Synthesis and biological evaluation of arylated novobiocin analogs as Hsp90 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2011.09.073

Novobiocin analogs lacking labile glycosidic ether have been designed, synthesized and evaluated for Hsp90 inhibitory activity. Replacement of the synthetically complex noviose sugar with simple aromatic side chains produced analogs that maintain moderate cytotoxic activity against MCF7 and SkBR3 breast cancer cell-lines. Rationale for the preparation of des-noviose novobiocin analogs in addition to their synthesis and biological evaluation are presented herein.

Full text of DOI:10.1016/j.bmcl.2011.09.073

Bioorganic & Medicinal Chemistry Letters 21 (2011) 7170–7174
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of arylated novobiocin analogs
as Hsp90 inhibitors
⇑
Bhaskar Reddy Kusuma, Adam S. Duerfeldt, Brian S.J. Blagg
Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott Hall 4070, Lawrence, KS 66045-7563, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Novobiocin analogs lacking labile glycosidic ether have been designed, synthesized and evaluated for
Hsp90 inhibitory activity. Replacement of the synthetically complex noviose sugar with simple aromatic
side chains produced analogs that maintain moderate cytotoxic activity against MCF7 and SkBR3 breast
cancer cell-lines. Rationale for the preparation of des-noviose novobiocin analogs in addition to their syn-
thesis and biological evaluation are presented herein.
Received 3 August 2011
Revised 16 September 2011
Accepted 19 September 2011
Available online 1 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Hsp90
Novobiocin
Chaperone
Inhibitors
Heat shock protein 90 kDa (Hsp90) is a remarkably versatile
molecular chaperone that plays a key role in homeostasis.1,2
However, Hsp90 is unregulated in malignancies and facilitates
the maturation, stabilization and/or activation of more than 50
oncogenic proteins, including several kinases and transcription
factors.3–6 Thus, Hsp90 has attracted the attention of both
industrial and academic laboratories as a promising target for the
development of cancer chemotherapeutics.
Hsp90 exists as an obligate homodimer and possesses two nucle-
otide binding regions: (1) an N-terminal ATP-binding pocket that
manifests ATPase activity, and produces the requisite energy for
client protein maturation, and (2) a C-terminal nucleotide binding
OH
OH
H
OH
OH
H
N
O
N
O
O
O
O
O
O
O
Cl
O
MeO
O
O
MeO
H2N
OH
Clorobiocin
O
OH
O
Novobiocin
NH
O
OH
O
OH
HN
H
N
H
N
H
O
O
O
N
O
O
O
O
O
O
O
OMe
MeO
Coumermycin A1
O
O
OH
OH
O
NH
Figure 1. Representative natural product Hsp90 C-terminal inhibitors.
⇑
Corresponding author. Tel.: +1 785 864 2288; fax: +1 785 864 5326.
E-mail address: bblagg@ku.edu (B.S.J. Blagg).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.09.073

B. R. Kusuma et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7170–7174
7171
acid chloride
coupling
pocket that exhibits allosteric control over substrate and co-chaper-
X = CH2, Pd-catalyzed
Sp3-Sp2 coupling
ones.2,7–10 Traditional inhibitors of Hsp90 disrupt the N-terminal
ATP binding pocket, resulting in client protein degradation and inhi-
bition of cell proliferation. At present, no N-terminal Hsp90 inhibitor
has been approved by the FDA. Detriments related to N-terminal
inhibition have include; induction of the pro-survival heat shock re-
sponse, as well as undesired toxicity profiles.1,11,12 Thus, new oppor-
tunities for Hsp90 modulation, includingC-terminal inhibition, have
been sought after for Hsp90 disruption.13–21
H
N
R1
R2
R
{
O
H-bond acceptor
and/or donor
X
O
O
X = O, Coupper mediated
boronic acid coupling
X = NH, Pd-catalyzed N-arylation
cross coupling
OAc
OH
OMe
X = O, NH, CH2
Natural products identified as C-terminal Hsp90 inhibitors in-
clude the coumarin family of antibiotics such as novobiocin,
chloropicrin and coumermycin A1 (Fig. 1).22,23 Structure–activity
relationship (SAR) studies on novobiocin, which was originally
identified as a bacterial DNA gyrase inhibitor, transformed this
broad spectrum antibiotic into a potent cytotoxic Hsp90 inhibi-
tor.13 In addition, SAR studies revealed a class of C-terminal
Hsp90 inhibitors that manifest cytotoxic activity at concentra-
tions significantly lower than that which is needed for induction
of the heat shock response, unlike the N-terminal inhibitors in
clinical trials.24,25 Furthermore, evidence suggests that C-terminal
inhibition may improve selective client protein degradation, pro-
ducing a potential improvement over N-terminal inhibitors.24
R1 = H, OH, OMe, OMOM, tBu
OMe
R =
,
,
R2 = H, OMe
Figure 2. Non-hydrolysable novobiocin analogs.
Syntheses of aryl ethers 13–21 were initiated from previously
reported coumarin scaffold 1,22 via the oxidative coupling with
commercially available boronic acids 2–4 in the presence of
Cu(OAc)2 and pyridine to yield intermediates 5–7 in excellent
yields.31,32 Removal of the carboxybenzyl (Cbz) protecting group
and subsequent coupling with acid chloride 11or 1225–27 provided
compounds 13, 15, 17 or 19–21, respectively. Finally, hydrolysis of
13, 15, and 17 under mild conditions produced the free phenols 14,
16, and 18 (Scheme 1).
In parallel, a series of NH-linked aryl analogs 30–32 were syn-
thesized for direct comparison to their aryl ether counterparts
(Scheme 2). Furthermore, these analogs incorporated a hydrogen
bond donor in lieu of the ether acceptor and may therefore provide
enhanced interactions with the C-terminal binding pocket.
The NH-linked aryl analogs 30–32, were synthesized from com-
mercially available 3-nitro-2-methyl phenol 23, which was trans-
formed to the corresponding amino phenol 24, upon reduction of
the nitro functionality. Intermediate 26 was afforded in reasonable
yield via a Buchwald N-arylation cross coupling33,34 of compound
24 with 4-iodo anisole 25 in the presence of Pd(dppf)Cl2 and KOtBu
in dioxane. Phenol 26 was condensed with enamine 2725–27 in ace-
tic acid under reflux conditions to provide N-arylated coumarin 28
in acceptable yield. Hydrogenolysis of the Cbz protecting group
and subsequent coupling with acid chlorides 11 or 12, provided
Thus, C-terminal inhibitors of Hsp90 represent
a promising
option for Hsp90 modulation and may possess attributes that
overcome limitations manifested with the N-terminal inhibitors.
In pursuit of the development of more potent novobiocin ana-
logs, we recently reported derivatives that contain sugar surrogates
in lieu of the stereochemically complex noviose (Fig. 2). These stud-
ies resulted in the attainment of compounds that exhibit nanomolar
inhibitory activity against both breast and prostate cancer cell-
lines.22,25–27 In continuation of previous optimization efforts; it
was desired to replace the noviose sugar with substituted phenyl
rings via various linkages (–O, –NH and –CH2). Rationale for the
design of these analogs was three-fold: (1) aryl ethers of novobiocin
represent a novel class of uninvestigated analogs; (2) elimination of
the stereochemically complex sugar moiety (which requires 11-
steps to prepare28), and (3) removal of the hydrolytic sensitive gly-
cosidic linkage, which may limit its utility for therapeutic applica-
tions.29,30 As
a result of these studies, a non-labile and
synthetically accessible class of novobiocin analogs was pursued.
R1
R2
B(OH)2
NHCbz
O
R1
R2
NHCbz
O
Pd/C, H2
2-4
HO
O
Cu(OAc)2, pyridine
THF, rt, 1 h
O
O
4 Ao MS, DCM, rt, 1h
1
2,
5, R1 = OMe, R2 = H
6, R1 = H, R2 = OMe
7, R1 = tBu, R2 = H
R
1 = OMe, R2 = H
3, R1 = H, R2 = OMe
t
4, R1 = Bu, R2 = H
R1
R2
NH2
H
R1
N
R
11 or 12
O
O
O
O
T
HF, pyridine
rt, 16 h
R2
i
O
O
O
8, R1 = OMe, R2 = H
9, R1 = H, R2 = OMe
13, R = a, R1 = OMe, R2 = H
OAc
OMe
Cl
14, R = b, R1 = OMe, R2 = H
Cl
OMe
10, R1 = Bu, R2 = H
1
t
, R = , R = H, R2 = OMe
15
16
17
18
a
b
a
b
O
O
i
i
, R = , R1 = H, R2 = OMe
11
12
, R = , R = tBu , R2 = H
1
, R = , R1 = Bu, R2 = H
t
OAc
OH
OMe
19, R = c, R1 = OMe, R2 = H
20, R = c, R1 = H, R2 = OMe
21, R = c, R1 = tBu, R2 = H
OMe
b
a
c
conditions: i). Et3N, MeOH
rt, 16 h
Scheme 1. Synthesis of O-linked non-labile novobiocin analogs.

7172
B. R. Kusuma et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7170–7174
MeO
I
MeO
25
Pd/C, H2
H2N
OH
O2N
MeO
OH
23
Pd(dppf)Cl2, KOtBu
dioxane, 120 °C
in sealed tube, 71%
EtOH, rt, 4h
97%
N
H
OH
26
24
O
NHCbz
N
MeO
NHCbz
O
MeO
NH2
O
Pd/C, H2
27
N
O
THF, rt, 1 h, 88%
AcOH, reflux, 2 h
44%
N
H
O
H
28
29
H
MeO
N
R
11 (or) 12
OAc
OH
OMe
O
THF, pyridine
rt, 6 h, 68-87%
OMe
N
O
O
H
30, R = a
31
a
Et3N, MeOH
b
c
b
, R =
32, R = c
Scheme 2. Synthesis of N-linked non-labile novobiocin analogs.
analogs 30 and 32, in good yields, respectively. Finally, methanol-
ysis of acetate 30 yielded the corresponding phenol, 32 (Scheme 2).
To further investigate the influence of surrogates on the activity
of aryl-containing replacements, linkers containing of a methylene
in lieu of the ether or amine were also pursued (Scheme 3). These
analogs were prepared in an effort to provide direct comparison
the aryl ethers/amines previously described. Methylene linked
analogues 43–54 were prepared in 3–5 steps commencing with
the coumarin 1, which was converted to triflate 33 in the presence
of Tf2O and pyridine. Utilizing Pd-mediated borylation chemistry,35
intermediate 34 was obtained in one-step. Interestingly, the vinyl-
ogous amide was deprotected simultaneously under the enlisted
conditions, which was required for benzamide formation. Subse-
quent coupling of amine 34 with acid chloride 11 or 12 provided
analogs 35 and 36 respectively, in excellent yield.
groups present in 49 and 51 in single step. Intermediate 36 was
also coupled with benzyl bromides 37 and 38 to yield compounds
53 and 54, respectively (Scheme 3).
Upon preparation of these non-hydrolysable novobiocin ana-
logs with various linkers (–O, –NH and –CH2), the compounds were
evaluated for anti-proliferative activity against SkBR3 and MCF7
breast cancer cell-lines. In general, the ether analogs containing a
prenylated aryl side chain (13–18) maintained moderate efficacy,
whereas compounds exhibiting the biaryl side chain (19–21) dis-
played IC50 values >100 lM (Table 1). This observation is notewor-
thy, as the presence of the prenylated functionality in noviosylated
novobiocin analogs attenuates the antiproliferative activity, sug-
gesting that simple replacement of the sugar moiety with an aryl
appendage significantly alters the mode of binding. Furthermore,
analysis of analogs 13–18 suggests a cell-line sensitivity to the ap-
pended methyl ether. The 30-OMe analogs (15 and 16) were
slightly more active than the corresponding 40-OMe analogs (13
and 14) against SKBr3 cell lines; however, 13 and 14 were more
active against MCF-7 cell lines (Table 1). The aryl ether analogs also
indicate that steric bulk at the 40-position attenuates activity, as all
aryl ethers containing a 40t-BuOH moiety (17, 18, and 21) exhibited
Finally, palladium-catalyzed Sp2–Sp3 coupling36–38 of 35 with
benzyl bromides 37–42 in the presence of K2CO3 yielded com-
pounds 43, 45, 47, 49, and 51, respectively, in respectable yields.
Methanolysis of aryl acetates 43, 45, and 47 yielded compounds
44, 46, and 48, respectively. In addition, analogs 50 and 52 were
produced via acid mediated hydrolysis of the acetate and MOM
NH2
NHCbz
NHCbz
Tf2O, py.
Pd(dppf)Cl2, KOAc
O
B
O
O
O
(pin)2B, dioxane
reflux, 16 h, 74%
HO
O
O
O
DCM, rt, 16 h
TfO
O
O
1
34
33
H
H
N
N
R
37-42
R1
R2
R
11 or 12
Pd(dppf)Cl2, K2CO3
O
O
B
O
O
THF, py.
rt, 16 h
dioxane, reflux,
16 h, 54%-83%
O
O
O
35, R = a
36, R = c
R1
, R = a, R1 = OMe, R2 = H
, R = b, R1 = OMe, R2 = H
43
44
i
i
Br
R2
45, R = a, R1 = H, R2 = OMe
46, R = b, R1 = H, R2 = OMe
47, R = a, R1 = OMe, R2 = OMe
48, R = b, R1 = OMe, R2 = OMe
37, R1 , R2 = H
38, R1 = OMe, R2 = H
i
39, R1 = H, R2 = OMe
, R = OMe, R2 = OMe
1
40
41
42
, R = a, R1 = OMOM, R2 = OMe
, R = b, R1 = OH, R2 = OMe
, R = a, R1 = OMOM, R2 = H
ii
49
50
51
, R = OMOM, R2 = OMe
1
, R = OMOM, R2 = H
ii
1
OAc
52, R = b, R1 = OH, R2 = H
53, R = c, R1, R2 = H
OH
OMe
OMe
54, R = c, R1 = OMe, R2 = H
conditions: i). Et3N, MeOH, rt, 16 h
ii). 4N HCl in dioxane, rt, 10 min.
b
a
c
Scheme 3. Synthesis of methylene linked novobiocin analogs.

B. R. Kusuma et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7170–7174
7173
Table 1
Antiproliferative activity of non-labile novobiocin analogs
H
OAc
OH
R1
R2
N
R
OMe
OMe
O
X
O
O
b
a
c
Entry
X
R
R1
R2
SkBR3
MCF7
13
14
15
16
17
18
19
20
21
30
31
32
43
44
46
48
49
50
51
52
53
54
O
O
O
O
O
O
O
O
a
b
a
b
a
b
c
c
c
a
b
c
a
b
b
b
a
b
a
b
c
OMe
OMe
H
H
H
OMe
OMe
H
H
H
OMe
H
H
H
H
H
H
OMe
OMe
OMe
OMe
H
19.51 1.8
42.72 2.1
13.68 1.1
33.14 0.9
72.39 1.9
68.27 3.8
>100
>100
>100
>100
>100
>100
23.49 0.7
11.08
14.83 1.3
>100
14.24 0.4
10.69 1.1
13.50 0.7
21.46 0.5
4.09 0.2
>100
18.20 2.1
6.51 0.7
15.69 2.3
62.8 4.4
74.99 4.9
20.55 0.8
>100
>100
>100
>100
>100
H
tBu
tBu
OMe
H
O
tBu
NH
NH
NH
OMe
OMe
OMe
OMe
OMe
H
OMe
OMOM
OH
>100
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
11.5 0.9
13.25 1.2
19.65 2.0
13.94 3.3
14.88 0.9
14.62 1.4
22.67 1.7
32.11 3.2
7.11 1.6
>100
OMOM
OH
H
H
H
H
c
OMe
inferior anti-proliferative activities, suggesting spacial limitations
at this region of the binding pocket.
Methylene linked analogs,43, 44, 46, and 48–54, were also eval-
uated for anti-proliferative activity. With the exception of 54 and
48, methylene linked compounds exhibited a relatively flat SAR,
manifesting equipotency against both MCF-7 and SkBR3 cell lines.
53 represents the most active aryl linked compound identified in
M against
SkBR3 and MCF-7 cancer cells, respectively. Surprisingly, the
NH-linked analogs exhibit no anti-proliferative activity against
MCF-7 or SkBR3 cell lines up to 100 lM, suggesting that replace-
ment of the ether linker with an NH moiety precludes binding. This
result suggests that a hydrogen bond donor at this location and/or
the conformational induced via the NH linker may be detrimental
to binding and novobiocin analogs containing such features should
not be pursed.
this series, and manifested IC50 values of ꢀ4 and ꢀ7
l
Compound 48, exhibits moderate activity (ꢀ13
lM) against MCF-7
cells, but is inactive up to 100 M against SkBR3 cells. Although,
l
novobiocin-based analogs are typically slightly more active against
MCF-7 cells, the ꢀ10-fold sensitivity to 48 is intriguing. Compound
0.1
1
10
50
100 GDA DMSO
Her2
Hsp90
Raf
Akt
Actin
Her2
Hsp90
Raf
Akt
Actin
Figure 3. Western blot analyses of Hsp90 client protein degradation assays against MCF-7 cells. Concentrations (in lM) of 14 (top) and 43 (bottom) are indicated above each
lane. GDA (geldanamycin, 500 nM) and DMSO were respectively employed as positive and negative controls.

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B. R. Kusuma et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7170–7174
12. Kim, Y. S.; Alarcon, S. V.; Lee, S.; Lee, M. J.; Giaccone, G.; Neckers, L.; Trepel, J. B.
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Hsp90 client protein degradation. As expected for a C-terminal
Hsp90 inhibitor, client protein degradation was observed and
indicative of C-terminal inhibition, no Hsp90 induction was seen.
This is in contrast to N-terminal Hsp90 inhibitors, which induce
the heat shock response at the same concentration needed to in-
duce client protein degradation (Fig. 3).
In conclusion, a series of non-hydrolyzable novobiocin analogs
that contain non-hydrolysable linkers (–O, –NH and –CH2) was
designed, synthesized and evaluated for Hsp90 inhibitory activity
against SkBR3 and MCF7 breast cancer cell-lines. Replacement of
the synthetically complex noviose sugar with simple ether or
methylene linked aromatic side chains resulted in moderate
anti-proliferative activity that is attributable to Hsp90 C-terminal
inhibition. These non-hydrolyzable novobiocin analogs provide a
class of C-terminal Hsp90 inhibitors that can be obtained through
an expedient process, as the synthetically complex noviose has
been eliminated.
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Acknowledgements
26. Zhao, H.; Kusuma, B. R.; Blagg, B. S. J. ACS Med. Chem. Lett. 2010, 1, 311.
27. Zhao, H.; Donnelly, A. C.; Kusuma, B. R.; Brandt, G. E. L.; Brown, D.; Rajewski, R.
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The authors gratefully acknowledge the support of this project
by NIH CA120458, the Madison and Lila Self Graduate Fellowship
(A.S.D.), the American Foundation of Pharmaceutical Education
Pre-doctoral Fellowship (A.S.D.) and the Institute for Advancing
Medical Innovation Pre-doctoral Fellowship (A.S.D.) for financial
support.
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