A comparative assessment of α-lipoic acid N-phenylamides as non-steroidal androgen receptor antagonists both on and off gold nanoparticles

Article abstract of DOI:10.1016/j.bioorg.2011.11.007

A group of α-lipoic acid N-phenylamides were synthesized employing a variety of amide coupling protocols utilizing electron deficient anilines. These compounds were then assessed for their ability to block androgen-stimulated proliferation of a human pros

Full text of DOI:10.1016/j.bioorg.2011.11.007

Bioorganic Chemistry 40 (2012) 1–5
Contents lists available at SciVerse ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Preliminary Communications
A comparative assessment of
a-lipoic acid N-phenylamides as non-steroidal
androgen receptor antagonists both on and off gold nanoparticles
Luke C. Henderson a, , Jarrad M. Altimari a, Gail Dyson a, Linden Servinis a, Birunthi Niranjan b,
⇑
Gail P. Risbridger b
a Deakin University, Pigdons Road, Waurn Ponds Campus, Geelong, Victoria 3216, Australia
b Department of Anatomy and Developmental Biology, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria 3800, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 September 2011
Available online 8 December 2011
A group of a-lipoic acid N-phenylamides were synthesized employing a variety of amide coupling proto-
cols utilizing electron deficient anilines. These compounds were then assessed for their ability to block
androgen-stimulated proliferation of a human prostate cancer cell line, LNCaP. These structurally simple
compounds displayed anti-proliferative activities at, typically, 5–20 lM concentrations and were compa-
rable to a commonly used anti-androgen BicalutamideÒ. The inclusion of a disulfide (RS-SR) moiety, serv-
ing as an anchor to several metal nanoparticle systems (Au, Ag, Fe2O3, etc.), does not impede any
biological activity. Conjugation of these compounds to a gold nanoparticle surface resulted in a high
degree of cellular toxicity, attributed to the absence of a biocompatible group such as PEG within the
organic scaffold.
Keywords:
Androgen receptor
a-Lipoic acid
Flutamide
Bicalutamide
Prostate cancer
Ó 2011 Elsevier Inc. All rights reserved.
1. Introduction
Our interest in these compounds stems from a nanomedicine
perspective, whereby biologically active compounds are tethered
Prostate cancer is the most commonly diagnosed cancer in men
and a leading cause of death in the male population [1]. As prostate
cancer development and disease progression is hormone depen-
dent, blockade of androgen action is the cornerstone of most
therapies and can be achieved by inhibiting the androgen receptor
(AR). In primary prostate cancer cells, testosterone and dihydrotes-
to a nanomaterial, for example, inorganic nanoparticle, nanotube,
micelle, liposome or nanorod. These ‘nanoconjugates’ are evalu-
ated for any potential therapeutic benefits in vivo compared to
the corresponding (untethered) small molecule.
The advent of nanomedicine has accelerated research intensity
in this field and can be attributed to the advancement in the ability
to control morphology, aspect ratio, surface chemistry and mag-
netic properties of a given nanoparticle allowing for combined
therapies, diagnostics and targeted release strategies for various
diseases [3]. Despite the growth of the nanomedicine field there
has been little work focusing on therapies applied to prostate can-
cer and is the goal of this project.
Gold nanoparticles (AuNP) are the most common metal based
nanoparticles employed for medicinal application, due to their
ease of synthesis, surface functionalization and biocompatibility.
Nevertheless other less expensive metal nanoparticles, such as sil-
ver, copper and iron oxide (Fe2O3), are emerging in medicinal
applications [3]. A common feature of all these metals are their
ability to be surface functionalized by treatment with compounds
bearing a thiol (SH) or disulfide (RS-SR) moiety [4]. Therefore the
purpose of this study was to synthesize a small range of com-
pounds bearing structural similarity to the aryl portion of Flutam-
ideÒ 1 while incorporating a suitable sulfur-based functional group
for potential attachment to a range of inorganic nanoparticles
(Fig. 2). Investigation of any potential anti-proliferative properties
towards hormone responsive prostate cancer cells would provide a
tosterone (5aDHT) binding to the AR enhances tumor cell
proliferation. Prostate cancer therapy originally centered on the
modification of the naturally occurring steroidal ligands, but due
to poor bioavailability, hepatotoxicity and a lack of tissue specific
action has led to their discontinued clinical use [2]. Nevertheless,
blockade of the proliferative effect of androgens remains a major
focus of prostate cancer treatment and includes development of
small molecule AR binding inhibitors to mitigate cellular
proliferation.
The most notable examples of AR antagonists are FlutamideÒ
1
and BicalutamideÒ 2; Bicalutamide has superseded the use of
Flutamide. Flutamide 1 is converted to its the active form hydroxy-
flutamide 1a in vivo. With respect to the aryl amide portion of these
compounds they are, by and large, electron deficient aromatic rings
commonly bearing a trifluoromethyl group in addition to a severely
deactivating group at the meta- and para-positions, such as a nitro
(NO2) or nitrile (CN) in the cases of 1/1a and 2 respectively.
⇑
Corresponding author. Fax: +61 3 52271040.
E-mail address: luke.henderson@deakin.edu.au (L.C. Henderson).
0045-2068/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.bioorg.2011.11.007

2
L.C. Henderson et al. / Bioorganic Chemistry 40 (2012) 1–5
effort to reduce reaction time we applied microwave irradiation to
F
H
N
the EDCI mediated reaction, but unfortunately the yield was re-
duced (53%, entry 2, Table 1). Exchanging the coupling reagent to
Bromo-tris-pyrrolidino phosphoniumhexafluoro phosphate (PyB-
rop), known to promote difficult amide formations [7], again lead
to moderate yield while heated with microwave irradiation (56%,
entry 3, Table 1). The reduced yield obtained in entries 2 and 3
was surprising as microwave irradiation is often touted for its abil-
ity to promote difficult transformations both efficiently and cleanly
R
HO
O
O
S
H
N
O
O
O2N
NC
CF3
1 R = H
CF3
2
1a R = OH
[8]. Accessing compound 4a via an a-lipoic acyl chloride interme-
Fig. 1. AR antagonists commonly used for prostate cancer.
diate, by treatment with thionyl chloride [6], gave a good yield
(72%, entry 4, Table 1), but was still inferior to our initial reaction
conditions (EDCI, 16 h, room temp). Although these protocols pro-
duced varying yields of the desired product 4a, their collective suc-
cess in furnishing the desired N-phenylamide confirmed each set of
conditions as valid routes of inquiry when dealing with more prob-
lematic electron withdrawn anilines.
‘baseline’ cellular activity for comparison to the corresponding
nanoparticle conjugates.
In this study
a-lipoic acid 3 was chosen as the scaffold to incor-
porate a disulfide group for nanoparticle conjugation.
a
-Lipoic acid
is a naturally occurring antioxidant that has shown extensive
promise in the treatment of several diseases such as: atherosclero-
sis, type 2 diabetes, Parkinson’s disease and has excellent anti-
Our attention turned now to the synthesis of various N-aryl li-
poic amides bearing a range of electron withdrawing functional
groups commonly employed for androgen receptor antagonist de-
sign. Our focus on electron withdrawing substituents on the aryl
ring was due to literature precedence indicating that these groups
(e.g. CF3, CN, Cl, etc.) were crucial to affect AR binding [9].
Coupling chloroaniline 5b to lipoic acid 3 under the reaction
conditions specified in method A gave a poor yield of 27% (entry
1, Table 2) while under microwave irradiation for a much shorter
duration (method B) gave a higher and acceptable yield (71%. entry
2, Table 2). Surprisingly the formation of 4c [11] using method A
was higher yielding (44%, entry 3, Table 2) than 4b under the same
conditions despite the deactivating presence of a trifluoromethyl at
the meta-position on the aniline reactant. Given the moderate yield
of 44%, we conducted the same coupling using methods B and C
with the highest yield of 5c being obtained for method B (75%, en-
try 4, Table 2). The synthesis of compound 4d has been reported
previously giving good yield using method D [5], but in our hands
this protocol was not optimal. Indeed, synthesizing 4d proved very
problematic and complex mixtures of products were isolated from
the crude reaction mixture for all methods investigated. Analysis of
these crude products by 1H NMR showed only method C to have an
appreciable amount of 4d, but still gave a moderately low yield of
36% (entry 7, Table 2). Finally, employing trifluoromethyl cyanoan-
iline 5e, despite bearing a very deactivating cyano group at the
para-position, performed better than 5d which possesses a nitro
group at this position. In our hands we found that either method
B or C was optimal, though the yields of 4e [11] were still moderate
(46%, entries 9 and 10, Table 2).
inflammatory properties [5]. Further to this,
a-lipoic acid has
shown to induce apoptosis in a variety of cancer cell lines and, as
a dietary supplement, displays minimal toxicity to healthy cells.
Also, flutamideÒ 1 is known to induce hepatotoxicity during ther-
apy, thus inclusion of the disulfide moiety of a-lipoic acid (known
to be hepatoprotective) may mitigate this toxic effect to some ex-
tent [5].
Recently Hu et al. [7] synthesized a range of dihydrolipoic acid
derivatives and screened their proliferation properties across a
broad range of cancer cell lines. Though prostate cancer cells did
feature to a small extent in this study, the cell line chosen (PC-3)
do not express AR and thus no conclusions regarding antagonistic
versus agonistic interactions can be drawn. As such we have syn-
thesized several of these compounds (in addition to several novel
compounds) and reevaluated them for their AR binding properties
in the hormone dependant prostate cancer cell line (LNCaP) serv-
ing as a model for primary tumors of the prostate. In this commu-
nication we present the synthesis of several N-phenylamide based
a
-lipoic acid derivatives and their potent anti-proliferative effect
on androgen responsive prostate cancer cells.
2. Results and discussion
Our approach was to use a single step peptide coupling as this is
the simplest route to the desired compounds. It is well known that
amide formation using anilines can be low to moderate yielding as
they are not strongly nucleophilic, which in this study, is com-
pounded by the presence of electron withdrawing groups such as
CF3, CN and NO2. Therefore a short preliminary investigation to
various well established peptide formation reactions were under-
taken to elucidate which protocol may be most suitable for appli-
cation to electron deficient anilinic nitrogens. As such we chose the
simplest aniline 5a to undertake this study.
With a range of these compounds in hand our attention turned
to investigating their AR interaction properties. The data in Fig. 1
show cell proliferation rates after 6 days in culture with the target
compounds (4a–e) and are normalized against dihydrotestoster-
one (5
In this study a significant anti-proliferative effect was observed
when these compounds, and several novel -lipoic derivatives,
a
DHT) while using BicalutamideÒ 2 as a positive control.
a
were incubated in the presence of androgen responsive prostate
cancer cell lines (LNCaP). The development of compounds which
Initially, we chose EDCI mediated coupling (entry 1, Table 1) at
room temperature overnight, giving an excellent yield of 81%. In an
R
O
NH2
R
O
OH
N
H
S
S
S
S
Nanoparticle Anchor
AR Antagonist
3
Fig. 2. General structure of desired compounds.

L.C. Henderson et al. / Bioorganic Chemistry 40 (2012) 1–5
3
Table 1
Validation of synthetic protocols to synthesize N-phenylamides (see supp info).
Entry
Reagent
Solvent
Time (h)
Temp (°C)
Yield (%)a
1
2
3
4
EDCI
EDCI
PyBrop
SOCl2
CHCl3
CHCl3
MeCN
CH2Cl2
16
0.5
1
r.t.
81
53
56
72
100
100
50
7
a
Isolated yield.
Table 2
Methods to generate N-phenyl a-lipoic acid derived amides using electron deficient anilines [10].
Entry
Compound
Method
R1
R2
Yield (%)
1
2
3
4
5
6
7
8
9
4b
4b
4c
4c
4c
4d
4d
4d
4e
4e
A
B
A
B
C
B
C
D
B
C
Cl
Cl
Cl
Cl
H
H
27
71
44
75
55
22
36
24
46
46
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Cl
NO2
NO2
NO2
CN
CN
10
Method A: EDCI (1.2 equivalents), CHCl3,
Method B: EDCI (1.2 equivalents), microwave irradiation, CHCl3,
Method C: PyBrop (1.2 equivalents), microwave irradiation, CHCl3,
Method D: (i) -lipoic acid, SOCl2, 50 °C, 3 h, reduced to dryness; (ii) NEt3, aniline, r.t., 6 h.
a-lipoic acid, r.t., 16 h.
a
-lipoic acid, 100 °C, 0.5 h.
a-lipoic acid, 100 °C, 1 h.
a
display anti-proliferative behavior on LNCaP cells is important as
these serve as potential leads for the treatment of primary prostate
tumors in men. As mentioned above, Hu et al. [7] has evaluated 4a,
4b and 4e against hormone independent prostate cancer cell line
(PC-3) for their anti-proliferative properties. These compounds
very mildly suppressed cancer cell growth (8–13% and 14–15%
suppression for 4a and 4b respectively). A similar result was ob-
served for compound 4e which demonstrated very poor cancer
growth inhibition (approximately 5%) [6].
As can be seen from Fig. 3, compound 4a displayed a significant
decrease in cell proliferation at 10 lM but not 20 lM while 4b,
bearing a chlorine substituent at the 4-position on the aromatic
ring, showed excellent anti-proliferative activity at both 10 and
structural similarity between 4b and 4c and the persistence of tri-
fluoromethyl groups at the meta-position in potent AR antagonists
reported in the literature and used in the clinic [9,11].
Compounds 4d and 4e bear the identical aryl portion to Flutam-
ideÒ 1 and BicalutamideÒ 2 respectively, and as such were exam-
ined for their anti-proliferative properties at an additional
concentration of 5
excellent with significant reduction in cell growth demonstrated
at both 20 and 10 M while a statistically non-significant reduc-
tion was observed at 5 M concentration. By far the best result
was obtained with compound 4e which displayed significant cellu-
lar growth depression at 20, 10 and 5 M. Comparison of bicaluta-
mide and 4e at 5 M shows the amount of cellular growth
lM. The dose response behavior for 4d was
l
l
l
l
20
lM. Unfortunately 4c failed to reduce cell proliferation to any
inhibition to be within 10% of each other, which is significant when
statistical significance. This result is very interesting given the
considering comparative molecular and synthetic complexity.

4
L.C. Henderson et al. / Bioorganic Chemistry 40 (2012) 1–5
Fig. 3. Cell proliferation data for compounds 4a–e day six after administration of compounds.
Fig. 4. LNCaP cells treated with fucntionalized gold nanoparticles.
Given these positive results we were interested in how conjuga-
tion to an inorganic nanoparticle would affect the biological effi-
cacy of these compounds. Given that these compounds already
determination of anti-proliferative properties. It was found that
concentrations diluted from a 1 mg/mL stock solution to a range
of 1:300–1:1200 suitable for assessment using LNCaP cells. These
possessed a disulfide due to the
a
-lipoic acid moiety, thus the
dilutions correspond to concentrations of 3.5 lg/mL to 0.88 lg/
use of gold nanoparticles (AuNP) was determined to be the best
choice. Gold nanoparticles were synthesized according to a modi-
fied Brust–Schiffrin protocol [12], and were found to be very uni-
formly dispersed around 6.5 nm using dynamic light scattering
[10].
The functionalization of gold nanoparticles is a straight forward
process whereby tetraoctaneammonium bromide (TOAB) used in
the synthesis of the nanoparticles is relatively weakly bound to
the gold nanoparticle surface. This is easily displaced by the favor-
able Au-S bond which is thought to occur almost instantaneously.
To ensure an ordered self-assembled monolayer (SAM) we left the
mL, respectively of the nanoparticle conjugates. As before, these
compounds were assessed using BicalutamideÒ as the positive
control.
Two separate inprotocols were undertaken using the function-
alized gold nanoparticles, this consisted of one proliferation assay
conducted in the absence of 1 nM DHT (Fig. 4 – right) to assess po-
tential toxicity of these compounds and another carried out under
identical conditions but in the presence of 1 nM DHT to determine
agonist activity.
By comparing the gold nanoparticle conjugates with and with-
out DHT it is possible to elucidate any antagonistic activity shown
by these gold conjugates. In most cases high levels of cell toxicity
were observed at lower dilutions (1:300 and 1:400) while no
anti-proliferative properties of these compounds were observed
at higher dilutions (1:800 and 1:1200). Thus it seems that there
a-lipoic amides stirring in the presence of the AuNPs overnight. A
simple procedure of precipitation, centrifugation and washing en-
sured the removal of excess TOAB [10]. With these AuNP conju-
gates in hand our attention turned to reassessment of their
ability to block the androgen-stimulated growth of LNCaP cells,
as before BicalutamideÒ was used as the positive control.
Initially, the AuNP conjugates were dissolved in DMSO at a
concentration of 1 mg/mL and serially diluted to find a concentra-
tion at which these conjugates are not toxic, thus allow the
is
a serious tradeoff between toxicity and anti-proliferative
activity, whereby dilutions which are not toxic to the cells are so
dilute that there is no effect on cellular proliferation. The reason
for both of these effects is more than likely due to the absence of
biocompatible polymers (such as polyethylene glycol, PEG) being

L.C. Henderson et al. / Bioorganic Chemistry 40 (2012) 1–5
(f) O.C. Farokhzad, R. Langer, ACS Nano 3 (1) (2009) 16–20;
5
incorporated into the AR antatonist molecular design. It has been
shown that the use of PEG spacers between the AuNP surface
and the small molecular drug has profound influence on cellular
and systemic toxicity [13]. The use of a large spacer between AuNP
and the small molecule has another benefit to the system whereby
this spacer ensures that the biologically active molecule conju-
gated to the gold core protrudes from the surface a sufficient
amount to allow interaction with the cellular surface. As such these
compounds, while effective on their own require a slight redesign
and synthesis to allow for a biocompatible polymer to be incorpo-
rated into the scaffold to by-pass the cellular toxicity observed in
this case.
(g) X. Li, J. Guo, J. Asong, M.A. Wolfert, G-J. Boons, J. Am. Chem. Soc. 133 (29)
(2011) 11147–11153.
[4] Selected examples: (a) S. Chen, J.M. Sommers, J. Phys. Chem. B 105 (2001)
8816–8820;
(b) K.C. Anyaogu, A.V. Fedorov, D.C. Neckers, Langmuir 24 (2008) 4340–4346;
(c) E. Wassanayantasee, W. Cynthial, S. Thanaponsangvanich, R.S. Addleman,
T.G. Carter, R.J. Wiacek, G.E. Fryxell, C. Timchalk, M. Warner, Environ. Sci.
Technol. 41 (2007) 5114–5119;
(d) A.G. Kanaras, Z. Wang, A.D. Bates, R. Cosstick, M. Brust, Angew. Chem. 115
(2) (2003) 201–204;
(e) M-C. Daniel, D. Astruc, Chem. Rev. 104 (2004) 293–346;
(f) J.C. Love, L.A. Estroff, J.K. Kriebel, R.G. Nuzzo, G.M. Whitesides, Chem. Rev.
105 (2005) 1103–1169;
(g) M. Brust, C.J. Kiely, Colloids Surf. A: Physicochem. Eng. Aspects 202 (2002)
175–186;
(h) C.A. Fernandez, C.M. Wai, Small 2 (11) (2006) 1266–1269;
(i) H. Ke, J. Wang, Z. Dai, Y. Jin, E. Qu, Z. Xing, C. Guo, X. Yue, J. Liu, Angew.
Chem. Int. Ed. 50 (2011) 1–6.
3. Summary
[5] Selected examples: (a) D.K. Wysowski, J.L. Fourcroy, J. Urol. 155 (4) (1996)
209–212;
In summary we have synthesized a range of a-lipoic acid N-phe-
(b) J. Bustamante, J.K. Lodge, L. Marcocci, H.J. Tritschler, L. Packer, B.H. Rihn,
Free Radical Biol. Med. 24 (6) (1998) 1023–1039;
(c) A. Bast, G.R.M.M. Haenena, Biochim. Biophys. Acta, Lipids Lipid Metab. 963
(3) (1998) 558–561;
(d) C. Müller, F. Dünschede, E. Koch, A.M. Vollmar, A.K. Kiemer, Am. J. Physiol.
Gastrointest. Liver Physiol. 285 (4) (2003) 769–778.
nylamides 4a–e bearing a representative range of electronic sub-
stituents and these compounds were then assessed for their
ability to block androgen-stimulated proliferation of a human pros-
tate cancer cell line, LNCaP. Various synthetic protocols were used
for the synthesis of these compounds showing that no one method
is optimal for both electron withdrawn and electron neutral ani-
lines. Additionally these compounds generally displayed excellent
[6] E. Frérot, J. Coste, A. Pantaloni, M. Dufour, P. Jouin, Tetrahedron 47 (2) (1991)
259–270.
[7] S-J. Zhang, Q-F. Ge, D-W. Guo, W-X Hu, H-Z. Liu, Bioorg. Med. Chem. Lett. 20
(2010) 3078–3083.
[8] (a) L.C. Henderson, N. Byrne, Green Chem. 13 (4) (2011) 813–816;
(b) M.D. Johnstone, A.J. Lowe, L.C. Henderson, F.M. Pfeffer, Tetrahedron Lett. 51
(45) (2010) 5889–5891;
anti-proliferative activities in the 20–5 lM range with compound
4e showing by far the best cancer cell growth inhibition.
Conjugation of these compounds a gold nanoparticle and reas-
sessment of their anti-proliferative potential has shown that cellu-
lar toxicity shown by the nanoparticle conjugates in a limiting
factor before any further studies can take place.
(c) M. Larhed, C. Moberg, A. Hallberg, Acc. Chem. Res. 35 (2002) 717–727;
(d) P. Lidstrom, J. Tierney, B. Wathey, J. Westman, Tetrahedron 57 (2001)
9225–9283.
[9] Selected Examples (a) D.J. Hwang, J.Yang.X. Huiping, I.M. Rakov, M.L. Mohler,
J.T. Dalton, D.D. Miller, Bioorg. Med. Chem. 14 (2006) 6525–6538;
(b) H-Y. Xiao, A. Balog, R.M. Attar, D. Fairfax, L.B. Fleming, C.L. Holst, G.S.
Martin, L.M. Rossiter, J. Chen, M-E. Cvjic, J. Dell-John, J. Geng, M.M. Gottardis,
W-C Han, A. Nation, M. Obermeiera, C.A. Rizzo, L. Schweizer, T. Spires Jr., W.
Shan, A. Gavai, M.E. Salvati, G. Vite, Bioorg. Med. Chem. Lett. 20 (2010) 4491–
4495;
Acknowledgments
The authors gratefully acknowledge the CASS foundation for the
funding to carry out this work. We would also like to thank the
Deakin University Strategic Research Center for biotechnology,
chemistry and systems biology for their financial contribution.
(c) S.M. Singh, S. Gauthier, F. Labrie, Curr. Med. Chem. 7 (2) (2000) 211–247;
(d) W. Gao, J.T. Dalton, Drug Discov. Today 12 (5/6) (2007) 241–248.
[10] See Electronic Supplementary Information for Representative Procedures for
Each Method A–D, and for the Biological Evaluation Process, Gold Nanoparticle
Synthesis and Dynamic Light Scattering Analysis.
[11] Characterisation data for compounds 4c and 4e: 4c 1H NMR (CDCl3, 270 MHz):
d 7.84 (1H, s, Ar-H) 7.70–7.68 (1H, d, J = 8 Hz, Ar-H) 7.42–7.39 (1H, d, J = 12 Hz,
Ar-H) 3.58–3.53 (1H, m, CH) 3.17–3.11 (2H, m, CH2) 2.39–2.36 (4H, m, CH2)
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bioorg.2011.11.007.
1.93–1.87 (2H, m, CH2) 1.77–1.64 (2H, m, CH2) 1.51–1.46 (2H, m, CH2) (NH is
2
not observed); 13C NMR (CDCl3, 67.5 MHz): d 171.8, 132.0, 128.6 (q, JC–F
=
1
3
32 Hz), 126.9, 122.6 (q, JC–F = 272 Hz), 120.6, 118.9 (q, JC–F = 6 Hz), 116.6,
56.5, 40.4, 38.6, 37.3, 34.7, 28.9, 25.2; 19F NMR (CDCl3, 270 MHz) ꢀ62.67;
HRMS (ESI m/z): Calcd. For [C15H17F3N2OS2 Na+] 406.02844, found 406.02763;
4e 1H NMR (CDCl3, 270 MHz): d 8.4 (1H, s, NH) 8.04–8.03 (1H, d, J = 1.6 Hz, Ar-
H) 7.93 (1H, dd, J = 1.89, 8.64 Hz, Ar-H) 7.74–7.71 (1H, d, J = 8.64 Hz, Ar-H)
3.59–3.49 (1H, qui, J = 6.48 Hz, CH) 3.20–3.03 (2H, m, CH2) 2.50–2.32 (4H, m,
CH2) 1.97–1.77 (2H, m, CH2) 1.72–1.62 (2H, m, CH2) 1.59–1.30 (2H, m, CH2);
References
EDCI = N-(3-dimethylaminopropyl)-N0-ethylcarbodiimide
hydrochloride; PyBrop = bromotripyrrolidinophosphonium
hexafluorophosphate.
2
13C NMR (CDCl3, 67.5 MHz): d 172.1, 142.7, 136.9, 134.0 (q, JC–F = 32.5 Hz),
121.8122.2 (q, 1JC–F = 272 Hz), 117.3 (q, 3JC–F = 5.5 Hz), 117.2, 103.6, 56.4, 40.3,
38.6, 37.4, 34.6, 28.8, 24.9; 19F NMR (CDCl3, 270 MHz) ꢀ62.05; HRMS (ESI m/z):
Calcd. For [C16H117F3N2OS2 Na]+ 397.06266, found 397.06197.
[12] M. Brust, M. Walker, D. Bethell, D.J. Schiffrin, R. Whyman, Chem. Commun.
(1994) 801–802.
[1] A. Jemal, H. Thomas, T. Murray, M. Thun, Cancer J. Clin. 52 (2002) 23.
[2] J.T. Dalton, W. Gao, Toxicity of steroids for use to treat prostate cancer, in: C.M.
Bunce, M.J. Campbell (Eds.), Nuclear receptors, Proteins and Cell Regulation,
vol. 8, C _Springer Science & Business Media B.V, 2010, pp. 143–182. doi:
10.1007/978-90-481-3303-1_6.
[3] (a) E. Lavik, H. von Recum, ACS Nano 5 (5) (2011) 3419–3424;
(b) T.W. Odom, C.L. Nehl, ACS Nano 2 (4) (2008) 612–616;
(c) R. Arvizo, R. Battacharya, P. Mukherjee, Expert Opin. Drug Deliv. 7 (6)
(2010) 753–763;
[13] (a) K. Knop, R. Hoogenboom, D. Fischer, U.S. Schubert, Angew. Chem. Int. Ed. 49
(2010) 2–23;
(b) C.M. Cobley, L. Au, J. Chen, Y. Xia, Expert Opin. Drug Deliv. 7 (5) (2010) 577–
587;
(c) E.C. Dreaden, S.C. Mwakwari, Q.H. Sodji, A.K. Oyelere, M.A. El-Sayed,
Bioconjugate Chem. 20 (2009) 2247–2253;
(d) M. Mahmoudi, K. Azadmanesh, M.A. Shokrgozar, W.S. Journeay, S. Laurent,
Chem. Rev. 111 (5) (2011) 3407–3432.
(d) X. Huang, X. Peng, Y. Wang, Y. Wang, D.M. Shin, M.A. El-Sayed, S. Nie, ACS
Nano 4 (10) (2010) 5887–5896;
(e) H.T. Ke, Z.F. Dai, Y.S. Jin, Z.W. Xing, C.X. Guo, X.L. Yue, Angew. Chem. Int. Ed.
50 (2011) 1–6;