Facile photochemical synthesis of mixed siloxyacetal glycosides as potential pH-sensitized prodrugs for selective treatment of solid tumors

Article abstract of DOI:10.1039/b405786d

Photochemical reactions of a variety of acylsilanes with peracetylated free glycosides in anhydrous benzene at ambient temperature yielded novel, highly acid-sensitive siloxyacetal glycosides in 75-90% yields with complete retention of configuration at the anomeric center. Subsequent deacetylation of triisopropylsiloxy- and tert-butyldimethylsiloxy derivatives with sodium methoxide in methanol afforded deprotected siloxyacetal glycosides in nearly quantitative yields. Acid hydrolysis of trimethylsilyl siloxyacetals proceeded with a half-life of 17.5 minutes at pH 6.2 which is vastly superior to the decomposition rate of conventional acetals under similar conditions. The structure of one of the novel siloxyacetals was confirmed by X-ray crystallography. In vitro biological studies showed that glucose-derived siloxyacetals may serve as potential pH-activated prodrugs for selective treatment of solid tumors.

Full text of DOI:10.1039/b405786d

View Article Online / Journal Homepage / Table of Contents for this issue
A R T I C L E
Facile photochemical synthesis of mixed siloxyacetal glycosides as
potential pH-sensitized prodrugs for selective treatment of solid
tumors†
Serge A. Svarovsky,*a Marc B. Tarabanb and Joseph J. Barchi, Jr.a
a
Laboratory of Medicinal Chemistry, National Cancer Institute, 376 Boyles Street, Frederick,
MD 21702, USA. E-mail: ssvarovs@ncifcrf.gov; Fax: +(301)846-6033; Tel: +(301)846-5899
Institute of Chemical Kinetics and Combustion, Siberian Division of the Russian Academy of
b
Sciences, Institutskaya 3, Novosibirsk 630090, Russia
Received 19th April 2004, Accepted 20th August 2004
First published as an Advance Article on the web 30th September 2004
Photochemical reactions of a variety of acylsilanes with peracetylated free glycosides in anhydrous benzene at
ambient temperature yielded novel, highly acid-sensitive siloxyacetal glycosides in 75–90% yields with complete
retention of configuration at the anomeric center. Subsequent deacetylation of triisopropylsiloxy- and tert-
butyldimethylsiloxy derivatives with sodium methoxide in methanol afforded deprotected siloxyacetal glycosides in
nearly quantitative yields. Acid hydrolysis of trimethylsilyl siloxyacetals proceeded with a half-life of 17.5 minutes
at pH 6.2 which is vastly superior to the decomposition rate of conventional acetals under similar conditions. The
structure of one of the novel siloxyacetals was confirmed by X-ray crystallography. In vitro biological studies showed
that glucose-derived siloxyacetals may serve as potential pH-activated prodrugs for selective treatment of solid
tumors.
administration12,13 without affecting pH of the surrounding nor-
Introduction
mal tissues. Therefore, any therapy that exploits this marginal,
The ultimate goal of cancer drug research is to develop therapies
yet conceptually significant, pH difference could be interesting
that can selectively kill tumor cells without adverse effects on
to explore.
the host.1 To address this issue, considerable efforts have been
One of the modern approaches that takes advantage of
made to utilize some of the distinctions between normal and
tumor acidity is the targeting of malignant cells through the use
tumor cells. Traditionally, cancer has been thought of as a
of ionophores that equilibrate pHe and pHi and thus selectively
disease of abnormal cell proliferation. This belief has provided
inhibit the growth of tumor cells.14 The tumor pH gradient was
a basis for the development of most of the currently used
also exploited to selectively increase uptake of weakly acidic
chemotherapeutic agents that achieve selectivity as a result
drugs into tumors compared to the normal tissues.15 pH-
of the drugs being taken up to a greater extent by the rapidly
responsive micelles loaded with anticancer drugs have also been
proliferating cancer cells. The recent advances in molecular
explored.16
biology has allowed development of a number of mechanism-
It is well known that acetals reveal virtually unlimited
based drugs. These drugs potentially offer greater selectivity and
stability to basic conditions while being quite fragile towards
reduced toxicity as they attempt to target specific biochemical
acids,17 a property that makes them interesting candidates
or molecular pathways inherent to the malignant phenotype.
for pH-based therapies. In a recent study, proteins were
However, most of these drugs still remain dose-limiting due to
extreme cytotoxicity.
While most of the latest attempts for selective cancer
encapsulated within acetal cross-linked hydrogels which,
at acidic pH, released the entrapped molecules, while, at
neutral pH, the cross-linker remained largely intact.18 In another
treatment are focused on the molecular target approaches,
example, acid-degradable polyacetal–doxorubicin conjugates
the profound microphysiological differences discovered
were used for improved tumor targeting.19 Yet another approach
by Warburg2 more than seven decades ago received much
involves designing appropriate non-toxic acid-labile agents that
less attention.3 It is now well recognized that the tumor
are stable at physiological pH but are cleaved rapidly at slightly
microenvironment is characterized by dramatically in-
acidic pH with the liberation of cytotoxic compounds. The prog-
creased glucose intake, slow blood flow, hypoxia, and low
ress in the development of such “proton-activated prodrugs”
extracellular pH (pHe).4–6 The functional vasculature of tumors
has been recently reviewed by Tietze and Feuerstein.20 Thus,
is often inadequate to supply the nutritional needs of the rapidly
the utility of conventional acid-labile acetals, ketals and acetal
expanding population of cells, leading to deficiency in oxygen
glycosides for selective treatment of solid tumors had been ex-
and many other nutrients. As a result, production of lactic acid
plored.21–24 These acetal glycosides could be chemisensitized
under anaerobic conditions and the hydrolysis of ATP in the
at pH 6.2 with a release of cytotoxic aldehydes. Although the
energy-deficient environment contribute to the acidic micro-
rates of acid-catalyzed hydrolysis were relatively low at pH 6.2
(t1/2 = 2–76 hours) some of these compounds exhibited nearly no
environment found in many types of tumors.7–10 Non-invasive
pH measurements reveal the presence of large regions of acidic
toxicity at physiological pH while at pH 6.2 the survival rate of
pHe in tumors, with the intracellular pH (pHi) being maintained
cancer cells decreased by a factor of 50000.25 Another interest-
in the neutral to alkaline range.10 The standard pH difference
ing use of acetals in nucleoside prodrug design has been recently
between normal tissues and tumors is rather small at 7.4 versus
described by Matsuda et al.22
ca. 6.9–7.0 pH units. However, this differential can be enhanced
For this promising approach to be successful, it is crucial
to develop agents that are cleaved as quickly as possible at pH
by as much as 1–1.5 units by hyperthermia,11 and/or glucose
6.2 in order to avoid their excessive circulation prior to activa-
tion. Considerable efforts have been undertaken to synthesize
† Electronic supplementary information (ESI) available: Materials and
Methods and characterization data for compounds 24, 25, 29–34. See
http://www.rsc.org/suppdata/ob/b4/b405786d/
acetal glycosides with appropriate acid lability.25 However, the
conventional acetal glycosides have insurmountable limitations
T h i s j o u r n a l i s
©
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 1 5 5 – 3 1 6 1
3 1 5 5

View Article Online
with respect to the further increases of their hydrolysis rates. In
this paper we present a facile and general photochemical synthe-
sis of a novel class of highly acid-sensitive siloxyacetal glycosides
which are stable under physiological pH but are rapidly trans-
formed into cytotoxic aldehydes at slightly acidic conditions
found in extracellular environment of solid tumors. Hydrolysis
and in vitro biological activity of these novel carbohydrate
derivatives are also discussed.
enolate anion (obtained from tert-butyldimethylsilyl allene)47
following the literature procedure48 failed yielding instead an
interesting and previously unreported bi-functional acylsilane 9
as a sole product (eqn. 2).
(2)
Results and discussion
A. Synthesis of acylsilanes
B. Synthesis of siloxyacetal glycosides
The photoreaction of acylsilanes with various peracetylated free
glucopyranosides was carried out in a solution or suspension
of these substrates in anhydrous benzene, with or without trace
amounts of pyridine added to stabilize the acid-sensitive acetal
glycosides from solvolysis by the photogenerated acids.31 Prog-
ress of the photoreaction was monitored either by TLC or by the
disappearance of the brightly colored acylsilanes. In general, a
solution of 2 equivalents of the free glycoside and 1 equivalent
of acylsilane in anhydrous benzene in the presence of a catalytic
amount of dry pyridine in a Pyrex® tube was purged with dry
argon and irradiated at kmax = 350 nm using a Rayonet photo-
chemical chamber reactor RPR-100. The reaction was usually
complete within 30 min. The reaction solution was evaporated
to dryness and the residue purified by flash-chromatography
using eluants containing 0.3% Et3N for stabilization of the acid-
sensitive acetal glycosides from decomposition on the slightly
acidic silica gel. The siloxyacetal glycosides were obtained in
70–90% yields.
Since original reports by Brook et al indicated the highly un-
stable nature of siloxyacetals formed by reacting acylsilanes with
simple primary alcohols,31 we set out to explore the stability of
siloxyacetals formed at different positions on the sugars. First,
three positional isomers 14, 17, and 18 were prepared by reacting
2,3,4,6-tetra-O-acetyl-b-D-glucopyranoside,49 (10) 1,2,3,6-tetra-
O-acetyl-a-D-glucopyranoside49 (11) and 1,2,3,4-tetra-O-acetyl-
b-D-glucopyranoside49 (12) with benzoyltrimethylsilane 5. The
photoadduct 18 of the primary alcohol 12 was too unstable to
be isolated and partially decomposed on silica gel even in the
presence of stabilizing triethylamine. At the same time, adduct
17 of the secondary alcohol 11 was isolated as a stable oil and
could be stored indefinitely at −20 °C without any signs of
decomposition. Remarkably, the photoadduct 14, with a 1,1-
diacetal structure, not only was exceptionally stable but also
was isolated in a solid form and could be recrystallized from
hot ethanol solution. The 1,1-diacetal structures are known to
be difficult to synthesize by conventional organic methods and
supposedly they must be more acid-labile than corresponding
monoacetals.21
Since their first synthesis by Brook26 nearly 50 years ago,
acylsilanes (a-silyl ketones) have attracted considerable
interest not only because of their special physical properties,
but also because of the synthetic utility of these compounds
due to the unusual reactivity of the carbonyl group located
alpha to the silicon atom. Numerous synthetic transforma-
tions that are pertinent to the acylsilane functionality have
been recently reviewed.27–30 In addition, acylsilanes show
photochemistry that is not possible with other carbonyl com-
pounds, such as the [1,2]-silyl shift to form highly reactive
siloxycarbenes.31–35 These carbenes are extremely labile and
react by intramolecular insertion into H–X bonds of polar
reagents (HOAc, HCN, pyrrole, HSPh, HCl, HOR)36 and elec-
tron-poor olefins.37 In the dark or in the absence of polar traps,
siloxycarbenes rapidly rearrange into the original acylsilanes
(eqn. 1).32 For example, with alcohols as solvents, mixed acetals
of an aldehyde with 1 mol each of silanol and alcohol were
formed in 60–100% yields.38 These acetals were highly sensitive
towards acid-catalyzed solvolysis and could be isolated only in
the presence of base.31
(1)
Although numerous methods for the synthesis of acylsilanes
have appeared in the literature in recent years,29 the original
dithiane route developed simultaneously by Brook et al.39 and
by Seebach and coworkers40 remains quite general and conve-
nient for the preparation of a great variety of acylsilanes. We
have chosen this method, with slight modifications, for the
preparation of sterically crowded acylsilanes 3 and 4 (Scheme 1)
from commercially available 2-phenyl-1,3-dithiane (1). Dithiane
1 was first silylated with TIPS-triflate or TBDMS-Cl41 and then
hydrolyzed with chloramine-T42 to afford the corresponding
acylsilanes 3 and 4 in good overall yields. Benzoyltrimethylsi-
lane (5) was readily prepared from benzyltrimethylsilyl ether via
dibromination with two equivalents of N-bromosuccinimide
followed by hydrolysis with silver acetate in acetone–etha-
nol–water.43 The cyclic 1,1-diphenyl-1-silacyclohexanone-2 (6)
was synthesized starting from 5-chloro-1-pentyne as previously
described by Brook and Pierce44 and by Benkeser and Cunico45
Synthesis of cyclopropoyldimethylphenylsilane (7) and 2-furoyl-
dimethylphenylsilane (8) was accomplished by reaction of cyclo-
propanecarbonyl chloride and 2-furoyl chloride, respectively,
with dimethylphenylsilyl–zinc cyanocuprate acting as a silyl
anion source.46
In addition, glucopyranoside 10 was reacted with
acylsilanes 7 and 8 to afford photoadducts 15 and 16, respec-
tively. Photoadduct 15 survived purification on silica gel but
decomposed slowly on storage without added base, while
adduct 16 could not survive even purification on silica gel.
Finally, stable mannose-derived photoadduct 19 was prepared
from 1,3,4,6-tetra-O-acetyl-b-mannopyranoside50 (13) and
acylsilane 5 (Scheme 2).
All of the siloxyacetal glycosides were isolated as 1:1 in-
1
separable mixtures of diastereomers at the acetal center. H
NMR spectra were consistent with the structures of acetals,
i.e. the presence of characteristic singlets at 5–6 ppm of a
hydrogen attached to the acetal carbon.31 The stereochemistry
at the anomeric center of the adducts 14 and 15 remained un-
changed, as judged by the NMR spectroscopy. All of the above
siloxyacetals gave satisfactory elemental analyses. However,
FAB mass spectra of trimethylsiloxy acetals failed to give the
molecular ion signals (see Experimental section). Therefore, the
structure and relative stereochemistry of the crystalline diacetal
photoproduct 14 was unambiguously determined by the X-ray
crystal structure analysis (Fig. 1).
Attempted preparation of the a,b-unsaturated vinyl
acylsilane by hydrolysis of the intermediate lithium silaacrolein
Scheme 1
3 1 5 6
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 1 5 5 – 3 1 6 1

View Article Online
radical pathways.31 All cyclic photoadducts were separated as
1:1 mixtures of diastereomers at the acetal center, were ex-
ceptionally stable towards separation on silica gel and could
be stored neat or in solution at room temperature without any
decomposition.
The critical stage in the synthesis was the deacetylation of the
trimethyl- and the cyclic diphenyl siloxyacetal glycosides. Since
potassium carbonate in anhydrous alcohols was used in the ear-
lier work of Brook et al. to stabilize photochemically generated
trimethylsiloxyacetals of simple alcohols,31 it was expected that
the silyl functionality would remain intact during the deacety-
lation procedure using catalytic K2CO3 in anhydrous methanol.17
However, all our attempts to deacetylate compounds 14–19 and
23–26 with K2CO3 in anhydrous methanol led to decomposition
of the acetal functionality. A variety of other literature methods
for the mild basic deprotection of acetyl groups were attempted;
all of which also led to the rapid destruction of the acetal func-
tionality, presumably via nucleophilic attack at the vulnerable
silicon center (see Experimental section). For example, deacety-
lation of 14 and 23 also failed using a basic ion-exchange resin
in water-free methanol with ultrasound as developed by Tietze
and Fischer-Beller specifically for deacetylation of acid-labile
glycosides.23
Scheme 2
This has led us to use other more sterically hindered trialkyl-
silyl groups that are more resistant to the basic conditions used
during the deacetylation procedures. To this end, we have synthe-
sized a series of sterically-crowded siloxyacetal glycosides 27–33
via reaction of acylsilanes 3 and 4 with glycopyranosides 10 and
20 (eqn. 4). These siloxyacetal glycosides could be easily de-
protected with catalytic sodium methoxide in methanol to give
compounds 28–34 in nearly quantitative yields. In contrast to
the trimethylsilyl derivatives, all of the triisopropyl and tert-
butyldimethyl siloxyacetals gave consistent elemental analyses
and FAB mass spectra (see Experimental section).
(4)
Interestingly, photoreaction of the novel bi-functional acyl-
silane 9 with benzyl alcohol evidently led to the photoadduct
35 (eqn. 5) in which only the unsaturated side of the acylsilane
functionality reacted with the OH-bond, leaving the unsaturated
segment intact.
Fig. 1 X-Ray crystal structure of photoadduct 14. Displacement
ellipsoid plot is drawn at the 50% probability level. There is some
disorder (65/35) of the atoms O1, O1A and C1A and only the major
form is shown. HFIX 33 was used to generate the coordinates; it is likely
that the methyl H atoms are incorrectly oriented.
A series of seven-member ring cyclic photoadducts 23–26
was prepared by reaction of glucopyranoside 10, 2,3,4,6-tetra-
O-acetyl-a-D-galactopyranoside (20), lactose heptaacetate
(21), and mannopyranoside 13 with cyclic acylsilane 6 (eqn. 3).
Interestingly, the photoreaction of 6 was much more efficient
than that of 5 with completion times of less than 20 min and
with nearly quantitative yields. This can be explained by greater
tendency of cyclic acylsilanes to react via siloxycarbenes com-
pared to their acyclic analogs that are also known to react via
(5)
C. Hydrolysis studies
There is substantial evidence that the specific acid-catalyzed
hydrolysis of acetals, ketals, and orthoesters proceeds by an
A-1 mechanism.51 The siloxyacetals are not an exception. The
precedent for the studies of the rate of hydrolysis of mixed
acetals of silanol, simple alcohols, and an aldehyde may be
found in the earlier work of Brook et al.31 For example, the
kinetics of decomposition of Ph3SiOCHPh(OMe) siloxyacetal
was determined at 0 °C and the plot of log of concentration vs.
time was linear in accordance with the pseudo first-order kinet-
ics required by the A-1 mechanism (Scheme 3). The first step
is the equilibrium protonation of the siloxy-oxygen followed
by rate-limiting loss of silanol (C–O bond cleavage) to give a
resonance-stabilized oxocarbenium ion 38 which then suffers
nucleophilic attack by water with the release of a sugar and
an aldehyde via breakdown of the highly unstable hemiacetal
(3)
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 1 5 5 – 3 1 6 1
3 1 5 7

View Article Online
39. A second mode of decomposition is believed to involve
a Si–O bond cleavage via nucleophilic attack on the silicon
atom by water; in this case hemiacetal 39 is formed without the
intermediacy of the oxocarbenium ion 38.31 In both cases, how-
ever, the observed pseudo first-order rate constant depends only
on pH with no catalysis by undissociated acids.51 The advantage
of siloxyacetals over conventional acetals can be explained by
the much higher basicity of the silicon-bound oxygen atom
relative to carbon-bound oxygen.28 This causes the protonation
equilibrium to shift towards the protonated form of the acetal
which in turn will effectively increase the rate of formation of
the oxocarbenium ion 38. The higher nucleophilicity of the
siloxy oxygen atom is attributed to the large inductive effect due
to low electronegativity of silicon (1.8) relative to carbon (2.5),
and by the larger mass of silicon;28 the same reason responsible
for the unusual reactivity of a-silyl ketones compared to con-
ventional ketones.
14 were prepared in acetonitrile. Kinetic runs were initiated by
injecting the stock solution into a temperature equilibrated
buffer directly into the UV cuvette to make the final concen-
tration of the substrate 10−8 M. Fig. 2 shows the results of the
kinetic runs at different pH values. The kinetic trace at pH 6.2
was fitted linearly in accordance with the first-order kinetics law
to give the rate constant for the hydrolysis k = 3.94 × 10−2 min−1,
which corresponds to a half-life of only 17.5 minutes at ambi-
ent temperature. The acid lability of benzaldehyde acetals can
be either increased or decreased by introducing electon-donat-
ing or electron-withdrawing substituents, respectively, in the
para position of the phenyl ring. For example, the half-life of
benzaldehyde acetals was reduced by as much as 200 times
simply by reducing a p–NO2 group to an amine.22
Fig. 2 Kinetics of acid-catalyzed hydrolysis of adduct 14 in McIlvaine
buffer monitored by the appearance of benzaldehyde at kmax = 250 nm.
D. Biological activity
In vitro anticancer evaluation of siloxyacetal glycosides 14
(NSC 725089), 23 (NSC 725091), 24 (NSC 725090), and 25
(NSC 725092) was performed in the NCI’s three cell line pre-
screen assay against two standard drugs with well-documented
activity, namely 5-fluorouracil (NSC 19893) and adriamycin
(NSC 123127). The three cell lines were MCF-7 (breast cancer),
NCI-H460 (lung cancer), and SF-268 (CNS tumor), and the
tests were performed according to the protocol outlined in the
Materials and Methods section.†
The results of the testing are shown in Table 1. It is evident
that benzaldehyde-bearing siloxyacetal 14 was completely inac-
tive against all tested cell lines. Among the cyclic acetals 23–25,
which bear masked lipophilic 5-(diphenylhydroxy)silyl pentanal
37, on the other hand, only glucoside 23 appeared to be effective
against the MCF-7 cell line (inhibiting cell growth to 31% rela-
tive to control) while galactoside 24 and lactoside 25 analogs had
very little if any cytotoxic effect (see Table 1).
Scheme 3
We first investigated the products of acid-catalyzed degrada-
tion of acyclic siloxyacetal 14 and cyclic siloxyacetal 23. Thus,
the siloxyacetals were completely hydrolyzed in chloroform
solution by addition of a catalytic amount of 1 M HCl. The
hydrolysis was followed by TLC and was usually complete
within a few minutes. The products of decomposition were
separated by flash-column chromatography and identified by
TLC, NMR and by comparing to the literature data. It was
found that 14 decomposes with a release of glucopyranoside 10,
benzaldehyde, and trimethylsilanol, which under acidic condi-
tions spontaneously dehydrates to yield siloxane Me3SiOSiMe3.
Cyclic siloxyacetal 23 gave exclusively glucopyranoside 10 and a
known 5-(diphenylhydroxysilyl) pentanal52 37 (eqn. 6).
Since an accelerated rate of glucose transport is one of
the most prominent biomarkers of many tumor tissues,54 we
assume that the relative efficiency of siloxyacetal 23 compared
to 24 and 25 may be attributed to the preferential uptake of
this compound by MCF-7 cells. The inactivity of 14 versus 23,
in turn, may be explained by low cytotoxicity of benzaldehyde
versus lipophilic silyl-terminated pentanal 37. The cyto- and
genotoxic activity of aliphatic aldehydes is well documented.55
For example, studies on cyto- and genotoxicity of n-alkanals
have shown that these aldehydes are markedly toxic to human
and rodent cells and that the toxicity increases with increasing
chain length (lipophilicity).56 Thus, hexanal and nonanal have
been found to be extremely toxic but not mutagenic, while
propanal, butanal, and pentanal, in addition to being toxic, were
able to cause DNA mutations.56 In contrast, to our knowledge,
no studies exist on the antitumor activity of aromatic aldehydes
since they are rarely observed in natural systems.
(6)
The rate of hydrolysis of siloxyacetal 14 at different pHs
was measured spectrophotometrically by following the ab-
sorbance increase due to the appearance of benzaldehyde at
kmax = 250 nm. McIlvaine buffers (phosphate–citrate) at pH
4.3, 6.2, 6.98 and 7.4, with constant ionic strength, were used in
the studies.53 The ionic molarity of all buffers was maintained
constantly at 0.5 M with KCl. Stock solutions of the substrate
3 1 5 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 1 5 5 – 3 1 6 1

View Article Online
Si(CHMe2)3); 13C NMR (100 MHz, CDCl3) d = 141.4, 130.7,
128.2, 125.3, 49.9, 25.4, 25.3, 19.7, 12.0; FAB MS m/z 309
(MH+ − C3H8), 352.1 (M+), MW 352.7. Anal: calcd for
C19H32S2Si: C, 64.71; H, 9.15; found: C 64.87; H 9.25%.
Table 1 Percent growth of cells treated with 100 lM solutions of the
selected siloxyacetal glycosides relative to controls
Compound
Cell line
(14)
(23)
(24)
(25)
2-Phenyl-2-tert-butyldimethylsilyl-1,3-dithiane 2b42
NCI-H460
MCF-7
SF-268
109a
91
111
88
31
110
98
80
104
93
82
101
Compound 2b was prepared similarly to compound 2a in 92%
yield.
a Percent = growth treated/growth controls.
Benzoyltriisopropylsilane 358
A solution of 2.5 g (7.08 mmol) of 2a in 40 ml of acetone was
treated with 11 g (39.15 mmol) of chloramine-T in 80 ml of
80:20 MeOH–H2O. The reaction solution immediately turned
fluorescent yellow. After 15 min, 20 ml of 10% NaCl was added
followed by 20 ml of 0.5 M NaHCO3. The product was extracted
with hexanes until no yellow color remained in the aqueous
phase. The hexane extracts were evaporated and purified by FCC
to give 1.45 g (78%) of acylsilane 3 as a bright yellow liquid.
Conclusions
In summary, a series of highly acid-sensitive siloxyacetal
glycosides have been synthesized via facile photochemical in-
sertion of siloxycarbenes into the OH-bond of a variety of
carbohydrates. Although siloxyacetals of simple alcohols
have been prepared before, their low stability without added
base prevented them from being useful synthetic intermedi-
ates. In contrast, siloxyacetal glycosides reported in this study,
especially those having 1,1-diacetal structure, proved to be
exceptionally stable and could be stored indefinitely without
added base. These physical properties may potentially lead to
their use as orthogonal protecting groups in oligosaccharide
synthesis. In addition, it was shown that one glucose derivative
had moderate activity against the MCF-7 breast cancer cell line.
At the same time, similar lactose and galactose derivatives were
completely inactive. Further extension of this study to include
more cytotoxic aldehydes may provide a novel potent class of
anti-cancer agents that function by pH difference.
Benzoyl-tert-butyldimethylsilane 442
Compound 4 was prepared from 2b according to the preparation
of 3 above in 73% yield.
1,5-Bis-(tert-butyldimethylsilyl)-2-methylene-pentane-1,5-dione 9
A solution of 220 mg (1.29 mmol) of tert-butyldimethyl-
silylallenyl ether48 in 4 ml of THF was slowly treated with
0.7 ml (1.15 mmol) of 1.7 M solution of tert-butyllithium in
pentane at −78 °C. The solution became light yellow. After
40 minutes, the reaction was warmed to room temperature
and quenched with a solution of 1.25 ml 1 M H2SO4 in 10 ml
THF. The reaction was diluted with 1:1 hexane–diethyl ether,
washed with water and brine and dried over MgSO4. Evapora-
tion of the solvents followed by FCC with 15:1 hexanes–di-
ethyl ether afforded 160 mg (73%) of 9 as a bright yellow
viscous liquid. Rf 0.5 (10:1 hexanes–diethyl ether); IR (neat)
1752, 1642 cm−1; 1H NMR (400 MHz, CDCl3) d = 5.89 (s, 1H,
CCH2), 5.79 (s, 1H, CCH2), 2.52 (m, 2H, –CH2–), 2.23 (m,
2H, –CH2–), 0.750 (s, 9H, t-Bu), 0.747 (s, 9H, t-Bu), 0.09 (s,
6H, SiMe2), 0.0 (s, 6H, SiMe2); 13C NMR (100 MHz, CDCl3)
d = 250.5 (TBDMSC(O)CH2), 241.2 (TBDMSC(O)CCH2),
154.6 (CCH2), 129.6 (CCH2), 49.0, 26.9, 26.6, 22.6, 16.9,
16.7, −4.3, −6.8. FAB MS m/z (relative intensity) 341.2 (MH+),
MW 340.7. Anal: calcd for C18H36O2Si2: C, 63.47; H, 10.65;
found: C 63.70; H 10.63%.
Experimental
General procedure for the synthesis of siloxyacetal glycosides
14–19, 23–27, 29, 31, 33
All photoreactions were carried out in the Rayonet Photo-
chemical Chamber Reactor Model RPR-100 equipped with
RPR-3500A lamps (kmax = 350 nm) under argon atmosphere in
anhydrous benzene at ambient temperature. The progress of the
reactions was monitored by TLC (thin layer chromatography),
IR (disappearance of the OH-bond in excess of acylsilanes), and
visually (disappearance of bright yellow acylsilanes in excess of
peracetylated free glycosides).
General procedure for deacetylation of triisopropyl- and tert-
butyldimethylsilyl acetals 27, 29, 31, 33
A solution of 0.17 mmol of a siloxyacetal in 5–10 ml of
anhydrous MeOH (Aldrich) was treated with 2–3 drops of
25% v/v NaOMe–MeOH (Aldrich). After 30 min the reaction
was carefully neutralized with weakly acidic ion-exchange
resin (Amberlite® IRC-50), filtered, evaporated and separated
by FCC (flash column chromatography) with 10% MeOH in
CH2Cl2.
Photoreaction of acylsilane 9 with benzyl alcohol. 35
To a solution of 25 mg (0.07 mmol) of 9 in 5 ml of anhydrous
benzene was added 50 mg (0.40 mmol, 5.7 equiv.) of anhydrous
benzyl alcohol followed by 1 drop of pyridine for stabilization
purposes. The solution was purged with argon for 20 min,
sealed and placed in a photoreactor. In ca. 10–20 min the reac-
tion was complete. Separation of the products on silica gel with
10:1 hexanes–diethyl ether gave 20 mg (64%) of 35 as a clear
oil. Rf 0.60 (5:1 hexanes–diethyl ether); IR (neat) 2930, 2858,
1752 (TBDMSCO), 1691 cm−1; 1H NMR (400 MHz, CDCl3)
d = 7.17–7.32 (m, 5H, Ph), 5.11 (s, 1H, acetal CH), 5.07 (s, 1H,
CH2), 4.85 (s, 1H, CH2), 4.43 (ABq, 2H, J = 11.71 Hz,
PhCH2O), 2.78 (m, 2H, CH2CO), 2.30 (m, 2H, CH2CCH2–),
0.8–0.9 (m, 18H, 2 × SiCMe3), 0.0–0.1 (m, 12H, 2 × SiMe2).
Anal: calcd for C25H44O3Si2: C, 66.91; H, 9.88; found: C 66.70;
H 9.82%.
2-Phenyl-2-triisopropylsilyl-1,3-dithiane 2a
A solution of 2 g (10.2 mmol) of 2-phenyl-1,3-dithiane (PDT)
in 16 ml THF was cooled to 0 °C. A solution of 1.6 M n-BuLi
in hexanes (9.5 ml, 15.2 mmol, 1.5 equiv.) was added dropwise
to the solution of PDT. After 10 min, 3.12 g (10.2 mmol) of
TIPSOTf was added at once. After stirring for 30 min at 0 °C,
the reaction was slowly warmed to ambient temperature. After
an additional 30 min the reaction was carefully quenched with
sat. NH4Cl, diluted with EtOAc, washed 2 times with water and
dried over MgSO4. After evaporation, the residue was separated
by FCC with 50:1 to 40:1 hexanes–EtOAc to give 2.5 g (70%)
1-(Trimethylsiloxy-phenyl-methoxy)-2,3,4,6-tetra-O-acetyl-b-D-
glucopyranoside 14
1
of crystalline product. Rf 0.8 (4:1 hexanes–EtOAc); H NMR
(400 MHz, CDCl3) d = 8.02–8.06 (m, 2H, Ph), 7.31–7.37 (m,
2H, Ph), 7.12–7.17 (m, 1H, Ph), 1.80–2.80 (m, 6H, S(CH2)3S),
1.25–1.38 (m, 3H, Si(CHMe2)3), 1.10 (d, 18H, J = 7.42 Hz,
A 1:1 mixture of two diastereomers at the acetal center
(designated arbitrarily as R(S) and S(R)). Yield 70%. Rf 0.5
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 1 5 5 – 3 1 6 1
3 1 5 9

View Article Online
(tert-butylmethyl ether–petroleum ether). White crystals‡, mp
0.19, 0.14 (s, 2 × 3H, SiMe2). 13C NMR data (100 MHz, CDCl3)
d = 175.72, 175.40, 174.47, 174.20, 145.35, 133.92, 133,86,
133.28, 131.44, 131.33, 103.13, 101.99, 100.09, 99.68, 78.08,
76.82, 76.39, 73.64, 67.07, 30.78, 25.82, 25.70, 25.65, 23.18,
0.79, 0.00. FAB MS m/z 607.3 (MK+), MW 568.7. Anal: calcd
for C27H40O11Si C, 57.02; H, 7.09; found: C, 57.23; H 7.14%.
1
95–97 °C; IR (neat) 1040, 1222, 1367, 1756 cm−1; H NMR
(400 MHz, CDCl3) d = 7.41–7.30 (m, 5H, aromatic), 6.05 (s, 1H,
PhCH (S(R)epimer), 5.93 (s, 1H, PhCH (R(S)-epimer)), 4.91
(d, 0.5H, H-1 (S(R)) epimer), 4.56 (d, 1H, H-1 (R(S)) epimer),
4.25–4.06 (m, 2H, H-6), 3.72 (ddd, 0.5H, H-5 (S(R)) epimer),
3.58 (ddd, 1.1H, H-5 (R(S)) epimer), 2.08, 2.07, 2.03, 2.01, 2.00,
1.98, 1.90 (s, 12H, CH3C(O)), 0.17 (s, 1H, SiMe3), 0.11 (s, 1H,
SiMe3); 13C NMR (100 MHz, CDCl3) d = 170.4 (CH3C(O),
(S(R))), 170.3 (CH3C(O), (R(S))), 170.1 (CH3C(O), (S(R))),
170.0 (CH3C(O), (R(S))), 169.2 (CH3C(O), (S(R))), 169.1
(CH3C(O), (R(S))), 169.0 (CH3C(O), (S(R))), 168.8 (CH3C(O),
(R(S))), 139.9 (C-1, Ph, (S(R))), 139.8 (C-1, Ph, (R(S)), 128.6
(C-4, Ph, (R(S))), 128.4 (Ph, (S(R))), 128.0 (C-3,5, Ph, (R(S))),
127.9 (Ph, (S(R))), 126.0 (C-2,6, Ph, (R(S))), 97.8, 97.1, 94.8,
93.9, 72.8, 72.6, 71.7, 71.5, 71.1, 70.8, 68.3, 68.2, 61.8 (C-6, S(R)),
61.8 (C-6, R(S)), 20.5, 20.4, 20.32, 20.3, 20.28, (CH3C(O)), 0.02
(SiMe3, (S(R)), 0.00 (SiMe3, (R(S))). Anal: calcd for C24H34O11Si
C, 54.74; H, 6.51; found: C, 54.81; H 6.51%.
1-(tert-Butyldimethylsiloxy-phenyl-methoxy)-a,b-D-
glucopyranoside 28
A mixture of four diastereomers at the anomeric and acetal cen-
ters. Glassy solid. Yield 95%. Rf 0.32 (10% MeOH in CH2Cl2);
1H NMR (400 MHz, CDCl3) d = 7.30–7.54 (m, 5H, Ph), 6.04
(s, 0.3H, PhCH), 6.00 (s, 0.2H, PhCH), 5.93 (s, 0.2H, PhCH),
5.88 (s, 0.3H, PhCH), 2.8–5.4 (11H, sugar ring protons), 0.86
(9H, Si(tert-Bu)), 0.00–0.19 (6H, SiMe2); 13C NMR (100 MHz,
CDCl3): d = 145.8, 145.7, 145.5, 133.7, 133.3, 133.2, 131.5,
131.4, 131.3, 131.2, 105.1, 103.5, 102.4, 102.3, 100.2, 99.5, 81.3,
80.6, 79.2, 78.3, 77.9, 77.0, 76.8, 76.6, 76.5, 74.1, 66.3, 30.7, 23.1,
0.6, 0.6, 0.30, 0.27, 0.2, 0.00. FAB MS m/z 439.3 (M + K+), MW
400.5. Anal: calcd for C19H32O7Si: C, 56.97; H, 8.05; found: C
56.34; H 7.95%.
4-(Trimethylsiloxy-phenyl-methoxy)-1,2,3,6-tetra-O-acetyl-a-D-
glucopyranoside 17
A 1:1 mixture of two diastereomers at the acetal center. Clear
oil. Yield 60%. Rf 0.2 (1:1 benzene–EtOAc); IR (neat) 1751 cm−1;
1H NMR (400 MHz, CDCl3): d = 7.21–7.33 (m, 5H, Ph), 6.22
(m, 1H, H-1), 5.68, 5.49 (s, 2 × 0.5H, PhCH), 5.44–5.54 (m, 1H,
H-4), 4.95–5.03 (m, 1H, H-3), 3.77–4.62 (m, 4H, H-2, H5, H-
6ab), 1.94–2.10 (s, 12H, Ac), 0.02, 0.01 (s, 9H, SiMe3); 13C NMR
(100 MHz, CDCl3): d = 170.6, 170.4, 170.1, 170.0, 169.9, 169.4,
168.9, 168.9, 140.5, 140.3, 129.0, 129.0, 128.5, 128.4, 128.4,
126.0, 125.9, 125.8, 125.8, 98.6, 98.2, 89.2, 89.1, 72.1, 72.0, 71.7,
71.1, 71.0, 69.9, 69.7, 69.4, 62.8, 61.7, 21.2, 20.9, 20.9, 20.8, 20.8,
20.5, 20.5, 14.1, 0.2, 0.04, 0.00. Anal: calcd for C24H34O11Si: C,
54.74; H, 6.51; found: C, 54.88; H 6.51%.
1-(2,2-Diphenyl-1-oxa-2-silacyclohept-7-yl)-2,3,4,6-tetra-O-
acetyl-b-D-glucopyranoside 23
Two diastereomers at the acetal center (arbitrarily assigned as
R(S) and S(R)). Glassy solid. Yield 90%. Rf 0.38 (R(S) epimer),
0.33 (S(R) epimer) (2:1 hexanes–ethyl acetate + 1% Et3N); IR
1
(neat) 1748 cm−1; H NMR (400 MHz, CDCl3) d = 7.57–7.67
(m, 4H, aromatic), 7.31–7.43 (m, 6H, aromatic), 5.16 (t, 1H,
J = 9.55 Hz, acetal H), 4.77 (d, 1H, J = 7.88 Hz, b-1H), 2.01,
2.00, 1.99, 1.86 (s, 12H, Ac); 13C NMR (100 MHz, CDCl3)
d = 170.7, 170.3, 169.4, 169.2, 136.0, 135.6, 134.3, 134.2, 134.1,
134.04, 129.9, 129.8, 128.1, 128.0, 127.9, 127.8, 101.3, 99.0, 72.9,
72.0, 71.6, 68.3, 62.1, 37.6, 25.4, 23.1, 20.8, 20.63, 20.6, 20.5,
14.5. FAB MS m/z 615.3 (MH+), MW 614.7. Anal: calcd for
C31H38O11Si: C, 60.57; H, 6.23; found: C 60.60; H 6.27%.
2-(Trimethylsiloxy-phenyl-methoxy)-1,3,4,6-tetra-O-acetyl-b-D-
mannopyranoside 19
A 1:1 mixture of two diasteromers at the acetal center (arbi-
trarily designated as R(S) and S(R)). Glassy solid. Yield 63%.
Rf 0.35 (1:1 hexanes–ethyl acetate + 0.6% Et3N); IR (neat)
2-(2,2-Diphenyl-1-oxa-2-silacyclohept-7-yl)-1,3,4,6-tetra-O-
acetyl-b-D-mannopyranoside 26
A 3:2 mixture of two diastereomers at the acetal center. Glassy
solid. Yield 86%. Rf 0.55 (1:1 hexanes–ethyl acetate); IR (neat)
1033, 1052, 1216, 1368, 1747, 2937 cm−1; 1H NMR (400 MHz,
CDCl3) d = 7.74–7.68 (m, 1H, aromatic), 7.68–7.62 (m, 1H,
aromatic), 7.58–7.51 (m, 2H, aromatic), 7.43–7.30 (m, 6H,
aromatic), 5.77 (d, J = 1.39 Hz, 0.6H (R(S)), H-1), 5.76 (d,
J = 0.76 Hz, 0.4H (SI), H-1), 5.40 (t, J = 9.72 Hz, 0.4H (SI),
H-4), 5.30 (t, J = 9.33 Hz, 0.6H (R(S)), H-4), 5.23 (dd, J = 7.63,
1.35 Hz, 0.4H, acetal H(SI)), 5.19 (dd, J = 6.55, 1.73 Hz, 0.6H,
acetal H (R(S))), 5.12 (dd, J = 9.48, 2.93 Hz, 0.6H, H-3 (R(S)),
4.93 (dd, J = 9.96, 3.32 Hz, 0.4H, H-3 (SI)), 4.42 (d, J = 2.93 Hz,
0.4H, H-2(SI)), 4.37 (q, J = 1.37 Hz, 0.6H, H-2(R(S))), 4.3–4.11
(m, 2H, H-6), 3.75 (m, 1H, H-5), 2.07, 2.03, 2.02, 1.94 (s, 12H,
1
1034, 1216, 1368, 1743 cm−1; H NMR (400 MHz, CDCl3)
d = 7.43–7.48 (m, 2H, aromatic), 7.29–7.37 (m, 3H, aromatic),
2.19, 2.12, 2.11, 2.04, 2.04, 2.03, 2.02, 1.99 (s, 12H, AcO), 5.91
(R(S)), 5.89 (S(R)) (s, 1H, PhCH), 5.78 (S(R)), 5.74 (R(S)) (d,
1H, H-1), 5.37, 5.34 (t, 1H, J = 9.51 Hz, H-4), 5.0 (dd, 1H,
J = 3.03, 9.73 Hz, H-3(R(S))), 4.90 (dd, 1H, J = 3.34, 9.75 Hz,
H-3(S(R))), 4.34 (dd, 1H, J = 1.17, 3.27 Hz, H-2), 4.23 (d, 1H,
H-6a), 4.18 (d, 1H, J = 5.32, H-6b), 3.72–3.78 (m, 1H, H-5), 0.16
(R(S)), 0.09(S(R)) (s, 9H, SiMe3), 13C NMR (100 MHz, CDCl3)
d = 170.6, 170.2, 169.7, 169.3, 169.3, 168.6, 168.4 (C(O)CH3),
140.6, 140.2, 129.6, 128.9, 128.7, 128.5, 128.0, 127.9, 126.5,
126.4, 98.1, 97.8 (PhCH), 92.4, 92.0 (2C), 73.1, 73.0, 72.1, 69.4,
69.2, 65.8, 65.5 (sugar CHs), 62.2 (6C), 21.0, 20.9, 20.8, 20.6,
20.57, 20.55, 20.53 (C(O)CH3), 0.16, 0.00 (SiMe3). Anal: calcd
for C24H34O11Si C, 54.74; H, 6.51; found: C, 54.90; H 6.53%.
CH3C(O)), 1.73, 1.58, 1.54, 2.1–1.18 (m, 8H, aliphatic ring); 13
C
NMR (100 MHz, CDCl3) d = 170.9, 170.7, 169.8, 169.7, 169.4,
168.6, 136.3, 136.2, 136.1, 136.0, 134.5, 134.4, 134.3, 134.2,
130.1, 130.09, 130.0, 129.97, 128.5, 128.2, 128.14, 128.11, 128.0,
101.2, 100.5, 92.4, 92.0, 73.5, 73.4, 72.7, 72.0, 71.3, 70.8, 66.6,
65.8, 62.7, 62.6, 37.72, 37.65, 25.9, 25.8, 23.6, 23.5, 21.0, 20.96,
20.9, 20.8, 20.6, 15.2, 15.0. FAB MS m/z 615.3 (MH+); MW
614.7. Anal: calcd for C31H38O11Si: C, 60.57; H, 6.23; found: C
60.32; H 6.21%.
1-(tert-Butyldimethylsiloxy-phenyl-methoxy)-2,3,4,6-tetra-O-
acetyl-a,b-D-glucopyranoside 27
A mixture of four diastereomers at the anomeric and acetal
centers (NMR of b-anomer given). Clear oil. Yield 78%. Rf 0.45
(2:1 hexanes–ethyl acetate + 0.3% NEt3); 1H NMR (400 MHz,
CDCl3) d = 7.34–7.46 (m, 5H, Ph), 5.00–5.20 (m, 3H, H-2, H-3,
H-4), 4.61 (d, 1H, J = 7.81 Hz, bH-1), 4.08–4.15 (m, 2H, H-6),
2.12, 2.04, 2.02, 1.94 (s, 4 × 3H, Ac), 0.93 (s, 9H, Si(tert-Bu)),
In vitro biological activity studies
Siloxyacetals were solubilized in dimethyl sulfoxide and stored
frozen. Compounds were then diluted with complete media with
0.1% gentamicin, and 20 ll of this solution was dispensed into
test wells containing 50 ll of cell suspension to yield a test con-
centration of 100 lM. After compound addition, plates were in-
‡ CCDC reference number 246339. See http://www.rsc.org/suppdata/
ob/b4/b405786d for crystallographic data in .cif or other electronic
format.
3 1 6 0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 1 5 5 – 3 1 6 1

View Article Online
23 L. F. Tietze and A. Fischer-Beller, Carbohydr. Res., 1994, 254,
169–182.
cubated at standard conditions for 48 hours. Following this, 10 ll
per well Alamar Blue was added and the plates were incubated
for an additional 4 hours. Fluorescence was measured using an
excitation wavelength of 530 nm and an emission wavelength of
590 nm. Percent test cell (PTC) growth/control (untreated) cell
growth (T/C) was calculated on a plate-by-plate basis for test
wells relative to control wells. Percent growth is expressed as the
ratio of fluorescence of the test well to the average fluorescence
of the control wells.57
24 L. F. Tietze, R. Hannemann, W. Buhr, M. Logers, P. Menningen,
M. Lieb, D. Starck, T. Grote, A. Doring and I. Schubert, Angew.
Chem., Int. Ed. Engl., 1996, 35, 2674–2677.
25 L. F. Tietze,
M. Beller,
R. Fischer,
M. Logers,
E. Jahde,
K. H. Glusenkamp and M. F. Rajewsky, Angew. Chem., Int. Ed.
Engl., 1990, 29, 782–783.
26 A. G. Brook, J. Am. Chem. Soc., 1957, 79, 4373–4375.
27 P. F. Cirillo and J. S. Panek, Org. Prep. Proced. Int., 1992, 24,
555–582.
28 P. C. B. Page, S. S. Klair and S. Rosenthal, Chem. Soc. Rev., 1990, 19,
147–195.
Acknowledgements
29 A. Ricci and A. Deglinnocenti, Synthesis. Stuttgart., 1989, 647–660.
30 A. F. Patrocinio and P. J. S. Moran, J. Braz. Chem. Soc., 2001, 12,
7–31.
31 J. M. Duff and A. G. Brook, Can. J. Chem., 1973, 51, 2869–2883.
32 M. Trommer and W. Sander, Organometallics, 1996, 15, 189–193.
33 M. E. Scheller and B. Frei, Helv. Chim. Acta, 1992, 75, 69–78.
34 M. E. Scheller and B. Frei, Helv. Chim. Acta, 1984, 67, 1734–1747.
35 A. G. Brook, Acc. Chem. Res., 1974, 7, 77–84.
36 R. A. Bourque, P. D. Davis and J. C. Dalton, J. Am. Chem. Soc.,
1981, 103, 697–699.
We greatly appreciate generous support of the initial stages
of this work by Prof. Charles Grissom (Department of
Chemistry and Biochemistry, University of Utah, Salt Lake
City). We thank Dr Cliff George (Laboratory for the Structure
of Matter, Naval Research Laboratory, Washington DC) for
X-ray crystal structure determination. SAS is grateful to the
Center for Cancer Research, NCI for an FTE loan extension.
37 J. C. Dalton and R. A. Bourque, J. Am. Chem. Soc., 1981, 103,
699–700.
38 A. G. Brook and J. M. Duff, J. Am. Chem. Soc., 1967, 89, 454–455.
39 A. G. Brook, J. M. Duff, P. F. Jones and N. R. Davies, J. Am. Chem.
Soc., 1967, 89, 431–434.
References
1 S. P. Linke, Nature, 1998, 395, 13.
2 O. H. Warburg, in The Metabolism of Tumors, (F. Dickens transl.),
Constable Press, London, 1930.
3 M. Stubbs, C. L. Bashford and J. R. Griffiths, Curr. Mol. Med.,
2003, 3, 49–59.
4 M. Stubbs, P. M. J. McSheehy, J. R. Griffiths and C. L. Bashford,
Mol. Med. Today, 2000, 6, 15–19.
40 E. J. Corey, D. Seebach and R. Freedman, J. Am. Chem. Soc., 1967,
89, 434–436.
41 T. H. Chuang, J. M. Fang, W. T. Jiaang and Y. M. Tsai, J. Org.
Chem., 1996, 61, 1794–1805.
5 J. R. Griffiths, Br. J. Cancer, 1991, 64, 425–427.
6 P. A. Schornack and R. J. Gillies, Neoplasia, 2003, 5, 135–145.
7 I. F. Tannock and D. Rotin, Cancer Res., 1989, 49, 4373–4384.
8 J. Luo and I. F. Tannock, Br. J. Cancer, 1994, 70, 617–624.
9 M. J. Boyer, M. Barnard, D. W. Hedley and I. F. Tannock, Br. J.
Cancer, 1993, 68, 890–897.
42 B. Dondy, P. Doussot and C. Portella, Synthesis. Stuttgart., 1992,
995–998.
43 A. G. Brook, G. J. D. Quigley, N. V. Peddle and C. M. Schwartz, J.
Am. Chem. Soc., 1960, 82, 5102–5106.
44 A. G. Brook and J. B. Pierce, J. Org. Chem., 1965, 30, 2566–2571.
45 R. Benkeser and R. Cunico, J. Organomet. Chem., 1965, 4,
284–290.
46 B. F. Bonini, M. Comesfranchini, G. Mazzanti, U. Passamonti,
A. Ricci and P. Zani, Synthesis. Stuttgart., 1995, 92–96.
47 I. A. Stergiades and M. A. Tius, J. Org. Chem., 1999, 64,
7547–7551.
48 M. A. Tius and H. P. Hu, Tetrahedron Lett., 1998, 39, 5937–5940.
49 T. Utamura, K. Kuromatsu, K. Suwa, K. Koizumi and T. Shingu,
Chem. Pharm. Bull., 1986, 34, 2341–2353.
50 H. Franzyk, M. Meldal, H. Paulsen and K. Bock, J. Chem. Soc.,
Perkin Trans. 1, 1995, 2883–2898.
51 A. T. N. Belarmino, S. Froehner, D. Zanette, J. P. S. Farah,
C. A. Bunton and L. S. Romsted, J. Org. Chem., 2003, 68, 706–717.
52 A. G. Brook, Can. J. Chem., 1971, 49, 1622–1628.
53 P. J. Elving, J. M. Markowitz and I. Rosenthal, Preparation of
buffer systems of constant ionic strength, Anal. Chem., 1956, 28(7),
1179–1180.
10 N. Raghunand and R. J. Gillies, Drug Resist. Updat., 2000, 3,
39–47.
11 S. K. Calderwood and J. A. Dickson, Adv. Radiat. Biol., 1983, 10,
135–190.
12 E. Jahde and M. F. Rajewsky, Cancer Res., 1982, 42, 1505–1512.
13 S. Osinsky, L. Bubnovskaja and T. Sergienko, Anticancer Res., 1987,
7, 199–201.
14 P. Wong, H. W. Kleemann and I. F. Tannock, Br. J. Cancer, 2002, 87,
238–245.
15 N. Raghunand, X. He, R. van Sluis, B. Mahoney, B. Baggett,
C. W. Taylor, G. Paine-Murrieta, D. Roe, Z. M. Bhujwalla and
R. J. Gillies, Br. J. Cancer, 1999, 80, 1005–1011.
16 J. Taillefer, M. C. Jones, N. Brasseur, J. E. van Lier and J. C. Leroux,
J. Pharm. Sci., 2000, 89, 52–62.
17 P. J. Kocienski, in Protecting Groups, ed. D. Enders, R. Noyori and
B. M. Trost, Thieme, Stuttgart, New York, 1994.
18 N. Murthy, Y. X. Thng, S. Schuck, M. C. Xu and J. M. J. Frechet, J.
Am. Chem. Soc., 2002, 124, 12398–12399.
54 J. S. Flier, M. M. Mueckler, P. Usher and H. F. Lodish, Science,
1987, 235, 1492–1495.
19 R. Tomlinson, J. Heller, S. Brocchini and R. Duncan, Bioconjugate
Chem., 2003, 14, 1096–1106.
20 L. F. Tietze and T. Feuerstein, Curr. Pharm. Design, 2003, 9,
2155–2175.
55 E. Schauenstein, H. Esterbauer and H. Zollner, in Pion Advanced
Biochemistry Series, 5. Aldehydes in Biological Systems: Their
Natural Occurrence and Biological Activities, (P. H. Gore, transl.),
Pion, London, 1977.
56 A. Martelli, R. Canonero, M. Cavanna, M. Ceradelli and
U. M. Marinari, Mutat. Res., 1994, 323, 121–126.
57 http://dtp.nci.nih.gov/branches/btb/ivclsp.html.
58 M. Burns and J. K. Coward, J. Org. Chem., 1993, 58(2), 528–532.
21 L. F. Tietze and R. Fischer, Angew. Chem., Int. Ed. Engl., 1981, 20,
969–970.
22 M. Nomura, S. Shuto and A. Matsuda, Bioorg. Med. Chem., 2003,
11, 2453–2461.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 1 5 5 – 3 1 6 1
3 1 6 1