H, J1= 5Hz, J2=6.7 Hz), 4.20 (s, 2H), 4.15-4.24 (m, 4H),
13
4.69-4.75 (m, 1H), 7.22-7.33 (m, 5H). C NMR (CDCl3, δ ppm): 16.4, 34.9, 37.6, 55.5, 62.8,
31
66.0, 127.3, 128.9, 129.4, 135.1, 165.0. P NMR (CDCl3, δ ppm) : 19.5. Elemental Analysis:
Calcd, C, 50.13; H, 6.17; N, 3.90; S, 8.92, Found, C, 50.10; H, 6.13; N, 3.87; S, 8.89.
Diethyl phosphonate {2-[(4S)-4-isobutyl-1,2,3-oxathiazolidin-3-yl-2,2-dioxide]-2-oxoethyl}
(7-b)
Yield : 89%, White oil, Rf: 0.60 (AcOEt), IR (KBr: ν cm-1): 1657 (C=O), 1131 & 1312 (SO2).
1H NMR (CDCl3, δ ppm): 0.90 (2d, 6H, J1-2 = 6.1 Hz), 1.30 (t, 6H, J1-2=5.9 Hz), 1.41 (m, 2H),
1.53 (m, 1H), 3.89-3.98 (dd, 2H, J1-2 = 10.4 Hz), 4.14 (s, 2H), 4.15-4.24 (m, 4H), 4.46 (m, 1H).
13C NMR (CDCl3, δ ppm): 16.3, 23.2, 24.8, 37.0, 40.6, 56.7, 61.5, 70.8, 168.4. 31P NMR
(CDCl3, δ ppm) : 19.5. Elemental Analysis: Calcd, C, 44.30; H, 7.44; N, 4.31; S, 9.85, Found,
C, 44.28; H, 7.40; N, 4.30; S, 9.83.
Diethyl phosphonate {2-[(4S)-4-isopropyl-1,2,3-oxathiazolidin-3-yl-2,2-dioxide]-2-oxoethyl}
(7-c)
Yields : 87%, White oil, Rf: O.61 (AcOEt), IR (KBr: ν cm-1): 1657 (C=O), 1131 & 1312 (SO2).
1H NMR (CDCl3, δ ppm): 0.83-0.87 (t, 6H, J1-2=6.8 Hz), 1.27 (t, 6H, J1-2= 5.9Hz), 2.07 (d, 2H),
2.33 (m, 1H), 3.59-3.74 (2dd, 2H, J1-2=9.8Hz), 4.09-4.14 (m, 4H), 4.38-4.43 (m, 1H). 13C NMR
(CDCl3, δ ppm): 16.3, 23.2, 24.8, 37.0, 40.6, 56.7, 61.5, 70.8, 168.4. 31P NMR (CDCl3, δ
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ppm) : 19.5. Elemental Analysis: Calcd, C, 42.44; H, 7.12; N, 4.50; S, 10.30, Found, C, 42.40;
H, 7.09; N, 4.48; S, 10.27.
Biological evaluation
Cell lines and culture conditions
Jurkat (acute T cell Leukemia, ATCC TIB-152), K562 (chronic myelognous leukemia, ATCC
CLL-243) and U266 (multiple myeloma, ATCC TIB-196) were routinely cultured in RPMI-1640
supplemented with 10% Fetal Bovine Serum (FBS, IDBIO, Limoges, France), 100U/ml
penicillin, 100µg/ml streptomycin), 2mM L-glutamine, 1mM sodium pyruvate, 1% vitamins and
1% non-essentials amino-acids). A431 (vulvar epidermoid carcinoma, ATCC CRL-1555) was
cultured in DMEM supplemented with 10% FBS, 100U/ml penicillin, 100µg/ml streptomycin),
2mM L-glutamine, 1mM sodium pyruvate. The cells were cultured at 37°C in a fully humidified
5% CO2 incubator. All supplements and culture were purchased from Gibco-BRL Life
Technologies, Cergy-Pontoise, France.
Cell viability assay
The cytotoxicity activity was evaluated using the MTT assay (3-(4,5-dimethylthiazol-2-yl)-
phenyl-tetrazolium bromide). Briefly, tumor cell lines were added into 96-well tissue culture
plates in culture medium. Compounds were prepared at a concentration of 4000µM in 10%
DMSO in complete culture medium (v/v). The solutions were used at concentration range from
4000 µM to 7.8 μM. Cells were incubated with or without drugs for 72 h. Then, the MTT
solution was added at a final concentration of 0.5mg/ml per well and cells were incubated for 3h
at 37°C. The purple formazan crystals were dissolved by adding 200µl DMSO. The absorbance
was read using a microplate spectrophotometer (Triad, Dynex Technologies) at 595 nm. The
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results were compared with those of a control reference plate fixed on the treatment day and the
growth inhibition percentage was calculated for each drug contact period. The concentration
required for 50% inhibition of cell viability (IC50) was calculated using the software OriginPro
(OriginLab, Northampton, USA). Assays were performed in hexaplicate on three independent
experiments.
Conclusion
In this work, we reported efficient and operationally simple methods for the synthesis a novel
class of -amidophosphonates using the chiral cyclic sulfamidates as precursors. A chiral
molecule (7-a) was evaluated from their anticancer activities. For all of these evaluations, this
compound showed a low cytotoxicity, even at high concentration levels.
Acknowledgements
This work was supported financially by The General Directorate for Scientific Research and
Technological Development (DG-RSDT), Algerian Ministry of Scientific Research, Applied
Organic Laboratory (FNR 2000). We also thank, Pr. Jacques Lebreton, Nantes University France
for his help to identification for all compounds in NMR and SM.
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Figure 1: General structure of -amidophosphonates.
Scheme 1: General procedure for the synthesis of cyclic sulfamidates.
Scheme 2: General procedure for the synthesis of -amidophosphonates.
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Table 1: Synthesis of cyclic sulfamidates.
Entry
Substrate
Product
Yield (%)
92
01
02
03
87
85
Table 2: N-Boc deprotection of cyclic sulfamidates.
Entry
Substrate
Product
Yield (%)
>95
01
02
03
>95
>95
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Table 3: Chloroacetylation of cyclic sulfamidates.
Entry
Substrate
Product
Yield (%)
01
82
02
03
80
79
Table 4: Phosphorylation of N-acetyl-(1,2,3)-oxathiazolidin-2,2-ones.
Entry
Substrate
Product
Yield (%)
Time (min)
10
01
91
02
03
89
87
12
14
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