Synthesis of pochoxime prodrugs as potent HSP90 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.04.030

Pochoximes are potent inhibitors of heat shock protein 90 (HSP90) based on the radicicol pharmacophores. Herein we present a pharmacokinetics and pharmacodynamics evaluation of this compound series as well as a phosphate prodrug strategy to facilitate for

Full text of DOI:10.1016/j.bmcl.2009.04.030

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3836–3840
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of pochoxime prodrugs as potent HSP90 inhibitors
Cuihua Wang a, Sofia Barluenga a, Girish K. Koripelly a, Jean-Gonzague Fontaine a, Ruihong Chen b,
Jin-Chen Yu b, Xiaodong Shen b, John C. Chabala b, James V. Heck b, Allan Rubenstein b, Nicolas Winssinger a,
*
a Institute de Science et d’Ingénierie Supramoleculaires, Université de Strasbourg, 8 allée Gaspard Monge, 67000 Strasbourg, France
b NexGenix Pharmaceuticals, 152 West 57th Street, NY 10019, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 February 2009
Revised 1 April 2009
Accepted 3 April 2009
Available online 17 April 2009
Pochoximes are potent inhibitors of heat shock protein 90 (HSP90) based on the radicicol pharmaco-
phores. Herein we present a pharmacokinetics and pharmacodynamics evaluation of this compound ser-
ies as well as a phosphate prodrug strategy to facilitate formulation and improve oral bioavailability.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
HSP90
Radicicol
Pochoxime
Prodrug
The heat shock protein 90 (HSP90) has emerged as an extremely
interesting therapeutic target in recent years.1–3 Despite the seem-
ingly ubiquitous functions of this highly expressed chaperone, its
role in stabilizing conformationally labile proteins has implications
in incredibly diverse pathologies. Inhibitors of HSP90 have been
shown to be broadly effective for a number of cancer indications,4,5
neurodegenerative diseases,6–10 infectious diseases,11 and inflam-
mation-related disorders.12
achieved through the formation of oximes.24 In fact, pochoxime A–
C, are amongst the most potent HSP90 inhibitors reported to date,
inducing client protein degradation in SKBR3 cell lines at low nM
concentration, and pochoxime A treatment leads to tumor regres-
sion in xenografts bearing BT474 breast tumor cells.
Further in depth analysis of pochoxime A’s pharmacokinetics
properties in mice demonstrated that while it was fairly rapidly
cleared from plasma (t1/2 2.5 h), it accumulated in tumors and ther-
apeutic concentration was maintained beyond 48 h following
intraperitoneal administration (Table 1). As shown in Figure 2, a
single dose was sufficient to achieve induction of Hsp90 client pro-
tein degradation, consistent with the observation that biweekly
treatment was sufficient in reducing tumor growth.24 A therapeu-
tic limitation of 17AAG is its induction of hepatotoxicity which
limits the dose schedule. To evaluate whether pochoxime A also in-
duces liver toxicity, mice treated with 100 mg/kg of pochoxime A
were compared to mice treated with the same dose of 17AAG three
times per week for four weeks. While high levels of ALT (alanine
aminotransferase) and AST (aspartate aminotransferase) were ob-
served in the 17AAG treated group, the respective enzyme levels
in the pochoxime A treated group were not elevated relative to
(or, were similar to those in) the untreated group.
Pochoxime A–C exhibited very similar anti-proliferative activ-
ity, demonstrating effectiveness across a broad range of cancer cell
lines (Table 2) including breast cancer (BT474 and MDA-MB468),
leukemia (K562 CML and MV4; 11 AML), colon (HCT116), prostate
cancer (PC-3), Tarceva- and Iressa-resistant non-small cell lung
cancer (NSCLC, HCC829 and H1975), gastric cancer (N87) as well
as glioblastoma (A172) cell lines. Interestingly, the pochoximes
Two natural products, radicicol and geldanamycin (1 and 2,
Fig. 1), both of which disrupt the ATPase activity of Hsp90, have
been instrumental in understanding the role of HSP90 in oncogenic
processes and the therapeutic potential of its inhibition.13–15 How-
ever, neither natural product has acceptable pharmacological
properties for clinical application. Medicinal chemistry efforts have
led to the discovery of novel scaffolds such as purines16 and oxaz-
oles17–19 carbazolone19 which are currently in clinical or preclinical
development5 however, improving the pharmacological properties
and potency of the natural pharmacophores remains important. In-
deed, the most advanced clinical candidate is a semi synthetic
derivative of geldanamycin, 17AAG (3, Fig. 1).20,21 Another semi
synthetic derivative with a dimethoxyhydroquinone functionality
has recently been reported to have better pharmacological proper-
ties than 17AAG while acting as a prodrug.22
We had previously shown23 that pochonin D represents a sim-
plified pharmacophore of radicicol which recapitulates its activity.
Furthermore, significant improvements in cellular efficacy could be
* Corresponding author.
E-mail address: winssinger@isis.u-strasbg.fr (N. Winssinger).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.04.030

C. Wang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3836–3840
3837
O
OH
Cl
O
Cl
N
R
N
N
O
O
N
O
H
N
HO
H
H2N
H
N
O
O
O
MeO
OH
MeO
1
: Radicicol
OH
O
OCONH2
4: CNF-2024/ BIIB021
O
2
3
: R = OMe; Geldanamycin
: R = NHAll; 17-AAG
HO
H2N
O
Cl
O
H
N
N
7 : Pochonin D
OH
O
R
OH
HO
N
O
N
HN
HO
F3C
X
OH
O
O
N
O
N
O
N
O
: X = Cl, R = H, Pochoxime A
: X = H, R = H, Pochoxime B
8
9
10
5: VER-52296
: SNX-2122
6
: X = H, R = Me, Pochoxime C
NVP-AUY922
Figure 1. HSP90 inhibitors.
tease inhibitor), etoposide and fosphenytoin are prominent exam-
ples of alkoxyl, phenolic or methyloxyphosphate prodrugs
respectively.25 Many phosphate prodrugs are also currently in clin-
ical trials.27
Table 1
Concentration of pochoxime A within tumor (BT474 xenoxraft) following IP injection
Time (h)
100 mg/kg
150 mg/kg
200 mg/kg
Pochoxime a concentration (ng/g) within tumor
As the bioactive pochoximes bear two phenols, the structure
lends itself to the application of a phosphate prodrug strategy.
In the course of scaling up the synthesis of the pochoxime A or
B macrocycle via the previously developed synthetic route28
based on a ring closing metathesis (RCM), we noted contamina-
tion with small amounts of the macrocycle containing the cis al-
kene produced by RCM. We thus investigated an alternative
strategy relying on a Mitsunobu macrolactonization with the
geometry of the aforementioned alkene fixed. As shown in
Scheme 1, esters 1124 were deprotonated with LDA and reacted
with Weinreb amide 19 to afford, after oxime formation, the mac-
rocycles 13. Global silyl deprotection followed by macrocycliza-
6
12
24
48
5491.7
5250.0
4025.0
1497.5
171,230
1712
6175.0
6500.0
7933.3
4583.3
293,751
1958
6525.0
8925.0
10,150.0
4025.0
351041
1755
AUCa(0–48 h)
AUCa/dose
a
AUC (area under time–concentration curve).
maintained anti-proliferative activity against MDA-MB468 which
was significantly less sensitive to 17-AAG (3).
However, pochoxime A and related analogues have poor water
solubility which limits the choices of formulations, and while poc-
hoxime A has good bioavailability when administered intraperito-
neally (F% = 60.5), its oral bioavailability in the tested formulation
(10% DMSO, 9% PEG 400, 72% plurol oleate #497, 9% lauroglycol,
and 0.09% Tween20) was insufficient (F% = 3.4). Closely related
pochoxime B and C were found to have similar profiles of bioavail-
ability (data not shown). An established strategy to improve solu-
bility is the introduction of a phosphate group on a hydroxyl or
phenol functionality.25,26 The polar nature of this functionality
makes the resulting prodrug more soluble enabling fast dissolution
thus facilitating IV or oral formulation. For oral delivery, the high
level of alkaline phosphatase on enterocytes lining the gastrointes-
tinal track convert the prodrug to the drug while hepatic phospha-
tase or even phosphatase present in the target tissue can convert
the prodrug when administered IV. Fosamprenavir (Fig. 3, HIV pro-
tion yielded pochoxime
A and B upon deprotection with
sulfonic acid resin. While the compounds were obtained as an
E/Z mixture of the oxime, the more active E isomer could be iso-
lated by recrystallization to greater than 90% purity or as a single
isomer by HPLC purification. The Weinreb amide 19 was obtained
from the alkene 15 containing the required trans alkene via a se-
quence based on well established chemistry. Pochoxime A and B
were thus obtained in 17% and 25% yield from 11a and b, respec-
tively. These syntheses could readily be scaled up to prepare over
10 g of the pochoxime A or B.
We next focused on the preparation of different permutations of
phosphorylated pochoximes with a single phosphate on the para or
ortho phenol, on both phenols or a phosphonooxymethyl on the
para phenol. As shown in Scheme 2, owing to the greater acidity
of the para phenol, pochoxime A–C could be selectively derivatized

3838
C. Wang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3836–3840
pochoxime A
0
6
12
24
48
hrs
HER2
p-HER2
p-AKT
AKT
c-Raf
Cyclin D
Cdk4
HSP70
PI3Kp85 (Control)
100 mg/kg, i.p.
Figure 2. Western blot analysis of HSP90 clients proteins in vivo following a single dose of pochoxime A (100 mg/kg).
Table 2
Growth inhibition and HSP90
a
affinity of pochoxime derivativesa
Cell line
Pochoxime A (8)
Pochoxime B (9)
Pochoxime C (10)
17AAG (3)
Growth inhibition (GI50) and HSP90 affinity of pochoxime derivative (nM)
BT474 (breast)
7
2
6
5
MDA231 (breast)
MDA-MB468 (breast)
N87 (gastric)
7
9
4
2
2
1
6
6
2
NM
780
1
K562 (leukemia)
MV4;11 (leukemia)
HCT116 (colon)
HCC827 (lung)
H1975 (lung)
A172 (glioblastoma)
6
3
9
31
25
42
21
4
2
7
3
48
11
NM
56
35
NM
32
11
NM
NM
NM
15
NM
NM
NM
NM
18
HSP90a affinity
a
The reported values are the average of three experiments performed in duplicates. Standard deviation for the assay was less than twofold for 2r.
at that position using 1.0 equiv of bis(dimethylamino)phosphoryl
chloride and 0.9 equiv of DBU. Hydrolysis of the phosphoramide
bond with wet TFA in dichloromethane followed by neutralization
using anion exchange resin (Amberlite) afforded the pochoxime
derivative 21–23 in excellent yield. To access the para phosphate,
the ortho phenol was first selectively protected with an EOM group
followed by the same methodology to introduce the phosphate
thus yielding pochoxime A derivative 24. The bis-phosphate deriv-
ative 25 was prepared in the same way as the ortho-substitued
analogue but using an excess of bis(dimethylamino)phosphoryl
chloride and two equivalents of DBU. Finally, the phosphonooxym-
ethyl derivative 26 could be accessed by the same methodology
using di-tert-butyl chloromethylphosphonate29 rather than
bis(dimethylamino)phosphoryl chloride. In all cases, the acidic
hydrolysis of the phosphoramide or tert-butyl deprotection re-
sulted in an isomerization of the oxime (ca. 1:1 E/Z).
important for binding to HSP90. Interestingly, pro-pochoxime A
21 showed comparable efficacy in depleting HSP90 client proteins
to pochoxime A (data not shown) and had similar cytotoxicity
against different cancer cell lines (Table 3), suggesting that these
cancer cell lines have sufficient extracellular phosphatases to
achieve the conversion. While the cytotoxicity values were nearly
twofold higher than for pochoxime A, they were consistent with
the fact that pochoxime A (8) is a single oxime isomer while
pro-pochoxime A 21 is a mixture of the two oximes. We then
evaluated the efficacy of prodrug conversion in vitro using tissue
homogenates and a mimic of gastric fluid (pepsin solution at pH
1.1). As shown in Table 4, marginal conversion occurred in the
gastric fluid and plasma, while significant conversion was afforded
by both the liver and intestine homogenates. Interestingly, pro-
pochoxime C was more efficiently converted than pro-pochoxime
B and A with the best results for the bis-phosphate 25 reaching
43.5% conversion with intestine homogenate in 60 min. This data
suggest that pro-pochoxime 25 would be the most suitable pro-
drug candidate and preliminary investigations in mice showed
that high concentration in the liver was achieved via intravenous
or oral administration (Cmax: 3 838 ng/g by IV (4 mg/kg) and 12
469 ng/g by oral (30 mg/kg)).
A single phosphate group on the pochoxime conferred an
aqueous solubility of P80 mg/ml while the bis phosphate ana-
logue was soluble at >100 mg/mL (higher concentration not
tested). When tested for their affinity to human HSP90a 30
,
none
of the prodrugs 21–26 showed any measurable affinity below
10 M. This is not surprising considering that both phenols are
l

C. Wang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3836–3840
3839
NH2
OPO3Na2
OMe
MeO
O
O
HN
O
O
O
H
H
O
S
O
O
N
O
OPO3Ca
O
O
O
Fosamprenavir: HIV protease inhibitor
O
OH
OH
Etoposide: Topoisomeraze II inhibitor
NH
N
OPO3Na2
HN
OPO3Na2
O
O
HN
N
N
N
HN
O
O
N
F
AZD1152: aurora B inhibitor
phase 1
Fosphenytoin: Treatment of seizure
Figure 3. Selected examples of phosphate prodrugs in the market or in clinical trials.
EOMO
O
EOMO
O
19
a. LDA;
SiMe3
SiMe3
TBDPSO
O
O
b.
ONH3Cl
EOMO
CH3
EOMO
O
X
X
N
12a: X = Cl
11a: X = Cl
O
12b
11b
: X = H
: X = H
20
SiMe3
e.
EOMO
c. TBAF
d. PPh3,
DIAD
O
EOMO
O
O
HO
O
SO3H
O
O
EOMO
TBDPSO
HO
N
EOMO
X
O
X
X
N
N
O
N
O
O
O
O
N
N
14a: X = Cl
14b: X = H
13a: X = Cl
13b: X = H
8: X = Cl, pochoxime A
9: X = H, pochoxime B
f. TBDPSCl, Imid.
OTBDPS
OH
HO
HO
g. I2, PPh3, Imid.;
KCN
15
16
h. Dibal-H
O
O
O
N
i.
N
18
PO(OEt)2
O
OTBDPS
OTBDPS
NC
19
17
Scheme 1. Altenative synthesis of pochoxime A and B. Reagents and conditions: (a) LDA (2.0 equiv), THF, À78 °C, 5 min; 19 (0.9 equiv), À78, 15 min, 12a (65%) 12b (54%); (b)
20 (2.5 equiv), pyridine, 40 °C, 24 h, 13a (50%) 13b (81%); (c) TBAF (2.5 equiv), 23 °C, 3 h; (d) Ph3P (1.5 equiv), DIAD (1.5 equiv), toluene, 0–23 °C, 5 h, 14a (60%) 14b (61%); (e)
PS-SO3H (5.0 equiv, 3.0 mmol/g), MeOH, 23 °C, 2 h, 8 (90%) 9 (95%); (f) TBDPSCl (1.0 equiv), Imid (1.5 equiv), DMF, 23 °C, 5 h, 85%; (g) Imid (1.5 equiv), Ph3P (1.1 equiv), iodine
(1.1 equiv), 0 °C, 6 h; KCN (5.0 equiv), DMSO, 60 °C, 2 h, >90%; (h) Dibal-H (1.05 equiv), CH2Cl2, À78 °C, 30 min, 85%; (i) LiCl (1.2 equiv), 18 (1.2 equiv), DBU (1.0 equiv), CH3CN,
23 °C, 45 min, 80%; DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene; Dibal-H = diisobutylaluminium hydride Imid = imidazole PS = polystyrene, TBDPSCl = tert-Butyl diphenyl
chlorosilane.
In conclusion, pochoxime A–C are potent HSP90 inhibitors effec-
tive against a broad range of cancer cell lines. Phosphorylation of a
single or both phenols of the pochoximes confers good aqueous sol-
ubility thus facilitating formulation. While the phospho-pochoxi-

3840
C. Wang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3836–3840
7, 8 or 9
e. Cl OPO(OtBu)2
b. TFA
c. PS-NMe3OH
a. P(O)Cl(NMe2)2
1.0 equiv
d. EOMCl
a. P(O)Cl(NMe2)2
3.0 equiv
a. P(O)Cl(NMe2)2
b. TFA
b. TFA
b. TFA
c. PS-NMe3OH
c. PS-NMe3OH
c. PS-NMe3OH
HO
O
R
HO
O
R
Na2O3PO
O
R
Na2O3PO
O
R
Na2O3PO
O
O
O
O
O
Na2O3PO
HO
X
Na2O3PO
X
X
X
O
N
O
N
O
N
O
O
N
O
N
O
O
N
21: X=Cl, R=H
22
N
N
: X=H, R=H
23: X=H, R=Me
24: X=Cl, R=H
26: X=H, R=H
25: X=H, R=Me
Scheme 2. Synthesis of pochoxime A–C prodrugs. Reagents and conditions: (a) P(O)Cl(NMe2)2 (1–3.0 equiv), DBU (0.9–2.0 equiv), DMAP (0.01 equiv), CH2Cl2, 23 °C, 12 h, 50–
60%; (b) TFA (5%), CH3CN/H2O 50/50; 23 °C, quantitative; (c) Amberlite IRA68, H2O/CH3CN 1/1, quantitative (d) EOMCl (1.0 equiv), iPr2EtN (1.0 equiv), CH2Cl2, 0–23 °C, 12 h,
49%; (e) di-tert-butyl chloromethylphosphonate (1.2 equiv), DBU (1.0 equiv), Bu4NI (0.2 equiv), CH2Cl2, 23 °C, 12 h, (68%); DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene;
DMAP = 4-Dimethyl aminopyridine; EOMCl = ethoxymethyl chloride; TFA = trifluoroacetic acid.
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Table 3
Growth inhibition and HSP90
a
affinity of pro-pochoxime
Pro-pochoxime A (21)
Cell line
Growth inhibition (GI50) and HSP90 affinity of pro-pochoxime A (nM)
BT474 (breast)
MDA-MB468 (breast)
N87 (gastric)
14
37
19
>10,000
HSP90
a
affinity
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Table 4
Conversion (%) of phosphate prodrug to parent drug in tissue homogenates
21
22
23
24
25
26
Liver
Intestine
Plasma
18.2
18.9
3.4
23.2
26.6
2.2
29.4
41.6
1.4
0
10.5
11.6
0
30.5
43.5
0
17.9
18.7
4.0
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Gastric fluid
0.4
0.4
0
0
0.3
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Med. Chem. 2006, 6, 1193.
mes do not bind to HSP90 with notable affinity, they are rapidly con-
verted to the corresponding pochoxime in the intestine or the liver
and are effective in cancer cell cultures.
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Acknowledgments
This work was funded in part by a grant from the Agence
National de la Recherche (ANR) and Conectus. A BDI fellowship
(J.-G.F.) is also gratefully acknowledged.
Supplementary data
Supplementary data (experimental procedures and physical
characterization) associated with this article can be found, in the
online version, at doi:10.1016/j.bmcl.2009.04.030.
27. For
a recent example, see: Mortlock, A. A. et al J. Med. Chem. 2007, 50,
2213.
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References and notes
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