Enantioselective synthesis and antiproliferative properties of an ilmofosine analog, 2'-(trimethylammonio)ethyl 3-(hexadecyloxy)-2- (methoxymethyl)propyl phosphate, on epithelial cancer cell growth

Article abstract of DOI:10.1021/jm960165b

An asymmetric synthesis of the 1-alkyloxy analog of the thioether phosphocholine ilmofesine (BM 41.440, rac-1), 2'-(trimethylammonio)ethyl 3- (hexadecyloxy)-2-(methoxymethyl)propyl phosphate (2), is described. Stereoselectivity was obtained in an asymmetric hydroborationoxidation sequence carried out on a 2,2-disubstituted 1-alkene, 3-(hexadecyloxy)-2- (methoxymethyl)-1-propene (9), which was prepared by starting with either ethyl acrylate or ethyl α-(hydroxymethyl)acrylate (3). (R)- and (S)-2 and rac-1 were highly effective in inhibiting the proliferation of the breast adenocarcinoma cell line MCF-7 (IC₅₀, 2 μM), moderately effective against A549 (non-small-cell lung adenocarcinoma) (IC₅₀, 8-10 μM), and less effective against A427 (large cell lung carcinoma) (IC₅₀, ~20 μM). The in vitro cytotoxicity against the three epithelial cancer cell lines was independent of the configuration about C-2 of the glycerol backbone of 2 and was also not altered by substitution of oxygen for sulfur in the sn-1 ether linkage of ilmofosine.

Full text of DOI:10.1021/jm960165b

J . Med. Chem. 1997, 40, 1391-1395
1391
Notes
En a n tioselective Syn th esis a n d An tip r olifer a tive P r op er ties of a n Ilm ofosin e
An a log, 2′-(Tr im eth yla m m on io)eth yl 3-(Hexa d ecyloxy)-2-(m eth oxym eth yl)p r op yl
P h osp h a te, on Ep ith elia l Ca n cer Cell Gr ow th
Robert Bittman,*,† Hoe-Sup Byun,† Kasireddy Chandraprakash Reddy,† Pranati Samadder,‡ and Gilbert Arthur‡
Department of Chemistry and Biochemistry, Queens College of The City University of New York,
Flushing, New York 11367-1597, and Department of Biochemistry and Molecular Biology, University of Manitoba,
Winnipeg, Manitoba, Canada R3E 0W3
Received February 29, 1996X
An asymmetric synthesis of the 1-alkyloxy analog of the thioether phosphocholine ilmofosine
(BM 41.440, rac-1), 2′-(trimethylammonio)ethyl 3-(hexadecyloxy)-2-(methoxymethyl)propyl
phosphate (2), is described. Stereoselectivity was obtained in an asymmetric hydroboration-
oxidation sequence carried out on a 2,2-disubstituted 1-alkene, 3-(hexadecyloxy)-2-(methoxy-
methyl)-1-propene (9), which was prepared by starting with either ethyl acrylate or ethyl
R-(hydroxymethyl)acrylate (3). (R)- and (S)-2 and rac-1 were highly effective in inhibiting the
proliferation of the breast adenocarcinoma cell line MCF-7 (IC50, 2 µM), moderately effective
against A549 (non-small-cell lung adenocarcinoma) (IC50, 8-10 µM), and less effective against
A427 (large cell lung carcinoma) (IC50, ∼20 µM). The in vitro cytotoxicity against the three
epithelial cancer cell lines was independent of the configuration about C-2 of the glycerol
backbone of 2 and was also not altered by substitution of oxygen for sulfur in the sn-1 ether
linkage of ilmofosine.
In tr od u ction
metric synthesis of (R)- and (S)-2, the enantiomers of
the oxygen analog of ilmofosine; the synthesis of rac-2
from 2-methoxy-1,3-propanediol was reported previ-
ously.11 There have been conflicting reports about the
role of chirality in the in vitro antitumor activity of
various ether lipids (e.g., ref 12), yet ilmofosine is used
as the racemic form in clinical studies. The enantiomers
of 2 have essentially the same in vitro cytotoxicity
against the three epithelial cancer cell lines we tested,
suggesting a lack of stereoselective interactions in vitro.
(R)- and (S)-2, like the thioether phosphocholine rac-1,
were highly effective in inhibiting the proliferation of
MCF-7 cells.
Ilmofosine (rac-1, 2′-(trimethylammonio)ethyl 3-(hexa-
decylthio)-2-(methoxymethyl)propyl phosphate, BM
41.440) is an experimental anticancer drug with activity
against a variety of malignant cell types of murine and
human origin.1-4 The antineoplastic action of the
synthetic ether phospholipids is as yet not fully estab-
lished, but it is membrane mediated. Interference in
cell signaling pathways is clearly an important aspect
of the mechanism of action.5 Although rac-1 inhibits
protein kinase C,6 its antineoplastic effects may arise
from its ability to suppress the cyclin-dependent cdc2
kinase.7 rac-1 blocks the accumulation of cyclin B1/cdc2
complexes and arrests human lymphoma cells in the G2
phase of the cell cycle.7 rac-1 also possesses antileish-
manial activity.8
Resu lts a n d Discu ssion
Ch em istr y. (R)- and (S)-2 were prepared by using
two routes. One route used 2-methylene-1,3-pro-
panediol (5) as the key intermediate (Scheme 1). As
shown in Scheme 1, 5 was made from ethyl acrylate by
a coupling reaction with formaldehyde catalyzed by
DABCO in THF, giving ethyl R-(hydroxymethyl)acrylate
(3).10 Reduction of 3 with 1 equiv of AlH3, which was
generated in situ by the reaction of LiAlH4 with n-butyl
bromide,13 is assumed to give aldehyde 4. The latter
was reduced without isolation with NaBH4 to give
2-methylene-1,3-propanediol (5) in 57% overall yield
from 3. Mono-O-alkylation of diol 5 via a 1,3-cyclic
stannoxane intermediate14 in chloroform/methanol (10:
Thioether phospholipid rac-1 was synthesized by a
Boehringer-Mannheim group in a long route with low
overall yield, starting with diethyl bis(hydroxymethyl)-
malonate.9 We recently communicated an improved
synthesis of rac-1 from ethyl R-(hydroxymethyl)acrylate
(3) in good overall yield.10 We report here an asym-
* Corresponding author: phone, 718-997-3279; fax, 718-997-3349;
e-mail, bittman@qcvaxa.acc.qc.edu.
† Queens College of CUNY.
‡ University of Manitoba.
X Abstract published in Advance ACS Abstracts, April 1, 1997.
S0022-2623(96)00165-3 CCC: $14.00 © 1997 American Chemical Society

1392 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 9
Notes
Sch em e 1. Synthesis of 6 from Ethyl Acrylate via
2-Methylene-1,3-propanediol (5)
F igu r e 1. Effect of (S)-2 on the proliferation of MCF-7 (b),
A549 (9), and A427 (2) cells. Cells were treated with the drug
for 48 h. The increase in cell number after 48 h was determined
and expressed as a percent of controls. The results are the
means ( SD of eight different determinations.
Sch em e 3. Synthesis of (R)-2 via Asymmetric
Hydroboration-Oxidation
Sch em e 2. Synthesis of 6 from Ethyl
R-(Hydroxymethyl)acrylate (3) via Ethyl
R-(Bromomethyl)acrylate (7)
indicated that the enantiomeric excess (ee) of 10 was
84%. Although asymmetric hydroboration of prochiral
2-substituted 1-alkenes generally proceeds in low ee,17,18
there is a precedent for a large difference in size,19 such
as that between the hexadecyloxy and methoxy groups
of the 2,2-disubstituted 1-alkene 9, giving rise to a high
level of asymmetric induction in this reaction. The
insertion of the phosphocholine group into alcohol 10
was accomplished by using 2-chloro-1,3,2-dioxaphos-
pholane 2-oxide, followed by ring opening of the inter-
mediate cyclic phospholane with trimethylamine in a
pressure tube, as described elsewhere,20 to give the
desired product (R)-2. (S)-2 was synthesized in analo-
gous fashion, using (-)-Ipc2BH, which was prepared
from (+)-R-pinene.
An tip r olifer a tive P r op er ties of (R)-2 a n d (S)-2
a n d Com p a r ison w ith r a c-1 Activity. The stereo-
chemical requirements about C-2 of the glycerol back-
bone of various ether lipids for optimal antitumor or
antiviral activity has been probed in previous in vitro
studies. There are conflicting reports about the role of
chirality of ether phospholipids in antineoplastic activ-
ity.21,22 In several closely related antitumor ether lipids,
no marked dependence on phospholipid chirality was
noted in vitro.12,23-26 However, it was recently reported
that the S enantiomer of SRI 62-834 was somewhat
more active than the R enantiomer against various
murine tumor cell lines.21 Further, stereoselectivity was
detected in the antiviral activity of ether-lipid-3′-azido-
3′-deoxythymidine conjugates in HIV-infected human
1), followed by treatment with cesium fluoride and
1-bromohexadecane in DMF, gave 3-(hexadecyloxy)-2-
(hydroxymethyl)-1-propene (6) in 86% overall yield.
In the other route, ethyl R-(hydroxymethyl)acrylate
(3) was used as the starting material. Scheme 2
outlines the conversion of 3 into 6. Ethyl R-(bromo-
methyl)acrylate (7) was prepared from 3 as described
previously.15 The reaction of bromide 7 with hexade-
cyloxycopper(I), generated by the reaction of the lithium
salt of 1-hexadecanol with cuprous iodide in THF at -23
°C, provided ethyl 2-[(hexadecyloxy)methyl]propenoate
(8) in 64% yield. Reduction of ester 8 with DIBAL in
THF at -78 °C gave alcohol 6 in 72% yield.
The enantioselective synthesis of 2 was completed as
shown in Scheme 3. After the hydroxy group of 6 was
methylated by using sodium hydride in THF in the
presence of a phase transfer catalyst to give 3-(hexade-
cyloxy)-2-(methoxymethyl)-1-propene (9), asymmetric
hydroboration was carried out with (+)-diisopinylcam-
pheylborane ((+)-Ipc2BH)16,17 followed by oxidation of
the intermediate borane with alkaline hydrogen perox-
ide to give (R)-10 in 94% yield. Analysis of the (R)-(+)-
R-methoxy-R-(trifluoromethyl)phenylacetic acid (MTPA)
ester derivative of (R)-10 by chiral HPLC analysis

Notes
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 9 1393
butyltin oxide (13.96 g, 56 mmol) in 60 mL of CHCl3/MeOH
(10:1) was refluxed until the solids were dissolved. The
solvents were evaporated under vacuum, and 14.71 g (97
mmol) of CsF was added to the residue. After the mixture
was further dried at room temperature under vacuum for 2 h,
50 mL of dry DMF was added. The mixture was stirred at 40
°C for 30 min and then cooled to room temperature. 1-Bro-
mohexadecane (17.13 g, 56 mmol) was added over a 10-min
period. After the mixture was stirred for 36 h, water (2 mL)
and ether (100 mL) were added, with stirring for 30 min. The
solids were filtered through a pad of Celite, which was washed
with Et2O (100 mL). The combined filtrate was washed with
brine (20 mL × 2); the ether layer was dried (Na2SO4),
concentrated, and purified by silica gel chromatography (elu-
tion with hexane:EtOAc, 9:1) to give 12.2 g (86%) of the
monoalkylation product 6 as a low-melting solid: Rf 0.70
(hexane:EtOAc, 3:1).
F igu r e 2. Effects of rac-1 (2), (S)-2 (b), and (R)-2 (9) on (A)
MCF-7 cell proliferation and (B) A549 cell proliferation. See
caption to Figure 1 for experimental details.
P r oced u r e B. To a stirred solution of 1.92 g (5.4 mmol) of
8 in 40 mL of dry toluene under nitrogen was added 8.0 mL
(12 mmol) of DIBAL (a 1.5 M solution in toluene) slowly via
cannula so as to keep the temperature of the reaction mixture
below -70 °C. The reaction mixture was stirred for an
additional 5 h at -78 °C; then the reaction was quenched by
the slow addition of MeOH (10 mL). The resulting emulsion
was poured slowly into 30 mL of 1 N HCl over 15 min, and
the product was extracted with EtOAc (50 mL × 3). The
combined organic layers were washed with brine, dried (Na2-
SO4), filtered, and concentrated under reduced pressure to give
the crude product as a semisolid. Purification by silica gel
chromatography (elution with hexane:EtOAc, 9:1) gave 1.25
g (73%) of 6: mp 45-46 °C; same Rf, IR, and 1H NMR as 6
prepared as above.
T-lymphocyte cell cultures.27 In an extension of these
studies, we probed the cytotoxicity of (R)- and (S)-2 (see
the Experimental Section). Figure 1 shows the anti-
proliferative effects of (S)-2 on various epithelial cell
lines after a 48-h treatment. The relative order of
selectivity against these cell lines was MCF-7 > A549
> A427 (IC50 values of 2.0, 7.5, and 20 µM, respectively).
The cytotoxicity profile of (R)-2 was very similar (not
shown) to that of (S)-2, with IC50 values of 2.0, 10, and
g20 µM, respectively, against MCF-7, A549, and A427
cells. The enantiomers of ilmofosine analog 2 have the
same cytotoxicity as rac-1 against MCF-7 and A549 cells
(Figure 2).
3-(Hexadecyloxy)-2-(m eth oxym eth yl)-1-pr open e (9). To
a suspension of 0.29 g (10 mmol, 80% in white oil, washed with
dry hexane twice) of NaH in 30 mL of dry THF was added a
solution of 1.00 g (3.2 mmol) of 6 in 2 mL of THF at room
temperature under nitrogen. After the evolution of hydrogen
had stopped, 0.70 mL (11.2 mmol) of MeI and 53.4 mg (0.16
mmol) of n-Bu4NHSO4 were added, and the reaction mixture
was stirred for 10 h at room temperature. Ethanol (1 mL)
and water (1 mL) were added, the solvents were removed
under vacuum, and the residue was extracted with hexane (50
mL). The organic layer was washed with brine (20 mL), dried
(Na2SO4), and concentrated. The residue was purified by silica
gel chromatography (elution with hexane), yielding 960 mg
(92%) of 9 as a colorless oil: Rf 0.60 (hexane:EtOAc, 9:1).
3-(H e x a d e c y lo x y )-2(R )-2-(m e t h o x y m e t h y l)-1-p r o -
p a n ol ((R)-10). To a stirred solution of (-)-R-pinene (1.44 g,
10.6 mmol) in 0.70 mL of THF was added 0.50 mL (5.6 mmol)
of borane-methyl sulfide complex in THF dropwise at -10
°C over a 10-min period under nitrogen. After the mixture
At the concentrations of drugs we examined, the
viability of A549 and A427 cells, as assessed by trypan
blue exclusion, did not differ significantly in the drug-
treated vs untreated cells. With MCF-7 cells, drug
concentrations > 15 µM resulted in significantly lower
viability relative to untreated controls.
Replacement of an oxygen in the glycerol backbone
by sulfur is one of the many chemical modifications that
have been introduced in ether phospholipid analogs in
efforts to improve the therapeutic efficiency. Substitu-
tion of a 1-alkylthio chain, as in 1, for the 1-alkyloxy
chain found in ET18-OCH3 or in the anti-HIV nucleoside
ether phospholipid conjugates has been reported in
many cases to either increase28 or not change26 the
cytotoxicity of the ether lipid. We found that replacing
the sulfur of 1 by oxygen did not alter the cytotoxicity
against the three epithelial cancer cell lines.
was stirred for 1.5 h at 0 °C, (+)-Ipc2
BH started to crystallize.
The resulting slurry was stored without stirring under nitro-
gen at -4 °C for 3 days and then washed with cold dry hexane
(10 mL × 2) under nitrogen. The white solid of (+)-Ipc2BH
was suspended in 10 mL of THF and cooled to -25 °C, 0.82 g
(2.51 mmol) of 9 was added, and the mixture was stirred for
6 h at -25 °C and then warmed to room temperature.
Methanol (20 mL) was added to the suspension followed by 5
mL of 3 N NaOH and 8 mL of 30% H2O2. After the reaction
mixture was stirred at room temperature for 5 h, the product
was extracted with ether (30 mL × 3). The combined ether
extract was washed with brine (10 mL × 2), dried (Na2SO4),
and concentrated. The residue was purified by silica gel
chromatography (elution with hexane:EtOAc, 9:1) to give 0.82
g (94%) of (R)-10 as a white solid: mp 46-47 °C; Rf 0.47
(hexane:EtOAc, 3:1); 84% ee. The % ee was estimated by chiral
HPLC (Pirkle type IA column, 4.6 × 250 mm, J . T. Baker) of
the crude (R)-(+)-MTPA ester derived from (R)-10: tR 39.6,
41.2 min; elution with hexane/2-PrOH, 99:1; flow rate 0.3 mL/
min. The MTPA ester was prepared as described previously.29
2′-(Tr im eth yla m m on io)eth yl 3-(Hexa d ecyloxy)-2(R)-2-
(m eth oxym eth yl)p r op yl P h osp h a te ((R)-2). To a solution
of 55 mg (0.16 mmol) of (R)-10 and 51 mg (0.50 mmol) of Et3N
in 20 mL of THF was added slowly a solution of 2-chloro-1,3,2-
dioxaphospholane 2-oxide (44 µL, 0.49 mmol) in THF at 0 °C.
Con clu sion
(R)- and (S)-2 are enantiomers of an O-alkyl analog
of thioether 1. They were prepared in a short synthetic
route, starting with either ethyl acrylate or ethyl
R-(hydroxymethyl)acrylate (3), in which the key step is
asymmetric hydroboration of the prochiral alkene 9 with
Ipc2BH followed by oxidation. No marked dependence
on chirality was found in inhibition of proliferation of
three epithelial cancer cell lines. (R)-2, (S)-2, and rac-1
have high cytotoxicity in vitro against the breast cancer
cell line MCF-7 (IC50, 2 µM). The three compounds had
a similar potency with respect to inhibition of A549
(non-small-cell lung adenocarcinoma) proliferation (IC50
values of 8-10 µM) and were less effective against A427
cells (large cell lung carcinoma) (IC50 values of ∼20 µM).
Exp er im en ta l Section
3-(H exa d ecyloxy)-2-(h yd r oxym et h yl)-1-p r op en e (6).
This compound was prepared by two different procedures.
P r oced u r e A. A mixture of 5 (4.0 g, 45 mmol) and di-n-

1394 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 9
Notes
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Effects of Thioether Phospholipid BM 41.440 on Protein Kinase
C and Phorbol Ester-Induced Differentiation of Human Leuke-
mia HL60 and KG-1 Cells. Cancer Res. 1988, 48, 6669-6673.
(7) Hofmann, J .; O'Connor, P. M.; J ackman, J .; Schubert, C.;
Ueberall, F.; Kohn, K. W.; Grunicke, H. The Protein Kinase C
Inhibitor Ilmofosine (BM 41 440) Arrests Cells in G2 Phase and
Suppresses CDC 2 Kinase Activation Through a Mechanism
Different from that of DNA Damaging Agents. Biochem. Biophys.
Res. Commun. 1994, 199, 937-943.
(8) Croft, S. L.; Neal, R. A.; Thornton, E. A.; Herrmann, D. B. J .
Antileishmanial Activity of the Ether Phospholipid Ilmofosine.
Trans. R. Soc. Trop. Med. Hyg. 1993, 87, 217-219.
(9) Bosies, E.; Herrmann, D. B. J .; Bicker, U.; Gall, R.; Pahlke, W.
Synthesis of Thioether Phosphocholine Analogues. Lipids 1987,
22, 947-951.
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An Improved Synthesis of Ilmofosine and an Enantioselective
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2679-2682.
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Phospholipids and Medicines Containing These Compounds.
Eur. Pat. Appl. EP 69,968; Chem. Abstr. 1983, 99, 5818b.
(12) Guivisdalsky, P. N.; Bittman, R.; Smith, Z.; Blank, M. L.; Snyder,
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The reaction mixture was stirred at 0 °C for 30 min and then
at room temperature for 5 h. The cyclic phosphate was opened
with anhydrous Me3N (1 mL) in dry CH3CN (10 mL) in a
pressure bottle as described previously,20,29 giving 46 mg (56%)
of (R)-2: Rf 0.38 (CHCl3:MeOH:H2O, 65:25:4).
For the synthesis of 2′-(trimethylammonio)ethyl 3-(hexade-
cyloxy)-2(S)-2-(methoxymethyl)propyl phosphate ((S)-2), the
enantiomer of Ipc2BH (prepared from (+)-R-pinene) was used
for the asymmetric hydroboration-oxidation of 9. The % ee
was 84, as estimated by chiral HPLC of the crude (R)-(+)-
MTPA ester derived from (S)-10: tR 40.6, 42.5 min; elution
with hexane/2-PrOH, 99:1; flow rate 0.3 mL/min.
Eth yl 2-[(Hexa d ecyloxy)m eth yl]p r op en oa te (8). To a
solution of 5.02 g (20.7 mmol) of 1-hexadecanol in 120 mL of
dry THF was added 8.2 mL (20.5 mmol) of n-butyllithium (a
2.5 M solution in hexane). After the mixture was stirred for
45 min at -23 °C under nitrogen, CuI (3.90 g, 20.5 mmol) was
added, and the reaction mixture was stirred for 1 h. A solution
of 2.0 g (10.4 mmol) of 7 in 10 mL of THF was added, and the
reaction mixture was stirred at -23 °C for 4 h and at 0 °C for
20 h. After addition of water (20 mL), THF was evaporated
under vacuum, and the product was extracted with CH2Cl2
(50 mL × 2). The organic layer was washed with 20% aqueous
NH4OH solution until the blue-green color persisted, washed
with water (25 mL × 2), dried (Na2SO4), and concentrated.
The residue was purified by silica gel chromatography (elution
with petroleum ether) to yield 2.35 g (64%) of 8 as a white
solid: mp 35-37 °C; Rf 0.78 (hexane:EtOAc, 9:1).
An tip r olifer a tive Stu d ies. The human epithelial cancer
cell lines were obtained from ATCC and grown as described
previously.30 The cell number was monitored with a Coulter
ZM counter. Log-phase cells were treated with medium
containing (R)- or (S)-2 or rac-1 at the desired concentration
for 48 h, and the cell number was compared with control cells
grown in media that did not contain the drug. Stock solutions
of the drugs (30 mM) were prepared in ethanol. Media
containing the drug at 30 µM were prepared and serially
diluted to give the required concentrations. The final concen-
tration of ethanol in all wells was 0.1% (v/v). Cell viability
was assessed by trypan blue dye exclusion.31
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supported in part by a grant from the National Cancer
Institute of Canada with funds from the Cancer Re-
search Society to G.A. FAB-MS were recorded at the
Michigan State University Mass Spectrometer Facility.
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