Revisiting Bromohexitols as a Novel Class of Microenvironment-Activated Prodrugs for Cancer Therapy

Article abstract of DOI:10.1002/cmdc.201900578

Bromohexitols represent a potent class of DNA-alkylating carbohydrate chemotherapeutics that has been largely ignored over the last decades due to safety concerns. The limited structure?activity relationship data available reveals significant changes in cytotoxicity with even subtle changes in stereochemistry. However, no attempts have been made to improve the therapeutic window by rational drug design or by using a prodrug approach to exploit differences between tumour physiology and healthy tissue, such as acidic extracellular pH and hypoxia. Herein, we report the photochemical synthesis of highly substituted endoperoxides as key precursors for dibromohexitol derivatives and investigate their use as microenvironment-activated prodrugs for targeting cancer cells. One endoperoxide was identified to have a marked increased activity under hypoxic and low pH conditions, indicating that endoperoxides may serve as microenvironment-activated prodrugs.

Full text of DOI:10.1002/cmdc.201900578

DOI: 10.1002/cmdc.201900578
Full Papers
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Revisiting Bromohexitols as a Novel Class of
Microenvironment-Activated Prodrugs for Cancer Therapy
+ [a]
+ [b]
[b]
[a]
Henrik Johansson , Omar Hussain , Simon J. Allison, Tony V. Robinson,
[b]
[a]
Roger M. Phillips,* and Daniel Sejer Pedersen*
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Bromohexitols represent a potent class of DNA-alkylating
carbohydrate chemotherapeutics that has been largely ignored
over the last decades due to safety concerns. The limited
structureÀ activity relationship data available reveals significant
changes in cytotoxicity with even subtle changes in stereo-
chemistry. However, no attempts have been made to improve
the therapeutic window by rational drug design or by using a
prodrug approach to exploit differences between tumour
physiology and healthy tissue, such as acidic extracellular pH
and hypoxia. Herein, we report the photochemical synthesis of
highly substituted endoperoxides as key precursors for dibro-
mohexitol derivatives and investigate their use as microenviron-
ment-activated prodrugs for targeting cancer cells. One
endoperoxide was identified to have a marked increased
activity under hypoxic and low pH conditions, indicating that
endoperoxides may serve as microenvironment-activated pro-
drugs.
Introduction
Treosulfan (1), dibromomannitol (2, DBM) and dibromogalacti-
tol (3, DBG) belong to a class of alkylating carbohydrate
chemotherapeutics that have been known for over 40 years
[1]
(
Figure 1). This family of chemotherapeutics has been demon-
strated to undergo in vivo transformation to generate reactive
species, including mono- and bis-epoxides (e.g., conversion of
[2]
3
to 4, Figure 1), that primarily alkylate DNA at guanine-N7,
[3]
but also histones and nuclear proteins to some extent. Despite
displaying interesting and potentially useful properties for the
treatment of various cancers this family of compounds is no
longer undergoing clinical evaluation due to severe side effects
and because no clear advantage could be demonstrated over
existing therapies. These compounds are nevertheless potent
cytotoxic agents and the challenge is to develop derivatives
with a greater therapeutic index.
Figure 1. Three known DNA-alkylating chemotherapeutics: treosulfan (1),
dibromomannitol (2, DBM) and dibromogalactitol (3, DBG). The cytotoxic
DNA alkylating agents (e.g., 4, DAG) are formed in vivo from the
[4]
dibromohexitol prodrug (e.g., 3) as illustrated. The reactive alkylating sites
[3e]
are highlighted with red circles.
Unlike other classes of DNA-alkylating chemotherapeutics,
there have only been modest attempts of exploring analogues
to reduce the toxicity of dibromohexitols, such as the synthesis
of other di-halogen or di-O-methane sulfonyl derivatives, as
well as acetylated analogues. Interestingly, for the known
dichloro-, bromo- and iodo-carbohydrates the cytotoxic activity
varies considerably between structural isomers (e.g., 2 vs.
[4,5c,6]
3).
Thus, even subtle changes in stereochemistry can alter
the cytotoxic properties of the compounds, yet no attempt at
exploring the structureÀ activity relationships has been reported.
Moreover, no attempts at synthesising novel bromohexitols
bearing substituents to their backbone or developing prodrugs
that may display selectivity towards for example hypoxic and
acidic tumours have been reported.
[5]
+
[
a] Dr. H. Johansson, Dr. T. V. Robinson, Prof. D. Sejer Pedersen
Department of Drug Design and Pharmacology
Faculty of Health and Medical Science
Endoperoxides (e.g., 5, Figure 2) are a useful class of starting
materials for the synthesis of a wide range of molecules that are
University of Copenhagen
[7]
Jagtvej 162, 2100 Copenhagen (Denmark)
E-mail: daniel.pedersen@sund.ku.dk
b] O. Hussain, Dr. S. J. Allison, Prof. R. M. Phillips
School of Applied Sciences
University of Huddersfield
Huddersfield HD1 3DH (UK)
E-mail: R.M.Phillips@hud.ac.uk
otherwise difficult to synthesise. As previously reported by us
and others, endoperoxides are particularly useful in the syn-
+
[
[
[8]
[9]
thesis of amino acids and carbohydrates. During previous
[9d,e]
work
on carbohydrate synthesis it came to our attention
that the endoperoxide chemistry developed by us might furnish
a concise route to a new series of substituted bromohexitols
+
] These authors contributed equally to this work.
(Figure 3). In addition, we hypothesised that the bromo-
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cmdc.201900578
endoperoxide intermediates could represent a novel class of
ChemMedChem 2019, 14, 1–9
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normal tissues where intracellular pH is generally maintained at
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[15]
7
.4.
Thus, in addition to evaluating the endoperoxide linkage as
a hypoxia trigger we decided to synthesise ligands that also
incorporate acid sensitive acetal groups that potentially could
serve as handles for further scaffold elaboration e.g., attach-
ment of cancer targeting biomolecules (Figure 3). Lastly, we
sought to explore the synthetic utility of endoperoxide
intermediates for alkene functionalisation (e.g., through epox-
ide or bromohydrin formation). In this initial report, we describe
i) the synthesis and functionalisation of substituted dibromo-
endoperoxides, ii) the application of dibromo-endoperoxides
for the synthesis and structureÀ activity relationship evaluation
of novel dibromohexitols, and iii) the first evaluation of
dibromo-endoperoxide derivatives as microenvironment-acti-
vated prodrugs for selective targeting of cancer cells.
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Figure 2. Hypothesised hypoxia induced reduction of endoperoxide 5 to
release dibromohexitol prodrug 6, followed by formation of the cytotoxic
agent 7. The reactive DNA-alkylating sites are highlighted with red circles.
Results and Discussion
Chemistry: Endoperoxide Synthesis
We first set out to synthesise the dibromodienes to be used in
the photochemical [4+2]-cycloaddition reaction. At first unsub-
stituted dibromodiene 19 was synthesised from the corre-
sponding diol by S 2 substitution using PBr , but we soon
N
3
discovered that the yields could be significantly increased when
applying S 2’ substitution to hexa-1,5-diene-3,4-diol 18 with
N
[16]
CuCl in aqueous HBr (Scheme 1A). With a robust synthesis
route to 19 in hand we decided to explore the analogous
synthesis of substituted dibromodienes 22 and 26. Diacetyl (20)
was treated with vinyl magnesium bromide at low temperature
to give diol 21, but the following substitution failed to yield any
of the desired dibromodiene 22 (Scheme 1B).
Figure 3. The outlined synthetic approach identified endoperoxides 11 as
key intermediates for the generation of oxidised (12 and 13) and acetal
derivatised (14) endoperoxides, as well as a range of substituted dibromo-
hexitol derivatives 15–17 through chemical reduction. Endoperoxides 11 are
synthesised by a photochemical [4+2]-cycloaddition between singlet oxy-
gen and substituted bromo-dienes 10, that can be obtained by nucleophilic
substitutions of various bis-allylic alcohol precursors.
Similarly, commercially available ketone 23 was treated with
an excess of vinyl magnesium bromide over two steps to
produce diol 25, but yet again we failed to produce the desired
dibromodiene product 26.
[10]
hypoxia activated prodrugs (HAPs) based on the reductively
labile endoperoxide linkage.
Following the unsuccessful synthesis of substituted dibro-
Hypoxia is a physiological characteristic of cancer cells
arising from a poor and inefficient vascular supply leading to
regions of tumours that are poorly perfused with blood.
modienes via S 2’ substitution reactions we decided to pursue
N
the synthesis of methyl-substituted dibromodiene 34 by HWE/
Wittig chemistry (Scheme 2). To this end, phosphonate 27 was
deprotonated using potassium tert-butoxide and treated with
aldehyde 28 to obtain a 1:1 mixture of E/Z isomers of alkene
29. In parallel, bromoacetate 30 was treated with triphenyl-
phosphine to yield phosphonium bromide 31, which in turn
was used in a Wittig reaction with ketone 29 to produce diene
32 as a mixture of two isomers (0.6:1 ratio). However, reducing
[11]
Taking advantage of the unique acidic and reductive micro-
environment, drugs can be attached to a linker that is cleaved
under acidic conditions or by one-electron reduction by
ubiquitous cellular reductases, such as NADPH cytochrome
[12]
P450 reductase, or by engaging glutathione (GSH) to release
[12a,13]
the cytotoxic agent.
Due to the susceptibility of the
endoperoxide linkage to be cleaved under reductive conditions,
we believed that it might be cleaved selectively under hypoxic
conditions, thus providing access to a new class of hypoxia
targeting cancer agents (Figure 2).
both carboxylic esters in 32 simultaneously, using LiAlH in THF
4
at À 78°C or NaBH and LiCl in THF at 0°C returned only
4
complex reaction mixtures. Eventually 32 was reduced to the
corresponding diol with diisobutylaluminium hydride (DIBALÀ H)
at low temperature (Scheme 2). Some variations in yields were
observed for this transformation, most likely due to variations in
moisture control which would affect the integrity of the
reducing agent, and the laborious work-up procedure to
In addition to hypoxia, other physiological parameters
change within these poorly perfused regions including a
[14]
reduction in extracellular pH (pHe). Extracellular pH in tumour
tissues are generally more acidic (0.5–1.0 pH units lower) than
[
17]
remove aluminium contaminants. The Fieser protocol using
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In this manner, gram quantities of diol 33 were obtained.
Unfortunately, when diol 33 was treated with HBr and CuCl
none of the desired dibromodiene 34 was isolated. However,
the synthesis of dibromodiene 34 was successful when using
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PBr in anhydrous diethyl ether.
3
With dibromodienes 19 and 34 in hand, we turned our
attention to the photochemical [4+2]-cycloaddition reaction
between a diene and singlet oxygen generated in the presence
of the photosensitiser rose bengal or tetraphenylporphyrin
(TPP). The cycloaddition reactions were carried out in a cooled
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immersion well glass photoreactor which had been fitted with a
sintered glass filter gas inlet and three white light 100 W
[9a]
halogen bulbs (Supporting Information Figure S1). The reac-
tor was charged with 19 or 34 and the photosynthesiser rose
bengal but in both cases this consistently resulted in multiple
products, sluggish reactions and poor yields. However, when
the reactions were repeated with the photosensitiser TPP the
desired endoperoxides 35 and 36 were obtained, albeit the
reactions were slow and required several additions of TPP
during the course of the reaction (Scheme 3). Dihydroxylation
of endoperoxides 35 and 36 using osmium tetraoxide installed
the central hydroxyl groups in a stereospecific manner anti to
the alkyl substituents, to give diols 37 and 38 in high yields.
Diols 37 and 38 were acetal-protected using 2,2-DMP to give 39
and 40. Tetraol 41 (dibromoallitol) was obtained by reducing
the endoperoxide-linkage in 37 with zinc dust in acetic acid.
Unfortunately, when the same conditions were applied to
methyl-substituted endoperoxide 38 the crude product proved
Scheme 1. A) Synthesis of dibromodiene 19 from diol 18 using aqueous HBr
and CuCl. B) Applying the same conditions on diols 21 and 25 failed to
produce the desired dimethyl- or phenyl-substituted dibromodienes 22 and
26, respectively.
very difficult to purify. Thus, tetraol 42 was only isolated in
1
~
80% purity ( H NMR) and consequently was not included in
the pharmacological characterisation.
While endoperoxides such as 35 are generally susceptible to
[
18]
ring-opening (e.g., Kornblum-DeLaMare rearrangement)
by
basic nucleophiles such as amines, they tolerate a range of
alkene oxidation reactions well. In addition to the dihydroxyla-
tion of alkene 35 (vide supra) the bromohydrin 47, and epoxides
4
(
3 and 44 were synthesised from this common intermediate
Scheme 4). The subsequent reductions of the endoperoxide-
linkage were straightforward and gave functionalised diols 45,
6, and triol 48 in excellent yields, illustrating the versatility of
4
the endoperoxide scaffold for generating highly functionalised,
pharmacologically relevant molecules in few synthetic steps.
For the pharmacological evaluation of the synthesised
endoperoxides and dibromo-polyols we decided to synthesise
dibromomannitol (2) and dibromogalactitol (3) as controls.
Compound 2 was synthesised in low yield from mannitol 49
[
5a]
using the procedure of Crombez-Robert et al. (Scheme 5).
Interestingly, we failed to synthesise dibromogalactitol 3 under
the same conditions, illustrating how elusive these diastereo-
meric sugars can be. Further attempts at synthesising 3 using
aqueous HBr also failed to give the desired product and we
eventually settled for dibromomannitol 2 as the control for
pharmacological characterisation.
Scheme 2. Synthesis of diol 33 using HWE/Wittig chemistry and its
subsequent conversion to methyl-substituted dibromodiene 34.
DIBALÀ H=diisobutylaluminium hydride.
NaOH and MgSO4 was generally successful in removing
aluminium side products before chromatographic purification.
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Scheme 3. Synthesis of key endoperoxide intermediates 35 and 36 from dienes 19 (E,E isomer) and 34 (mix of E,E and E,Z isomers) via [4+2]-cycloaddition
with singlet oxygen. Endoperoxides 35 and 36 were dihydroxylated and acetal-protected to provide target molecules 37–40. Endoperoxide 37 was further
reduced to give target 41 (dibromoallitol) but the reduction of endoperoxide 38 failed to yield pure product 42. Compounds 36, 38, and 40 were obtained as
racemic mixtures and have been displayed as single enantiomers for clarity. TPP=tetraphenylporphyrin, NMO=N-methyl morpholine, N-oxide; PTSA=para-
toluene sulfonic acid; 2,2-DMP=2,2-dimethoxypropane; n.p.=no product isolated.
Scheme 4. Epoxidation of alkene 35 yielded epoxides 43 and 44 that were further reduced to target compounds 45 and 46, and bromohydrin synthesis
followed by peroxide reduction yielded triol 48. Compounds 47 and 48 were obtained as racemic mixtures but have been displayed as single enantiomers for
clarity. NBS=N-bromosuccinimide; m-CPBA=meta-chloroperbenzoic acid.
ellular pH 7.4 (Table 1). Against the HTC116 cell line the
response ranged under aerobic conditions from inactive at the
highest dose tested (IC >100 μM; 39 and 41) to active with
5
0
the most potent compound (43) having an IC50 of 4.5�0.6 μM,
although most compounds were found to give a similar
response to the reference compound DBM (2). Somewhat
surprising, compound 41 which is a stereoisomer of 2 was
completely inactive. Considering that the corresponding endo-
peroxide 37 was active, the lack of activity for 41 is likely
because the compound is unable to reach its target due to
unknown factors (e.g., poor cell penetration or compound
stability). With respect to selectivity for HTC116 cancer cells
over ARPE-19 non-cancer cells, the selectivity index (SI) is here
defined as the IC50 values at ARPE-19 cells divided by the IC50
values for HCT116 under aerobic, pHe 7.4 conditions. A handful
of compounds (35, 43, 44) showed a modest ~2–3 fold
preference for the cancer cell line while most compounds
displayed no selectivity for the HCT116 cells (e.g., 37, 40, 45–
48).
Scheme 5. Synthesis of control compound 2 (dibromomannitol; DBM) from
mannitol 49 using acetyl bromide. The conversion of galactitol 50 to
dibromogalactitol (DBG) failed under the same conditions and when using
aqueous HBr.
Pharmacology: Chemosensitivity Studies
The response of ARPE-19 non-cancer cells and HCT116 color-
ectal cancer cells following continuous exposure to test
compounds or established anticancer drugs was evaluated
under aerobic and hypoxic cell culture conditions at extrac-
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[20]
Table 1. Cell toxicity following 96 h continuous compound exposure under aerobic and hypoxic conditions at pHe 7.4 determined by the MTT assay. Each
value represents the mean IC50 (μM)�standard deviation for at least three independent experiments. For the colorectal cancer cell line HCT116, experiments
were conducted under both aerobic and hypoxic conditions (0.1% oxygen). For the non-cancer ARPE-19 cell line, experiments were conducted under
aerobic conditions only. Values >100 indicate that full curves could not be obtained and that the IC50 was higher than the highest concentration tested
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(100 μM).
[
a]
Cytotoxicity IC50 (μM)
[
b]
[c]
Cmpd
2
Structure
ARPE-19 (Aerobic)
HCT116 (Aerobic)
HCT116 (Hypoxic)
SI
pHe 7.4)
HCR
(
(HCT116)
3.2�0.9
17.3�6.0
34.2�5.2
15.6�4.3
7.0�1.7
25.9�3.5
13.3�1.0
47.5�3.8
0.2
2.5
1.2
0.6
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
5
0.5
0.6
37
38
27.7�10.0
N/A
87.6�5.4
>100
72.2�9.3
>100
–
–
1.2
–
3
4
9
0
77.2�3.8
43.0�5.0
66.4�8.1
25.9�3.2
0.6
2.6
41
43
44
>100
>100
>100
–
–
15.0�4.3
9.8�1.5
4.5�0.6
4.9�1.9
21.6�1.4
12.4�1.0
3.3
2.0
0.2
0.4
4
4
5
6
35.9�0.6
15.1�6.9
13.6�1.4
22.0�0.5
14.2�2.3
12.2�2.2
71.7�5.2
2.1�0.7
19.2�0.5
1.6
1.1
1.1
0.3
6.8
0.6
47
48
25.8�9.8
18.6�3.0
16.2�1.6
1.4
1.1
Cisplatin
–
–
–
–
3.8�0.7
2.7�1.2
4.5�1.6
2.5�0.8
0.85�0.16
1.2�0.4
1.4
1.2
0.4
2.3
0.6
0.7
0.8
9.6
5
-FU
2.1�0.7
1.8�0.3
Etoposide
Tirapazamine
0.31�0.01
27.6�4.0
0.68�0.02
11.8�0.6
[a] N/A=data not available due to lack of compound availability; [b] The selectivity index (SI) is here defined as the IC50 values at ARPE-19 cells divided by the
IC50 values for HCT116 under aerobic, pHe 7.4 (values >1 indicate greater selectivity for cancer cells as opposed to non-cancer cells); [c] The Hypoxia
Cytotoxicity Ratio (HCR) for HCT116 cells is defined as the IC50 values under aerobic conditions divided by the IC50 under hypoxic (0.1% oxygen) conditions.
Values >1 indicate that compounds have selective toxicity towards cells under hypoxic conditions.
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In the context of identifying HAPs we further screened the
test compounds against the HCT116 cell line under hypoxic
conditions (0.1% oxygen, Table 1). The hypoxic cytotoxicity
ratio (HCR) was calculated as the ratio of IC50 values under
aerobic conditions and the IC50 values under hypoxic (0.1%
oxygen) conditions to illustrate selective toxicity towards cells
under hypoxic conditions. Tirapazamine was used as a positive
control and an HCR of 9.6 was obtained (Table 1), which is in
agreement with that reported in the literature. By contrast,
there was no measured increase in cytotoxicity under hypoxic
conditions for most test compounds, including the majority of
endoperoxides (35, 37, 43, 44 and 47). However, endoperoxide
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[19]
1
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0 demonstrated a statistically significantly greater activity
under hypoxic compared to aerobic conditions with an HCR of
.6. It is interesting to note that the acetal de-protected
2
analogue 38 only elicit a weak cellular response, which could
be caused by poor cell penetration, while the opposite is
observed for the structurally very similar pair 37 and 39. Most
noteworthy was the observed cytotoxicity for epoxide 46 for
two reasons: i) with an HCR of 6.8, epoxide 46 was markedly
more cytotoxic under hypoxic conditions despite not being an
endoperoxide, and ii) epoxide 46 was more than 50-fold more
toxic than its diastereoisomer 45 to HCT116 cells under hypoxic
conditions. Based on the available data it is not possible to
rationalise these findings as the activity of the cytotoxic agent
is a complex interplay of multiple factors, including compound
stability in solution, cell penetration and localisation, activation
of prodrug, and interactions with the target etc. It is possible
that 46, as an epoxide, causes cytotoxicity through non-specific
alkylation or GSH depletion although the striking difference
between 46 and its isomer 45 points towards a more specific
mechanism that would require further investigations beyond
the scope of this study to unravel.
Figure 4. Response of HCT116 cells to compound 40, and the cancer drugs
cisplatin, 5-fluorouracil (5FU) and etoposide under aerobic and tumour
microenvironment conditions. A) IC50 values are presented for different
combinations of oxygen tension and extracellular pH (pHe) including the
combination of hypoxia and acidic pHe. Each value represents the mean
IC50 �SD for three independent experiments. B) The selectivity index (SI) is
defined by the IC50 values at non-cancer ARPE-19 cells (under aerobic and
pHe 7.4 conditions, Table 1) divided by the IC50 values for cancer HCT116
cells under aerobic, hypoxic, pHe 7.4 or 6.5 conditions respectively (values
Although our results show that the endoperoxide motif is
neither a guarantee of increased compound cytotoxicity under
hypoxic conditions (e.g., 39), nor a requirement for such (e.g.,
>
1 indicate greater selectivity for cancer cells as opposed to non-cancer
cells).
4
6) we show that it is indeed possible to modify the properties
for this class of cytotoxic agents to make them microenviron-
ment-selective, as with endoperoxide 40. We decided to further
evaluate compound 40 as well as established anti-cancer drugs
under mildly acidic conditions (pHe 6.5) to mimic the conditions
associated with hypoxic tumours (Figure 4a, Supporting Infor-
mation Table S1). The activity of 40 was significantly enhanced
under aerobic conditions at pHe 6.5 (IC =26.5�7.0 μM) when
Lastly, to shed some light on the mode of action we treated
HCT116 cells with endoperoxide 40 (20 μM) under aerobic or
hypoxic conditions at pHe 6.5 and 7.4. The cell lysates were
then analysed by Western blot to demonstrate that compound
40 selectively causes phosphorylation of histone γ-H2AX, a
[21]
biomarker for DNA double-strand breaks,
under hypoxic
5
0
compared to neutral pHe 7.4 (66.4�8.1 μM). When 40 was
exposed to the combination of hypoxia and acidic pHe the
potency was increased even further (IC =16.3�4.1 μM) dem-
conditions at the given concentration (Figure 5). Taken togeth-
er, these results show that we have developed a dibromo-
endoperoxide 40 derived from the non-selective cytotoxic
agent DBM (2) that displays low potency towards the HTC116
cell line under aerobic conditions, but which is triggered under
hypoxic conditions to alkylate DNA.
5
0
onstrating that both hypoxia (0.1% oxygen) and acidic pHe
(pH 6.5) can generate additive effects when combined. The
observed effect could be due to increased lability of the
endoperoxide-linkage under reduced pHe resulting in more
effective release of the cytotoxic agent or due to acid-catalysed
cleavage of the acetal-protection group. The selectivity index Conclusions
for compound 40 thus increased from 0.6 under aerobic and
pHe 7.4 conditions to 2.6 under hypoxia and mildly acidic
pHe 6.5 (Figure 4b).
In this study we describe a photochemical synthesis approach
that enabled ready access to novel dibromo- and further
substituted and functionalised endoperoxides, and we further
ChemMedChem 2019, 14, 1–9
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Acknowledgements
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D.S.P. and H.J. acknowledge the Lundbeck Foundation – Natural
Sciences (Grant no. R141-2013-13342) for financial support. R.M.P.
acknowledges funding from the University of Huddersfield (funded
PhD studentship).
Conflict of Interest
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The authors declare no conflict of interest.
Keywords: endoperoxides · carbohydrate chemotherapeutics ·
DNA damage · hypoxia · photochemistry
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FULL PAPERS
Microenvironment matters: Novel
bromohexitols based on known
DNA-alkylating carbohydrate thera-
peutics such as dibromomannitol
were synthesised by a photochemical
approach. One such endoperoxide
was identified to have marked
increased activity under hypoxic and
low pH conditions, indicating that
endoperoxides may serve as cancer
microenvironment-activated
Dr. H. Johansson, O. Hussain, Dr. S. J.
Allison, Dr. T. V. Robinson, Prof. R. M.
Phillips*, Prof. D. Sejer Pedersen*
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Revisiting Bromohexitols as a Novel
Class of Microenvironment-
Activated Prodrugs for Cancer
Therapy
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prodrugs.