Development and Biological Evaluation of a Photoactivatable Small Molecule Microtubule-Targeting Agent

Article abstract of DOI:10.1021/acsmedchemlett.6b00483

Photoremovable protecting groups added to bioactive molecules provide spatial and temporal control of the biological effects. We present synthesis and characterization of the first photoactivatable small-molecule tubulin inhibitor. By blocking the pharmacophoric OH group on compound 1 with photoremovable 4,5-dimethoxy-2-nitrobenzyl moiety we developed the photocaged prodrug 2 that had no effect in biological assays. Short UV light exposure of the derivative 2 or UV-irradiation of cells treated with 2 resulted in fast and potent inhibition of tubulin polymerization, attenuation of cell viability, and apoptotic cell death, implicating release of the parent active compound. This study validates for the first time the photoactivatable prodrug concept in the field of small molecule tubulin inhibitors. The caged derivative 2 represents a novel tool in antitubulin approaches.

Full text of DOI:10.1021/acsmedchemlett.6b00483

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Letter
Development and biological evaluation of a photoactivatable
small molecule microtubule-targeting agent
Alexander Doebber, Athena F. Phoa, Ramzi H Abbassi, Brett W. Stringer, Bryan W.
Day, Terrance G Johns, Mohammed Abadleh, Christian Peifer, and Lenka Munoz
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.6b00483 • Publication Date (Web): 15 Mar 2017
Downloaded from http://pubs.acs.org on March 19, 2017
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Development and biological evaluation of a photoactivatable small
molecule microtubuleꢀtargeting agent
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Alexander Döbber , Athena F. Phoa , Ramzi H. Abbassi , Brett W. Stringer , Bryan W. Day , Terrance
d,e
b,§
b*
a*
G. Johns , Mohammed Abadleh , Christian Peifer and Lenka Munoz
a
b
School of Medical Sciences and Charles Perkins Centre, The University of Sydney, NSW 2006, Australia; Institute of
c
Pharmacy, ChristianꢀAlbrechtsꢀUniversity of Kiel, Gutenbergstraße 76, 24118 Kiel, Germany; QIMR Berghofer Medical
Research Institute, 300 Herston Road, Herston QLD 4006, Australia; Oncogenic Signalling Laboratory and Brain Cancer
d
Discovery Collaborative, Centre for Cancer Research, Hudson Institute of Medical Research, 27ꢀ31 Wright Street, Clayton,
e
VIC 3168, Australia; Monash University, Wellington Road, Clayton, VIC 3800, Australia
KEYWORDS: photoactivatable caged prodrug, tubulin inhibitor, glioblastoma
ABSTRACT: Photoremovable protecting groups added to bioactive molecules provide spatial and temporal control of the biologiꢀ
cal effects. We present synthesis and characterization of the first photoactivatable smallꢀmolecule tubulin inhibitor. By blocking the
pharmacophoric OH group on compound 1 with photoremovable 4,5ꢀdimethoxyꢀ2ꢀnitrobenzyl moiety we developed the photoꢀ
caged prodrug 2 that had no effect in biological assays. Short UV light exposure of the derivative 2 or UVꢀirradiation of cells treatꢀ
ed with 2 resulted in fast and potent inhibition of tubulin polymerization, attenuation of cell viability and apoptotic cell death, imꢀ
plicating release of the parent active compound. This study validates for the first time the photoactivatable prodrug concept in the
field of small molecule tubulin inhibitors. The caged derivative 2 represents a novel tool in antiꢀtubulin approaches.
8
ꢀ10
Delivering bioactive molecules to cells with temporal and
spatial precision is useful for elucidating complex biological
processes. One method for regulating the action of bioactive
naling pathways.
Furthermore, photocaging has been apꢀ
plied for delivery of molecules across membranes and for the
control of side effects.
1
1,12
1
molecules employs photolabileꢀprotecting groups (PPGs).
Microtubuleꢀtargeting agents (MTAs) disrupt polymerizaꢀ
tion of αꢀ and βꢀtubulin to form microtubules. Microtubules
are crucial for cell division in mitosis and this explains why
compounds that bind to tubulin and interfere with tubulin
polymerization are highly effective in killing rapidly proliferꢀ
ating cancer cells. Importantly, tubulin has a crucial role also
in nonꢀmitotic cells, which underlies the overall success of
The PPG is a chromophore covalently attached to the pharmaꢀ
cophoric moiety of the bioactive molecule, thus blocking its
biological activity – a concept known as ‘caging’. The covaꢀ
lent bond between the bioactive molecule and the PPG is
cleaved by irradiation with ultraviolet (UV) light, leading to
the release of the parent bioactive molecule – ‘uncaging’. A
number of PPGs have been developed for this purpose, inꢀ
cluding pꢀnitrobenzyl, 4,5ꢀdimethoxyꢀ2ꢀnitrobenzyl (DMNB)
13ꢀ15
MTAs in cancer therapy.
2
MTAs are structurally diverse and very often structurally
complex molecules as the vast majority of these agents are
natural products isolated from bacteria, plants and marine
and 6ꢀbromoꢀ7ꢀhydroxycoumarineꢀ4ꢀylmethyl and the caging
concept has been successfully applied to phototrigger calcium,
3,4
neurotransmitters, nucleic acids and antibiotics. For examꢀ
ple, photocaged rapamycin has been used to induce controlled
16
sponges. With the long history of clinical efficacy, MTAs
5
remain to date the most classical yet reliable chemotherapeuꢀ
tics. Microtubules targeting Vinca alkaloids (vinblastine, vinꢀ
cristine) and taxanes (paclitaxel, cabazitaxel) are frontline
treatments for breast, ovarian and hormoneꢀrefractory prostate
cancers. However, the acquired resistance developed over the
time of treatment has plagued the success of these drugs.
activity of the small GTPase Rac in the cellular context and
photocaged anisomycin has been employed to locally inhibit
6
protein synthesis. Photocaged puromycin was effectively7
applied for spatiotemporal monitoring of mRNA translation.
We have recently developed a number of caged kinase inhibiꢀ
tors that serve as valuable molecular probes to delineate sigꢀ
1
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Mechanisms of MTA resistance are manifold, including
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overexpression of efflux proteins, point mutations at the
paclitaxelꢀbinding site or polymorphism resulting in the overꢀ
1
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expression of various βꢀtubulin isotypes. Another major
limitation in the use of MTAs is the high rate of neuropathy
induced by these compounds. This effect manifests itself as a
painful peripheral axonal pain for which there is currently no
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effective symptomatic treatment. Myeloid toxicity and neuꢀ
tropenia is also frequently observed with MTAs, with subtle
differences between compounds within the same family.
Clinically approved MTAs are ineffective for treatment of
brain tumors as their large molecular weight (> 800 g/mol)
renders them unable to cross the bloodꢀbrain barrier. Hence,
there has been increasing research interest towards the develꢀ
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opment of effective MTA delivery methods
or identificaꢀ
Scheme 1. Synthesis of the photoactivatable tubulin inhibiꢀ
tor 2. (a) AlCl , HCl, N , 96 h; (b) Zn/Hg, HCl, toluene, 24 h;
(c) PYBOP, DIPEA, DMF; (d) Pd(PPh Na CO
EtOH/H O, MW 130°C, 20 min; (e) K CO , DMF, RT.
tion of smallꢀmolecule tubulin inhibitors able to cross the
3
2
21,22
bloodꢀbrain barrier.
We discovered that a smallꢀmolecule
3
)
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,
2
,
3
known as CMPD1 and initially developed to inhibit p38
2
2
3
23
MAPKꢀMK2 signaling pathway , primarily inhibits tubulin
24
In the photocaging concept it is essential that the parent
molecule is sufficiently stable under the conditions used for
uncaging by UV irradiation. Otherwise the irradiation would
degrade the released active drug immediately after the PPG
cleavage. Initially, in an analytical setup to examine the UV
stability of the tubulin inhibitor 1, we used a lightꢀemitting
diode (LED) reactor and a wavelength of 365 nm (5400 mW,
Figure S2, lamp A) to irradiate compound 1 (1 mM). HPLC
and LCꢀMS analysis of samples collected over the period of
polymerization. CMPD1 showed potent antiꢀmitotic and
apoptotic activity in a panel of cancer cells. This cytotoxic
activity and the small molecular weight (349 g/mol) made
CMPD1 an attractive lead for the development of potential
chemotherapeutic agents for brain tumors. Recently, we reꢀ
ported synthesis of CMPD1 analogues with improved molecuꢀ
lar properties and demonstrated their antiꢀcancer efficacy in
2
5
patientꢀderived glioblastoma cells.
Herein, we present a novel concept in the class of smallꢀ
molecule tubulin inhibitors. In order to reduce side effects
associated with tubulin inhibitors, we developed a caged tubuꢀ
lin inhibitor by addition of a photoactivatable protecting group
and describe its pharmacology in glioblastoma cells. We have
chosen glioblastoma cellꢀbased models as this heterogeneous
brain cancer represents a major unmet medical need. Although
glioblastoma was one of the first cancers to be profiled
through The Cancer Genome Atlas project, making it genomiꢀ
2
0 min confirmed that inhibitor 1 was stable under these conꢀ
ditions (Figure S3).
To determine the kinetics of the photoꢀrelease, caged anaꢀ
logue 2 was UV irradiated at 365 nm (2700 mW, Figure S2,
lamp A) and samples were collected at indicated time points
for quantitative HPLC analysis (Figure 1). After 1 min of
irradiation, approximately 80% of the bioactive inhibitor 1
was released from the photoꢀprodrug 2. The reaction progress
2
26
curve excellently fitted (R = 1) to the exponential oneꢀphase
cally a wellꢀcharacterized cancer, the results of glioblastoma
decay kinetics with a time constant (τ) of 0.605 min. The
maximum measured concentration of parent inhibitor 1 was
reached after 2 min of irradiation. This data confirm that
DMNBꢀcaged compound 2 possesses suitable uncaging kinetꢀ
ics.
trials using inhibitors of oncogenic drivers have been disapꢀ
27
pointing so far. Importantly, glioblastoma cells are sensitive
22,25
to MTAs,
suggesting that MTAs able to cross the bloodꢀ
brain barrier could be effective in glioblastoma therapy. The
photoactivatable approach presented in this work opens a new
avenue to reduce side effects of MTAs as the active drug may
be locally released at the tumor site.
1
1
20
00
80
To synthesize the photoactivatable tubulin inhibitor, the tuꢀ
bulin inhibitor 1 was converted into a photocaged derivative 2
(Scheme 1). We have chosen the 4,5ꢀdimethoxyꢀ2ꢀnitrobenzyl
(DMNB) as the PPG because of its excellent quantitative
cmpd 1
cmpd 2
60
1
,9,10
cleavage by UV irradiation.
DMNB was attached to the
40
phenol moiety of compound 1, as the SAR study demonstratꢀ
20
ed that the removal of the OH group resulted in significant
2
5
loss of cellular efficacy. DMNBꢀcaged derivative 2 was
obtained in 60% yield in the final synthetic step using
DMNBꢀbromide as a reagent, followed by reversedꢀphase
chromatography purification. UV spectra of compounds 1 and
0
0
1
2
3
4
5
irradiation time (min)
Figure 1. Photolytic characterization of the caged deꢀ
rivative 2. A solution of compound 2 (1 mM) was irradiated
at 365 nM and samples collected at indicated time points were
analysed by HPLC. Compound 2 was photolysed to produce
compound 1 in oneꢀphase decay kinetics (τ = 0.605 min, R =
1). Data represent mean ± SEM from two independent experꢀ
iments performed in duplicate.
2
3
(Figure S1) revealed that inhibitor 1 shows no absorption at
65 nm, whereas the photoꢀprodrug 2 possesses an absorption
maximum around 350 nm. As the high absorption of photoꢀ
caged molecules at the irradiation wavelength is crucial to
trigger the PPG cleavage, we identified 365 nm as suitable
irradiation wavelength.
2
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To assess the inactivity of caged prodrug 2, as well as reacꢀ
viable cells. The parent compound 1 decreased the viability of
U251 and RN1 cells with EC50 values of 1.3 and 0.3 ꢁM, reꢀ
spectively (Figure 2), which is in good agreement with previꢀ
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tivation and recovery of the cytotoxic effects, we performed a
series of cell viability assays using U251 and patientꢀderived
RN1 glioblastoma cells. The U251 cell line was established
prior to genome analysis of glioblastoma tumors and is not
assigned to any glioblastoma subtype. The patientꢀderived
24,25
ously published data.
UV irradiation of cells treated with
compound 1 did not affect the efficacy of the uncaged derivaꢀ
tive (Figure 2). In contrast to the bioactive compound 1 and as
expected by our PPG design, caged derivative 2 had no signifꢀ
icant cytotoxicity up to high micromolar concentrations (EC50
= 72 and 37.4 ꢁM for U251 and RN1, respectively), providing
evidence that addition of the PPG to compound 1 resulted in
the loss of cytotoxic activity. UV irradiation (30 s of RN1 and
2
8,29
RN1 cell line was established in our laboratories
and repꢀ
resents the most common (>60%) classical subtype of glioꢀ
blastomas. RN1 cells were grown as stem cells under defined
conditions in order to maintain the phenotype and genotype of
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the primary resected tumor.
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min of U251 cells) restored the activity of compound 2 and
First, we investigated the effects of UV light on cell viabilꢀ
ity in order to determine tolerable levels of UV exposure. We
exposed U251 and RN1 cells to UV light up to 5 min (lamp B,
efficacy in both cell lines was equivalent to the efficacy of the
uncaged compound (EC50 = 2.1 and 1.2 ꢁM for U251 and
RN1, respectively), suggesting that a recovery of the cytotoxic
activity is achieved with a short period of UV irradiation.
1
800 mW, Figure S2) and after 24 h of incubation performed
viability assay using Cell TiterBlue reagent. We found that
U251 and RN1 cells tolerated a continuous UV light exposure
of 1 min and 30s, respectively (Figure S4).
To confirm that addition of the bulky PPG was detrimental
to the cytotoxicity of compound 1, compound 3 containing a
benzyl moiety on the phenolic OH group was synthesized and
tested its cytotoxicity using U251 glioblastoma cells (Figure
3). Compound 3 affected U251 cell viability only at concenꢀ
trations higher than 40 ꢁM. We also synthesized 4,5ꢀ
dimethoxyꢀ2ꢀnitrobenzyl (tertꢀbutoxycarbonyl)alaninate 4 to
investigate if the DMNB moiety released via irradiation of the
caged derivative 2 could be cytotoxic to the cells. Importantly,
compound 4 when UV irradiated to release DMNB did not
change the viability of U251 cells up to 100 ꢁM concentration
cmpd 1 (EC50 = 1.3
cmpd 2 (EC50 = 72
±
±
0.3
9.5
µ
M)
A
µ
M)
cmpd 1 + UV (EC50 = 1.4
cmpd 2 + UV (EC50 = 2.1
±
±
0.2
0.5
µ
µ
M)
M)
1
20
100
80
60
40
(
Figure 3). Together, these data indicate that (i) the unsubstiꢀ
tuted phenolic group is crucial for the biological activity of 1
and that (ii) cytotoxicity after UV irradiation results from unꢀ
caging the inhibitor 1 and not from the released DMNB.
20
0
0
.01
0.1
1
10
M)
100
A
H
Concentration (
µ
N
O
B
O
cmpd 1 (EC50 = 0.3
±
0.03
0.7
µ
µ
M)
N
F
cmpd 2 (EC50 = 37.4
±
M)
3
cmpd 1 + UV (EC50 = 0.7 ± 0.3 µM)
cmpd 2 + UV (EC50 = 1.2 0.3 µM)
O
H
±
O
O
N
O
O
1
20
O
NO
2
100
4
80
60
40
B
120
cmpd 3
cmpd 4 + UV
20
0
100
80
0
.01
0.1
1
10
M)
100
6
4
2
0
0
0
0
Concentration (
µ
Figure 2. Evaluation of the uncaging protocol in a cell
viability assay. (A) U251 and (B) patientꢀderived RN1 glioꢀ
blastoma cells were grown as adherent cultures, treated with
uncaged inhibitor 1 and caged derivative 2. U251 cells were
UV irradiated (365 nm, 1800 mW) for 1 min, RN1 cells were
irradiated for 30s. Cellular efficacy (EC ) values were deterꢀ
0
.01 0.1
1
10
100
Concentration (
µ
M)
5
0
Figure 3. Efficacy of negative control compounds 3 and
4 in the cell viability assay. (A) Chemical structures of comꢀ
pounds 3 and 4. (B) Cellular efficacy of compound 3 and UVꢀ
irradiated (365 nm, 1800 mW, 1 min) compound 4 in U251
glioblastoma cells was determined using Cell TiterBlue viabilꢀ
ity assay after 72 h of drug treatment. Data represent mean ±
SEM from three independent experiments performed in tripliꢀ
cate.
mined using Cell TiterBlue viability assay after 72 h of drug
treatment. Data represent mean ± SEM from three independꢀ
ent experiments performed in triplicate.
To assess the cytotoxic effects, cells were treated with unꢀ
caged inhibitor 1 and caged derivative 2 for 72 h, and cell
viability assays were performed to evaluate the number of
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To further validate that the caging with DMNB caused was incubated with colchicine and tested compounds. Fluoꢀ
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loss of biological activities determined for compound 1 in
cells, we conducted an in vitro tubulin polymerization and
tubulin binding assays using uncaged and caged analogues 1
and 2, respectively (Figure 4). Purified βꢀtubulin was incubatꢀ
ed with clinical MTAs paclitaxel and vinblastine, as well as
with compounds 1 and 2. Compared to control, paclitaxel
enhanced tubulin polymerization, whereas vinblastine and
compound 1 inhibited tubulin polymerization (Figure 4A),
which is in agreement with their established mechanism of
action. In contrast, caged derivative 2 did not exhibit any
effect on the kinetics of tubulin polymerization. However, if
the same assay was performed with derivative 2 exposed to
UV irradiation, the inhibition of tubulin polymerization was
indistinguishable from that obtained with the uncaged comꢀ
pound 1. Thus, the uncaging of 2 by UV irradiation produced
a bioactive molecule inhibiting tubulin polymerization with
the same efficacy as the unmodified tubulin inhibitor 1 (Figꢀ
ure 4A).
rescence intensity (F) was normalized to the fluorescence of
the colchicineꢀtubulin complex (F ). Data represent mean ±
0
SEM from 4 independent experiments.
We next examined in greater detail how addition of the
PPG to compound 1 alters the microtubule network in cells.
For this, U251 glioblastoma cells were treated with 1 and 2,
and the effect on the microtubules was investigated via immuꢀ
nofluorescence staining of βꢀtubulin. Treatment of U251 cells
with compound 1 (5 ꢁM) led to a disassembly of microtubules
and pronounced changes in cell morphology (Figure 5). Howꢀ
ever, treatment with compound 2 had no effect on cell morꢀ
phology and the tubulin network; the images of cells treated
with 2 resembled the images of untreated control cells. Imꢀ
portantly, if cells were treated with UV irradiated (365 nm,
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800 mW, 5 min) compound 2, cells rounded up and lost their
starꢀshaped structure. Furthermore, tubulin filaments lost their
organization, suggesting that UV irradiation of compound 2
released a compound that acts as tubulin inhibitor and disrupts
the highly organized tubulin network in cells.
Small molecules inhibiting tubulin polymerization preꢀ
31
dominantly bind into the colchicine binding site on tubulin.
To investigate the binding site of compound 1, we performed
3
2,33
Microtubule targeting agents not only characteristically
disrupt the tubulin network and cell morphology as demonꢀ
strated in Figure 5, they also induce apoptosis through the
fluorescenceꢀbased colchicine binding assay.
Competition
of the inhibitor and colchicine for the binding site will deꢀ
crease the intrinsic fluorescence of colchicineꢀtubulin comꢀ
plex by reducing the amount of colchicine bound. With this
assay, we confirmed that compound 1, but not the caged deꢀ
rivative 2, decreased the intrinsic colchicine fluorescence in a
doseꢀdependent manner (Figure 4B). Nocodazole, tubulin
inhibitor binding to the colchicine site (positive control) also
efficiently decreased the fluorescence, whereas vinblastine
negative control) had no effect on the fluorescence. The obꢀ
servation that compound 1 caused a weaker decrease in the
fluorescence compared to nocodazole suggests that compound
is likely to bind in the vicinity or allosterically to colchicine.
34
intrinsic (mitochondrial) apoptotic pathway. In order to deꢀ
termine whether this mechanism contributes to the cellular
efficacy of the caged derivative 2 after UV irradiation, we
quantified apoptosis in drugꢀtreated RN1 cells by Annexin V
staining (Figure 6). UV irradiation (365 nm, 1800 mW, 30 s)
of the patientꢀderived RN1 cells did not increase the basal
level of Annexin Vꢀpositive cells (8.1% and 10.1% for Ctr
and UV treated cells, respectively; Figure 6). Treatment of
RN1 cells with the parent bioactive compound 1 (5 ꢁM, 48 h)
increased the amount of apoptotic cells to 47.8%. In agreeꢀ
ment with previous data, compound 2 was ineffective in inꢀ
ducing apoptosis (12.6% of Annexin Vꢀpositive cells). Howꢀ
ever, the quantity (55.9%) of apoptotic RN1 cells when treatꢀ
ed with compound 2 combined with UV irradiation (365 nm,
(
1
A 20000
Paclitaxel (3 µM)
1
5000
Ctr (DMSO)
cmpd 1 (50 µM)
cmpd 2 (50 µM)
cmpd 2 + UV (50 µM)
Vinblastine (3 µM)
1
800 mW, 30 s) was comparable to the quantity of apoptotic
10000
cells after treatment with compound 1 (47.8%), further conꢀ
firming that the uncaging with UV light released an active
compound.
5000
0
0
10
20
30
40
50
60
Time (min)
Ctr
cmpd 1
cmpd 2 cmpd 2 + UV
B
1
20
00
80
1
DAPI
βꢀtubulin
merged
6
4
2
0
0
0
0
Vinblastine
cmpd 2
cmpd 1
Nocodazole
0
20
40
60
Concentration (µM)
Figure 5. Immunofluorescence imaging of treated cells.
U251 cells treated with compound 1, 2 and UVꢀirradiated
Figure 4. Tubulin polymerisation and colchicine binding
assay. (A) Porcine brain tubulin was incubated with paclitaxꢀ
el, vinblastine, compounds 1 and 2 ± UV irradiation (365 nm,
1800 mW, 5 min). Assembly of microtubules was monitored
by an increase in fluorescence. Data represent the mean from
three independent experiments; each data point was performed
in triplicate. (B) Colchicine binding assay. Porcine tubulin
(
365 nm, 1800 mW, 5 min) compound 2. All treatments were
done with 5 ꢁM concentration for 24 h. Cells were fixed and
stained with Alexa488ꢀlabelled antiꢀβꢀtubulin antibody
(green) or DAPI (blue). Representative images of two indeꢀ
pendent experiments are shown.
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Funding Sources
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LM is a Cancer Institute NSW Career Development Fellow (grant
1
00
reference 15/CDF/1ꢀ07). This study was partially funded by the
National Foundation for Medical Research and Innovation
(NFMRI) and Sydney Medical School Foundation grants to LM;
and DFG (German Research Society) grant PE 1605/2ꢀ1 to CP.
AFP is supported by The University of Sydney Australian Postꢀ
graduate Award scholarship. MA was funded by the German
Academic Exchange Service (DAAD) and AD via the
DAAD/PROMOS scholarship funds from the Federal German
Ministry for Education and Research. TGJ was supported by the
NH&MRC (Project Grant #1028552) and Cure Brain Cancer
Foundation. TGJ, BWS and BWD are members of the Brain Canꢀ
cer Discovery Collaborative, which is supported by the Cure
Brain Cancer Foundation. This work was partly supported by the
Victorian Government's Operational and Infrastructure Support
Program (to TGJ).
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Figure 6. Tubulin inhibitor 1 and caged derivative 2
combined with UV irradiation induce apoptosis in RN1
glioblastoma cells. Cells were treated with 1 and 2 (5 ꢁM ±
UV irradiation) for 48 h. Control cells received an equivalent
amount of DMSO or UV irradiation (365 nm, 1800 mW, 30
s). Cells were stained with Annexin V and analysed using the
MUSE Cell Analyzer. Data represent mean ± SEM from three
independent experiments (**** P < 0.0001, 1ꢀway ANOVA
followed by Tukey’s multiple comparison test).
ABBREVIATIONS
DMNB, 4,5ꢀdimethoxyꢀ2ꢀnitrobenzyl; MAPK, mitogenꢀactivated
protein kinase; MK2, MAPKꢀactivated protein kinase 2; MTA,
microtubuleꢀtargeting agent; PPG, photolabileꢀprotecting group.
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Corresponding Authors
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. Horbert, R.; Pinchuk, B.; Davies, P.; Alessi, D.; Peifer, C.,
*
Photoactivatable prodrugs of antimelanoma agent vemurafenib.
ACS Chem. Biol. 2015, 10 (9), 2099ꢀ2107
Lenka Munoz (lenka.munoz@sydney.edu.au); Christian Peifer
cpeifer@pharmazie.uniꢀkiel.de)
Current address: College of Pharmacy, Taibah University,
Almadinah Almonawarrah, 41477 Saudi Arabia
(
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015, 10 (8), 1335ꢀ1338.
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AD and MA synthesized and characterized compounds presented
in this study. AD and AFP designed, performed and analyzed all
biological assays. BWS, BWD and TJG derived and characterꢀ
ized RN1 patientꢀderived glioblastoma cells. LM and PF designed
the study concept and supervised the study. All authors have givꢀ
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Photoac vatable tubulin inhibitor
H
N
O
O
O
Cell death
O
O
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Disrupted microtubules
N
F
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UV light
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Ac ve drug
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Table of Contents artwork
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