Design, synthesis and anticancer mechanistic studies of linked azoles

Article abstract of DOI:10.1039/c4md00387j

Herein we report the synthesis and biological activity evaluation of 2,4 linked azole-containing molecules. A total of 13 linked thiazole- and oxazole-containing compounds were synthesized in good yields. Cytotoxicity evaluation of those compounds showed

Full text of DOI:10.1039/c4md00387j

View Article Online
View Journal
MedChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: A. Islam, Y.
Zhang, Y. Wang and S. R. McAlpine, Med. Chem. Commun., 2014, DOI: 10.1039/C4MD00387J.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/medchemcomm

Medicinal Chemistry Communications
Page 1 of 6Journal Name
Dynamic Article Links►
View Article Online
DOI: 10.1039/C4MD00387J
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
CONCISE ARTICLE
Design, synthesis and anticancer mechanistic studies of linked azoles
Md. Amirul Islam,a Yuqi Zhang,a Yao Wang, a and Shelli R. McAlpine*a
Received (in XXX, XXX) XthXXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000
5
Herein we report the synthesis and biological activity evaluation
of 2, 4 linked azoleꢀcontaining molecules. A total of 13 linked
thiazoleꢀ and oxazoleꢀcontaining compounds were synthesized in
cytotoxicity with an IC50 = ~380ꢀ520 nM against a panel of
cancer cell lines.16
Inspired by the linked azoles observed within these three
good yields. Cytotoxicity evaluation of those compounds showed 50 biologically active molecules (Ustat A, HXDV, and
that they have lowꢀmicromolar anticancer potency against Marthiapeptide A) and the activity of linked azole molecules
13, 17ꢀ20
10 HCT116 colon cancer cells. Mechanism of action investigation
studies indicated that linked thiazoles were significantly more
biologically active than the corresponding oxazoleꢀcontaining
previously reported12,
we designed a series of short
fragments that investigated whether stereochemistry impacted the
heterocyclic portion of the fragment (Figure 2). Starting with
molecules in inducing apoptotic cancer cell death. Incorporation 55 either an R and S stereochemical orientation of the methyl moiety
of a stereocenter at an azole end and an amide cap at the other
15 end provided a compound that induces DNA damage and leads to
G2/M cell cycle arrest and activation of the G2/M DNA damage
checkpoint.
and then capping the fragment with 3 different moieties (ester,
amide, thioamide) showed that both the stereochemistry and the
capping moiety made a significant difference to the biological
activity of the compound. Testing the cytotoxicity of these
60 compounds against colon cancer cell lines and evaluating their
mechanism of action lead to a set of conclusions. First, linked
thiazoles have significantly higher biological activity than linked
oxazoles. Second, the most effective sequence is three linked
Introduction
Heterocycles play a prominent role in the biological activity of
20 natural products.1ꢀ8 Incorporating heteroatoms into a molecular
scaffold increases the drugꢀlike properties of molecules,
providing solubility, hydrogen bonding, and rigidity. The
presence of electron lone pairs on heteroatoms means that they
readily form hydrogen bonding with water, which increases their
25 solubility, and improves binding to their biological target thereby
enhancing the potency of a molecule.9 The limited number of
rotatable bonds in heterocyclic compounds makes them
structurally rigid, optimizing binding interactions and decreasing
their degradation by proteolytic enzymes. Moreover, the ability of
30 heterocycles to interact with a biological target via πꢀstacking
opens new opportunities for binding sites.10 The most common
heterocycles that are present in biologically active natural
products are thiazoles and oxazoles. The presence of these two
heterocycles in a number of diverse molecular scaffolds makes
35 them structurally and biologically interesting.
O
S
O
OMe
N
S
S
N
N
N
O
HN
N
N
O
O
HN
N
H
N
N
O
O
NHBoc
O
O
Urukthapelstatin A
O
O
O
N
H
O
OMe
N
N
N
N
O
N
N
O
N
N
O
N
O
H
N
O
O
NHBoc
O
O
HXDV
Urukthapelstatin A (Ustat A) (Figure 1) is a natural product
isolated from marine bacteria and it shows potent anticancer
activity against a panel of human cancer cell lines with an
average IC50 value of 12 nM.11ꢀ13 This molecule has a unique
40 bisoxazole and bisthiazole moiety located within the macrocycle.
HXDV (Figure 1) is a synthetic derivative of telomestatin, which
exhibits antiꢀproliferative and apoptotic activity by stabilizing Gꢀ
quadruplex, thereby inducing Mꢀphase cell cycle arrest.14ꢀ15 It has
two linked triꢀoxazoles within its macrocyclic backbone.
45 Marthiapeptide A (Figure 1) is another potent natural product
S
N
O
X
S
N
NH
R
S
N
N
X= O, S
S
N
S
O
R = OEt
= NH2
N
HN
H
N
S
N
R1 = H, or CH3
R2 = H or CH3
NHBoc
S
O
R2 R1
Marthiapeptide A
65 Figure 1. Heterocyclic fragments of three anticancer molecules that
contain linked oxazoles and thiazoles.
that contains
a linked trithiazoleꢀthiazoline system, and
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 |1

Medicinal Chemistry Communications
Page 2 of 6
View Article Online
DOI: 10.1039/C4MD00387J
thiazoles, where fewer linked thiazoles are less active. Third, the
S
O
O
c)
a)
b)
stereochemistry of the starting alanine alters the activity of the
compound, with the S enantiomer being more effective than R.
Finally, the capping moiety makes a significant difference in the
molecules biological activity, with the amideꢀcapping moiety
being the most active structure in cytotoxicity, apoptosis, cell
cycle, and DNA damage assays.
NH2
OH
NH2
NHBoc
3
NHBoc
1
NHBoc
2
5
10
15
20
25
O
O
S
OEt
NH2
NH2
d)
e)
b)
c)
S
S
S
N
N
N
NHBoc
5
NHBoc
NHBoc
6
4
O
O
S
OEt
b)
S
NH2
NH2
S
N
S
d)
e)
N
c)
N
N
S
N
N
S
S
NHBoc
NHBoc
NHBoc
7
8
9
S
O
O
NH2
NH2
OEt
S
S
S
N
N
N
c)
d)
e)
b)
N
N
S
N
N
S
S
N
N
S
S
S
NHBoc
NHBoc
NHBoc
12
10
11
Figure 2. Design of linked azoleꢀcontaining molecules.
S
cheme 1. Synthesis of linked thiazoles. Conditions: a) TMSD, Benzene/
30
MeOH (3:1, 0.1 M), quant. yield. b) NH4OH/MeOH (1:1, 0.05 M), quant.
60 yield. c) Lawesson's Reagent (0.75 eq), THF (0.05 M), 68% for 3, 65%
for 6, 62% for 9 and 12. d) KHCO3 (8 eq), DME (0.05 M), rt,
BrCH2COCO2Et (3 eq), 16 h. d) TFAA (4 eq), Pyridine (9 eq), DME
(0.05 M); then TEA (2 eq), 0°C to rt, 74% for 4, 70% for 7 and 10 (over 2
steps).
Results and Discussion
Several methods have been reported for the synthesis of
thiazoles and oxazoles.20ꢀ24 Employing a modified Hantzsch
reaction, which involves condensation of αꢀhaloketone with
35 thioamide derivatives, we generated the linked thiazoles (Scheme
1).25ꢀ28 The synthesis started with tertꢀBoc protected Dꢀ or Lꢀ
alanine carboxylic acid. The amino acid was converted to its
methyl ester using trimethylsilyldiazomethane (TMSD) in a
mixture of methanol and benzene and the ester was subjected to
40 amide formation using an ammonia hydroxide solution in a protic
solvent. The amide (2) was reacted with Lawesson’s reagent to
furnish Thioamide (3). The thioamide was then subjected to a
modified Hantzsch reaction using ethylbromopyruvate and
65
Generating linked oxazoles was accomplished via cyclization
and oxidation of serine (Ser) containing peptides (Scheme 2).6
BocꢀSerine (Bn) was converted to its methyl ester using TMSD.
Deprotection of the amine was done using TFA and the free
70 amine was subsequently coupled with free acid BocꢀAlaꢀOH to
form the dipeptide precursor using 2ꢀ(1Hꢀbenzotriazolꢀ1ꢀyl)ꢀ
1,1,3,3ꢀtetramethyluronoium hexafluorphosphate (TBTU) and
diisopropylethylamine (DIPEA). The benzyl protecting group
was removed by hydrogenation with Pd/C to generate compound
75 14, which then underwent an intramolecular cyclization using the
fluorinating agent diethylaminosulfur trifluoride (DAST) to form
the intermediate oxazoline. The oxazoline was subsequently
oxidized using BrCCl3 and the hydroxyl moiety eliminated using
1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene (DBU) to produce 15 with an
80 excellent yield (83%). Compound 15 was treated with LiOH to
generate the free acid, which was subsequently coupled with free
amine NH2ꢀSer(Bn)ꢀOMe to obtain 16. Deprotection of the alcohol
and formation of the oxazole resulted in 17 (83% for 3 steps).
Finally, hydrolysis of the ester on 17, coupling with serine,
85 deprotection of the alcohol and formation of oxazole generated 19
(78% for 3 steps).
KHCO3 to form
a hydroxyl thiazoline intermediate. The
45 thiazoline was then dehydrated using trifluoroacetic anhydride
(TFAA) and pyridine to form the monothiazole 4 in good yield
(74% for 2 steps)29
Amination of 4 was accomplished using an ammonia solution,
and then subsequent formation of the thioamide (6) was achieved
50 using Lawesson’s reagent. Formation of the hydroxyl thiazoline
using the modified Hantzsch conditions and subsequent
dehydration of thiazoline yielded 7 (70% for 2 steps). Repeating
this process we generated compound 10 with a 70% yield.
Amination of 10 generated 11 and treatment of the amide with
55 Lawesson’s reagent resulted in 12 (62%).
2
|Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 3 of 6
Medicinal Chemistry Communications
View Article Online
DOI: 10.1039/C4MD00387J
MeO
O
MeO
HO
O
OBn
O
Furthermore, the Lꢀalanine series (Sꢀ stereochem: 10Lꢀ 12L) is
consistently more active than the Dꢀalanine series (10Dꢀ12D).
Thus, the stereochemistry of the methyl moiety must be
25 impacting the planarity of the compound and hence its
mechanism of action. We also determined the IC50 values of
compounds that showed growth inhibition more than 70% at 50
µM concentrations (11L, 11D, 12L, and 12D). We found that
11L is the most potent compound having IC50 value of 7.64 µM
30 against HCT116 cells (Table 1).
1. a)
1. e)
2. f)
N
NH
O
OH
NHBoc
NHBoc
O
NHBoc
13
2. b)
c)
15
14
d)
OMe
O
N
OBn
O
OMe
HN
Table 1. IC50* values of potent compounds (µM) against HCT116 cancer
O
O
O
1. g)
2. h)
1. d)
cells
N
N
O
2. e)
f)
Compounds
11L
11D
12L
12D
NHBoc
NHBoc
7.6 ± 1.0
22.4 ± 1.6
38.1 ± 2.6
45.2 ± 2.1
16
17
IC50 (µM)
*IC50 values of 11L, 11D, 12L, and 12D with their standard error of mean
35 (SEM) against colon cancer cell line HCT116 using CCKꢀ8 assay. Data
OMe
O
OH
represents results from
a concentration curve taken from six
OMe
concentrations, where each concentration data point is from three separate
experiments performed in quadruplicate. Concentration curves are
available in supplementary material.
O
O
N
N
H
O
1. g)
1. e)
2. h)
O
O
O
N
N
40 Mechanistic studies
3) d)
2. f)
N
N
O
Performing an apoptosis analysis using AnnexinꢀV/7ꢀAAD
cytofluorometric staining supported the IC50 data, where 11L was
more potent than 11D at inducing apoptotic cancer cell death
(Figure 4a). Compared to the control treatment (DMSO), over
45 60% of HCT116 cells undergo apoptosis after 30 hrs of
incubation with 11L (30 µM) (versus 30% under the same
conditions with 11D). Treatment of HCT116 cells with 11L for
20 hrs significantly increased the population of living cells in
G2/M phase with a decrease in both G0/G1 and S phases,
50 compared to the control treatment (Figure 4b). These data
indicate that 11L induces a G2/M arrest in HCT116 cells.
NHBoc
NHBoc
18
19
Scheme 2. Synthesis of linked oxazoles. Conditions: a) MeOH/Benzene
(1:3, 0.1 M), TMSD (3.0 eq). b) TFA/CH2Cl2 (1:4, 0.1 M), Anisole (2.0
eq). c) BocꢀAlaꢀOH (1.1 eq), TBTU (1.1 eq), DIPEA (8.0 eq), CH2Cl2
(0.1 M). d) H2 (1 atm), Pd/C, EtOH (0.1 M). e) DAST (1.1 eq), K2CO3
(2.0 eq), CH2Cl2 (0.1 M), ꢀ78oC. f)DBU (2.0 eq), CBrCl3 (2.0 eq), CH2Cl2
(0.1 M), ꢀ47oC. g) LiOH (8.0 eq), MeOH (0.1 M). h)HꢀSer(Bn)ꢀOMe (0.9
eq), TBTU (1.1 eq), HATU (1.1 eq), DIPEA (10 eq), CH2Cl2 (0.1 M).
5
Structure-activity relationships
Since many chemotherapeutic agents arrest cancer cells in
G2/M phase by causing DNA damage, we examined if 11L also
induced DNA damage in HCT116 cells and if such damage
55 happens in a specific cell cycle phase. This was done by flow
cytometry detecting the phosphorylation of histone H2AX on
serine 139 (γꢀH2AX), which is a prominent marker of DNA
damage,31 while measuring DNA content with propidium iodide.
We found that in the treatments with 11L or 11D γꢀH2AX formed
60 at all cell cycle phases, although with a significant preference for
S and G2/M phases (Figure 4c). Similar effects were observed in
the Paclitaxel (Pac) and Doxorubicin (Dox) treatments.
Comparison to both Pac and Dox showed that 11L was more
effective at inducing DNA damage than either of these anticancer
65 agents when cells were treated at their respective IC50 values.
Those results indicated that 11L and 11D triggered apoptosis in
HCT116 cells through causing DNA damage, although 11L is
more effective than 11D in all cases. This damage manifested
primarily in the G2/M cell cycle arrest
10
The synthesized thiazole and oxazole molecules were tested at
50 µM in a cytotoxicity assay (CCKꢀ8), where we evaluated their
activity against colon cancer cell line HCT116 (Figure 3).30 As is
evident in the graph, the triꢀthiazoles (compounds 10ꢀ12) are
significantly more active than the oxazoles series.
p =0.0129
p =0.0192
p =0.0014
100
90
p =0.1312
80
70
60
50
40
30
20
10
0
Compounds (50 ꢀM)
15
Figure 3. Growth inhibition of compounds at 50 µM. Percentage growth
inhibition of treated HCT116 cells was measured using a CCK8 assay.
Data is from three separate experiments performed in quadruplicate and
the error bars are the standard errors of the mean (SEM). (P values were
70
Based on the previous observations in cell cycle analysis and
DNA damage detection, we speculated that 11L triggered
apoptosis in HCT116 cells possibly by activating the G2/M
checkpoint. In response to many types of DNA damage, cells
20 calculated using Graph pad Prism version 6)
.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 |3

Medicinal Chemistry Communications
Page 4 of 6
View Article Online
DOI: 10.1039/C4MD00387J
activate powerful DNA damageꢀinduced cell cycle checkpoints
d)
that coordinate cell cycle arrest with recruitment and activation of
DNA repair machinery.32ꢀ34 If cells fail to repair the damage in a
certain time period, pathways involved in programmed cell death
will be initiated, leading to the elimination of irreparably
damaged cells by apoptosis.32, 35 In order to prove our hypothesis,
we measured the population changes of mitotic cells (cells at M
a)
G2/M DNA Damage Checkpoint Activition
in HCT116 Cells
20 h Treatment
24 h Treatment
6.0
4.5
5
***
§
3.0
1.5
Apoptosis Analysis in HCT116 Cells
20 h Treatment
24 h Treatment
30 h Treatment
1.0
0.5
0.0
**
100
75
50
25
0
**
§
§
**
***
§
§
15
Figure 4. The effects of 11L and 11D on apoptosis, cell cycle
progression, and DNA damage response in HCT116 cells. a) After
indicated treatments cells were stained with Annexin VꢀFITC/7AAD and
analysed by flow cytometry for apoptosis analysis. b) After indicated
Annexin V - / 7AAD +
Annexin V + / 7AAD +
(late apoptotic cells)
Annexin V + / 7AAD -
(early apoptotic cells)
Annexin V - / 7AAD -
(living cells)
20 treatments cells were stained with PI for cell cycle analysis by flow
cytometry. The percentages of cells in the G0/G1, S, and G2/M phases of
cell cycle are indicated in bar graphs. c) Treatments with 11D and 11L for
20 or 24 h resulted in DNA damage in HCT116 cells. Treated cells were
stained with DNA damage marker γꢀH2AX and analysed by flow
25 cytometry. d) Treatment with 11L for 20 or 24 h activated the G2/M
DNA damage checkpoint in HCT116 cells. Treated cells were stained
with Histone H3 (phospho, Serꢀ10)/PI and analysed by flow cytometry.
All values presented are average ± SEM of at least three independent
experiments. Differences between indicated data and DMSO control are
30 represented with P values (*, P < 0.05; **, P < 0.01; ***, P < 0.005; and
§, P < 0.001).
10 b)
Cell Cycle Analysis in HCT116 Cells
after 24 h Treatment
G0/G1 phase
G2/M phase
80
70
60
50
40
30
20
10
0
§
§
§
§
§
§
S phase
***
§
**
phase) caused by drug treatments. Results are shown as the
mitotic index, which represents the percentage of mitotic cells in
35 the total population (Figure 4d, the index of DMSO control was
considered as 1). If the G2/M checkpoint is activated, we should
see a decrease in the population of M phase cells, that is, a
decrease in the mitotic index. Mitotic cells were determined and
distinguished from the entire population by flow cytometry.
40 Detection of the phosphorylated Histone H3 while measuring
DNA content with propidium iodide was used as it is an ideal
§
** ***
§
c)
DNA Damage Analysis in HCT116 Cells
after 24 h Treatment
G0/G1 phase
S phase
G2/M phase
indicator of mitotic cells.
Specifically, Histone H3 is
15
12
9
phosphorylated during mitosis.36 Our results showed that 11L
reduced the mitotic index in a timeꢀ and concentrationꢀdependent
45 manner (Figure 4d). Contrary to the control compound
Paclitaxol, which traps cells in M phase (indicated by the
dramatic increase of mitotic index), 11L arrests cells in G2 phase,
which is similar to the effect caused by Doxorubicin (Figure 4d).
Combined, those data demonstrated that 11L triggered apoptotic
50 cancer cell death by causing DNA damage, and leads to G2/M
cell cycle arrest and the activation of a G2/M DNA damage
checkpoint.
§
§
***
§
§
**
§
***
**
6
§
**
§
§
§
§
3
0
4
|Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 5 of 6
Medicinal Chemistry Communications
View Article Online
DOI: 10.1039/C4MD00387J
DaRe, F. Tian, W. Li, T. Gibson, R. Lemus, P. D. van
Poelje, S. C. Potter and M. D. Erion, J. Med. Chem.,
2011, 54, 153ꢀ165.
Conclusions
In conclusion, we have shown that linked thiazoles have
significantly higher biological activity than linked oxazoles, with
the most effective sequence being three linked thiazoles.
single stereocenter on the otherwise flat molecule alters the
activity of the compound and indicates that the molecule is
binding to a chiral target. The capping moiety makes an
important contribution to the biological activity, with the amide
being the most effective cap for these molecules. Recent work by
55
4. P. I. Dosa, J. C. Ruble and G. C. Fu, J. Org. Chem., 1997, 62,
444ꢀ445.
5. M. Duchler, J. Drug Target., 2012, 20, 389ꢀ400.
6. R. A. Hughes and C. J. Moody, Angewandte Chemie
International Edition, 2007, 46, 7930ꢀ7954.
7. B. Wagner, D. Schumann, U. Linne, U. Koert and M. A.
Marahiel, J. Am. Chem. Soc., 2006, 128, 10513ꢀ10520.
8. K. Sivonen, N. Leikoski, D. P. Fewer and J. Jokela, Appl.
Microbiol. Biotechnol., 2012, 86, 1213–1225.
65 9. A. Gomtsyan, Chem. Heterocycl. Compd., 2012, 48, 7ꢀ10.
10. M. Ma, Y. Cheng, Z. Xu, P. Xu, H. Qu, Y. Fang, T. Xu and
L. Wen, European Journal of Medicinal Chemistry,
2007, 42, 93ꢀ98.
A
5
60
10 Wipf and co workers37 shows that alcohol capping groups
generate compounds that have nanomolar IC50 values, thus, our
hypothesis is that our compounds might have improved potency
if they were converted to an alcohol. In addition, Wipf’s work
suggests that the NꢀBoc protecting group on our molecules may
15 be coming off once the molecule has entered the cell, generating
the free amine as the active compound. Mechanistic investigation
shows that the most effective molecule, 11L, induces apoptosis in
over 60% of HCT116 cells within 30 hrs of treatment, which is
significantly higher than 11D (25%). The G2/M cell cycle arrest
20 and the DNA damageꢀinduced G2/M checkpoint activation
caused by 11L indicate that its mechanism of action in inducing
apoptosis is associated with the pathways involved in DNA
damage and repair response. The loss of DNA damage
checkpoints during early stages of tumorigenesis facilitates
25 acquisition of additional mutations, and is an optimal mechanism
that is frequently exploited in chemotherapies. Given that 11L is
more effective than 11D in causing DNA damageꢀinduced G2/M
cell cycle checkpoint and apoptosis at the same concentrations,
the stereocenter must be play an important role in the events
30 associated with DNA damage and repair pathways. These
findings have implications for synthesizing derivatives of
heterocyclicꢀcontaining natural products and in designing
fragments of the heterocyclic portions of the compounds.
11. y. Matsuo, K. Kanoh, H. Imanaka, K. Adachi, M. Nishizawa
70
and Y. Shizuri, J. Antibiot., 2007, 60, 256ꢀ260.
12. C.ꢀC. Lin, W. Tantisantisom and S. R. McAlpine, Org. Lett.,
2013, 15, 3574ꢀ3577.
13. S.ꢀJ. Kim, C.ꢀC. Lin, C.ꢀM. Pan, D. P. Rananaware, D. M.
Ramsey and S. R. McAlpine, Med. Chem. Comm.,
2013, 4, 406ꢀ410.
14. Y.ꢀC. Q. Tsai, H.; Lin, C.ꢀP.; Lin, R.ꢀK.; Kerrigan, J. E.;
Rzuczek, S. G.; LaVoie, E. J.; Rice, J. E.; Pilch, D. S.;
Lyu, Y. L.; Liu, L. F., A J. Bio. Chem., 2009, 284,
22535ꢀ22543.
80 15. M. R. Satyanarayana, S. G.; LaVoie, E. J.; Pilch, D. S.; Liu,
A.; Liu, L. F.; Rice, J. E., , Bioorg. Med. Chem., 2008,
18, 3802ꢀ3804.
75
16. X. Zhou, H. Huang, Y. Chen, J. Tan, Y. Song, J. Zou, X.
Tian, Y. Hua and J. Ju, J. Nat. Prod., 2012, 75, 2251ꢀ
85
2255.
17. H. Wahyudi, W. Tantisantisom and S. R. McAlpine,
Tetrahedron Lett., 2014, 55, 2389ꢀ2393.
18. W. Tantisantisom, D. M. Ramsey and S. R. McAlpine, Org.
Lett., 2013, 15 4638ꢀ4641.
90 19. H. Wahyudi, W. Tantisantisom, X. Liu, D. M. Ramsey, E. K.
Singh and S. R. McAlpine, J. Org. Chem., 2012, 77,
10596ꢀ10616.
Acknowledgements
35 We thank the University of New South Wales for a tuition fee
waiver to A.I. and Y.W. We thank NHMRC APP1043561 for
support on this project.
Notes
20. E. Singh, D. M. Ramsey and S. R. McAlpine, Org. Lett.,
2012, 14, 1198ꢀ1201.
95 21. M. R. Davis, E. K. Singh, H. Wahyudi, L. D. Alexander, J.
Kunicki, L. A. Nazarova, K. A. Fairweather, A. M.
Giltrap, K. A. Jolliffe and S. R. McAlpine,
Tetrahedron, 2012, 68, 1029ꢀ1051.
aSchool of Chemistry, 219 Dalton, Gate 2 High Street, University of New
40 South Wales, Sydney, NSW, 2052, Australia. Fax: +61-2-9385-4000 Tel:
+61-4-1672-8896; E-mail:s.mcalpine@unsw.edu.au
† Electronic Supplementary Information (ESI) available: synthetic
procedures spectra for the intermediates and final structures of all
molecules.
Details of biological assays are also included. See
22. N. U. Güzeldemirci and Ö. Küçükbasmacı, European J. Med.
45 DOI: 10.1039/b000000x/
100
Chem., 2010, 45, 63ꢀ68.
23. J. P. Marino, P. W. Fisher, G. A. Hofmann, R. B. Kirkpatrick,
C. A. Janson, R. K. Johnson, C. Ma, M. Mattern, T. D.
Meek, M. D. Ryan, C. Schulz, W. W. Smith, D. G.
Tew, T. A. Tomazek, D. F. Veber, W. C. Xiong, Y.
Yamamoto, K. Yamashita, G. Yang and S. K.
Thompson, J. Med. Chem., 2007, 50, 3777ꢀ3785.
References
1. M. Baumann, I. R. Bazendale, S. V. Ley and N. Nikbin,
Beilstein J. Org. Chem., 2011, 7, 422ꢀ495.
2. D. L. Boger, Patent application: PCT/US2007/019471/
105
50
US2010/0075931 A1, 2012, 12/310,474.
3. Q. Dang, L. Yan, D. K. Cashion, S. R. Kasibhatla, T. Jiang,
F. Taplin, J. D. Jacintho, H. Li, Z. Sun, Y. Fan, J.
24. B. Soni, M. S. S. Ranawat, Rambabu, A. Bhandari and S.
Sharma, Eur. J. Med. Chem., 2010, 45, 2938ꢀ2942.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 |5

Medicinal Chemistry Communications
Page 6 of 6
View Article Online
DOI: 10.1039/C4MD00387J
25. K. M. Aitken and R. A. Aitken, Tetrahedron, 2008, 64, 4384ꢀ
4386.
26. M. Narender, M. S. Reddy, R. Sridhar, Y. V. D. Nageswar
and K. RamoRao, Tetrahedron Letters, 2005, 46, 5953ꢀ
5955.
27. T. M. Potewar, S. A. Ingale and K. V. Srinivasan,
Tetrahedron, 2007, 63, 11066ꢀ11069.
28. E. Aguilar and A. I. Meyers, Tetrahedron Lett, 1994, 35,
2473ꢀ2476.
10 29. C.ꢀM. Pan, C.ꢀC. Lin, S. J. Kim, R. P. Sellers and S. R.
McAlpine, Tetrahedron Lett., 2012, 53, 4065ꢀ4069.
30. H. Ohori, H. Yamakoshi, Tomizawa M, Shibuya M, Kakudo
Y, Takahashi A, Takahashi S, Kato S, Takao T, Ishioka
C, Iwabuchi Y and S. H., Mol. Cancer. Ther., 2006, 5,
32. M. V. Powers and P. Workman, FEBS Lett, 2007, 581, 3758ꢀ
3769.
33. E. L. Davenport, G. J. Morgan and F. E. Davies, Cell Cycle,
2008, 7, 865ꢀ869.
34. C. S. Mitsiades, N. S. Mitsiades, C. J. McMullan, V. Poulaki,
A. L. Kung and F. E. Davies, Blood, 2006, 107, 1092ꢀ
1100.
35. E. Y. Komarova, E. A. Afanasyeva, M. M. Bulatova, M. E.
Cheetham, B. A. Margulis and I. V. Guzhova, Cell
Stress Chaperones, 2004, 9, 265ꢀ275.
20
25
30
5
36. M. V. Powers, P. A. Clarke and P. Workman, Cancer Cell,
2008, 14, 250ꢀ262.
37. J. Salamoun, S. Anderson, J. C. Burnett, R. Gussio and P.
Wipf, Org. Lett., 2014, 16, 2034ꢀ2037.
15
35
2563ꢀ2571.
31. E. L. Davenport, H. E. Moore, A. S. Dunlop, S. Y. Sharp, P.
Workman and G. J. Morgan, Blood, 2007, 110, 2641ꢀ
2649.
6
|Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]