Adamantane-platinum conjugate hosted in β-cyclodextrin: Enhancing transport and cytotoxicity by noncovalent modification

Article abstract of DOI:10.1016/j.bmcl.2011.10.006

This work reports the synthesis of a complex of a carboplatin analog having tethered adamantane that is encapsulated in the hydrophobic cavity of β-cyclodextrin (βCD) and its cytotoxic activity towards human neuroblastoma cells (SK-N-SH). We found that this inclusion complex of βCD adamantane carboplatin analog exhibited higher cytotoxicity towards SK-N-SH cells than carboplatin itself, and the inclusion complex exhibited a higher binding to plasmid pBR322 deoxyribonucleic acid (DNA) than carboplatin. Confocal fluorescence images of SK-N-SH cells treated with βCD having an attached fluorescein isothiocyanate (FITC)-tag exhibited fluorescence in the vicinity of the nuclei of the neuroblastoma cells. Direct measurements of the platinum content in SK-N-SH cells using inductively coupled plasma mass spectrometry (ICP-MS) indicated that the uptake rate of carboplatin was about 4 times higher than βCD adamantane carboplatin analog inclusion complex. When compared to carboplatin, we believe that the higher cytotoxicity of inclusion complex towards SK-N-SH cells is due to its higher DNA binding ability as compared to carboplatin, and more efficient delivery to the nucleus of the cell. This work suggests that the advantage of deliberate noncovalent modification with βCD through host-guest chemistry may also be broadly applicable to other anticancer agents as well.

Full text of DOI:10.1016/j.bmcl.2011.10.006

Bioorganic & Medicinal Chemistry Letters 21 (2011) 7421–7425
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Adamantane–platinum conjugate hosted in b-cyclodextrin: Enhancing transport
and cytotoxicity by noncovalent modification
⇑
Deepali Prashar, Yi Shi, Debjyoti Bandyopadhyay, James C. Dabrowiak, Yan-Yeung Luk
Department of Chemistry, Syracuse University, Syracuse, NY 13244, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This work reports the synthesis of a complex of a carboplatin analog having tethered adamantane that is
encapsulated in the hydrophobic cavity of b-cyclodextrin (bCD) and its cytotoxic activity towards human
neuroblastoma cells (SK-N-SH). We found that this inclusion complex of bCD adamantane carboplatin
analog exhibited higher cytotoxicity towards SK-N-SH cells than carboplatin itself, and the inclusion
complex exhibited a higher binding to plasmid pBR322 deoxyribonucleic acid (DNA) than carboplatin.
Confocal fluorescence images of SK-N-SH cells treated with bCD having an attached fluorescein isothio-
cyanate (FITC)-tag exhibited fluorescence in the vicinity of the nuclei of the neuroblastoma cells. Direct
measurements of the platinum content in SK-N-SH cells using inductively coupled plasma mass spec-
trometry (ICP-MS) indicated that the uptake rate of carboplatin was about 4 times higher than bCD ada-
mantane carboplatin analog inclusion complex. When compared to carboplatin, we believe that the
higher cytotoxicity of inclusion complex towards SK-N-SH cells is due to its higher DNA binding ability
as compared to carboplatin, and more efficient delivery to the nucleus of the cell. This work suggests that
the advantage of deliberate noncovalent modification with bCD through host-guest chemistry may also
be broadly applicable to other anticancer agents as well.
Received 6 August 2011
Revised 30 September 2011
Accepted 4 October 2011
Available online 14 October 2011
Keywords:
Anticancer agents
DNA
Cyclodextrins
Host–guest chemistry
Solvation
Noncovalent modification
Ó 2011 Elsevier Ltd. All rights reserved.
Sugar derivatives including cyclodextrins and other benign mol-
ecules have been used in drug formulations often by simple mix-
ing, for improving the drug properties such as solubility, stability
and bioavailability.1–5 This work explores the enhancement of
the cytotoxic effect of a carboplatin analog compound by using a
host–guest chemistry to noncovalently tether a dicarboxylate plat-
inum(II) chelate with b-cyclodextrin. Platinum-based compounds
are an important class of active chemotherapeutic agents for treat-
ing various cancers,6–9 yet the mechanisms of drug action are still
unraveling.10–12 Recent work has shown that in the case of cis-
platin and carboplatin, a platinum carbonato complex rather than
the reactive mono-aqua complex may be responsible for biological
effects in cells.13,14 In spite of this growing understanding, the
development and optimization of the pharmaceutical properties
of platinum-based therapeutic agents has been largely empiri-
cal.15–18 In this work, we explore the strategy of noncovalent mod-
ification via host–guest chemistry to enhance the cytotoxicity of a
carboplatin analog. We used the cyclic sugar b-cyclodextrin (bCD)
to encapsulate an adamantane-derivatized dicarboxylate that was
complexed with a platinum(II) ion.
of desired properties such as increased water-solubility, cellular
uptake and targeted delivery without severely altering the efficacy
of the agents.19,20 Cyclodextrins have been widely used for improv-
ing drug properties such as solubility, stability and bioavailabil-
ity.2,3,5 Recently, Maxfield and co-workers discovered that bCD
has a high propensity to be taken up by mammalian cells, presum-
ably through pinocytosis.21 This discovery suggests the possibility
of enhancing the potency of platinum(II)-based compounds by
noncovalent modification of the agent with bCD. We synthesized
an adamantane–dicarboxylate which, after complexation with
believed to be bCD forms a host–guest complex, which is further
reacted with cis-[Pt(15NH3)2(H2O)2]+2 to afford 6 (Scheme 1). The
binding of adamantane with bCD is stoichiometric in water, with
one adamantane group hosted in the hydrophobic annular cavity
of bCD. We examined the cytotoxicity of this host–guest complex
against neuroblastoma (SK-N-SH) cells, and compared the cytotox-
icity of the carboplatin analog to that of carboplatin.
Scheme 1 shows the synthesis of the bCD adamantane carbo-
platin analog host–guest complex (6). Briefly, tosylation of ada-
mantane alcohol (1),22 afforded the tosylate (2). Displacement of
tosyl group in (2) with diethylmalonate gave the diethyl ester
(3), which on hydrolysis provided the diacid (4). We noted that di-
rect coupling of (4) and cis-[Pt(15NH3)2(H2O)2]+2 (5),23,24 gave a
grey solid that was insoluble in all solvents studied (see Supple-
mentary data, Scheme S1). The presence of 15N label in the
platinum diaqua complex facilitated the characterization of the
Noncovalent modification of pharmacologically active agents to
enable host–guest chemistry is a relatively unexplored approach
for controlling drug activities, and it offers potential enhancement
⇑
Corresponding author.
E-mail address: yluk@syr.edu (Y.-Y. Luk).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.10.006

7422
D. Prashar et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7421–7425
O
3
OH
OH
O
3
O
O
aq NaOH
TsCl, Et3N, DMAP
diethylmalonate, NaH, NaI
OTs
OH
O
O
O
O
O
reflux, 24 h
3
0 °C-rt, 3 h
3
THF, 0 °C-rt- reflux, 5 h
O
1
2
3
4
15NH3
O
O
O
OH
OH
Pt15
O
NH3
O
O
H315N OH2
Pt
βCD, MeOH:H2O (1:3)
H2O, 2h
3
O
O
pH 5, 1 h
H315N OH2
5
6
Scheme 1.
analog using heteronuclear single quantum coherence [1H, 15N]
HSQC NMR. Because cyclodextrins are known to form water solu-
ble host-guest complexes with hydrophobic groups,2 we tried
using bCD to possibly extract the product from the grey solid into
water. Addition of bCD to an aqueous suspension of the grey solid
did not result in detectable product. However, treating the diacid
(4) first with 1 equiv of bCD, followed by addition of cis-
[Pt(15NH3)2(H2O)2]+2 (5), resulted in the desired water-soluble con-
jugate (6). These details of the synthesis suggest that the exchange
rate of the bCD adamantane host–guest complex is likely slow, and
that using bCD likely provides a general approach to render hydro-
phobic small molecules soluble in water. The chemical shift (d,
ppm) in HSQC for 1H = 4.13 and 15N = À82.0, was similar to those
observed for carboplatin (Fig. 1).24
Because 6 and carboplatin share a common functional group,
we studied the cytotoxicity of both compounds towards human
neuroblastoma cells (SK-N-SH).14 The neuroblastoma (SK-N-SH)
cells were grown for 24 h in 96-well plates, and the cells were then
treated with different concentrations of 6 or carboplatin for an
exposure time (length of exposure of the cells to the agent) of
1 h. Viabilities were assayed immediately following exposure to
the agent and culturing cells in fresh medium for 24, 48 and
72 h, referred to as the recovery time.25 At each recovery time,
the number of live cells was determined by a colorimetric cell
counting assay (CCK-8 assay).26 The assay utilizes a water soluble
tetrazolium salt, which is reduced by dehydrogenases in the live
cells to give a yellow colored product (formazan). The amount of
the formazan dye produced in the culture medium is directly pro-
portional to the number of living cells. The survival (%) was calcu-
lated by using the equation (OD450 sample)/(OD450 control) Â 100,
where the sample OD was obtained from the cells treated with 6 or
carboplatin, and the control OD was obtained from cells.27
Figure 2 shows the plots of survival (%) of neuroblastoma (SK-
N-SH) cells as a function of concentration for 6 and carboplatin at
different recovery times. Immediately after exposure to carbo-
platin (0 h recovery time), there was no observable toxic effect
and the survival (%) does not change with drug concentration.
However for longer recovery times, the cells exhibit an unusual
dose dependent behavior to carboplatin. The cytotoxicity of car-
boplatin increases in the drug concentration range,
ꢀ500 M, reaches a maximum at ꢀ500 M and decreases in the
range, 500–1000 M (Fig. 2A). Recently it was shown that carbo-
0 to
l
l
l
platin exists in a monomer–dimer equilibrium in aqueous solu-
tion, and there is evidence that the same equilibrium may also
exist in culture media.28 Since the concentration of a species in
a monomer–dimer equilibrium is dependent on the total concen-
tration of the agent in the medium, it is possible that the reduced
cytotoxicity of carboplatin observed at high concentration is due
to the presence of the dimer which may be less toxic to the cells
than the monomeric form of the drug. Figure 2B shows the sur-
vival (%) of 6 as a function of concentration and recovery time
which sharply contrasts with that of carboplatin. While being
non-toxic at all concentrations for a recovery time of 0 h, 6 exhib-
ited the typical dose–response expected at longer recovery times
with the longest recovery time (72 h) producing the greatest
amount of cell death. Comparison of the survival (%) for 6 with
carboplatin indicates that overall 6 is more toxic to the neuro-
blastoma cells than is carboplatin.
We also examined the effects of different exposure times of 6
and carboplatin on neuroblastoma cells at a recovery time of 0 h
(viabilities were measured immediately following exposure). Con-
fluent layers of SK-N-SH cells were incubated with 500 lM of each
agent for 2, 4, 6, 8 and 12 h in 96-well plates. After each exposure
time, medium containing 6 or carboplatin was replaced with fresh
culture medium, and the number of live cells was immediately
determined by CCK-8 assay. Figure 3 shows that the survival (%)
for both carboplatin and 6 for exposure times up to 12 h, gives
the expected dose–response effect, as is shown in the low concen-
tration range of Figure 2, with 6 being more toxic to the cells than
carboplatin.
Figure 1. [1H, 15N] HSQC NMR of bCD adamantane carboplatin analog host–guest
complex (6) in 5% D2O/H2O: d (ppm) 1H = 4.13, d 15N = À82.0.
Maxfield and coworkers recently discovered that endocytosis of
bCD is responsible for cholesterol reduction in Niemann–Pick type

D. Prashar et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7421–7425
7423
Figure 2. Plots of survival (%) of SK-N-SH cells treated with (A) carboplatin, and (B) 6, as a function of concentration with different recovery times at 0, 24, 48 and 72 h.
Figure 3. Survival (%) of SK-N-SH cells when treated with 500 lM carboplatin and 6
for different incubation times of 2, 4, 6, 8, and 12 h with a recovery time of 0 h.
Figure 5. Platinum (amol) taken up per SK-N-SH cell, when exposed to carboplatin
(500 lM) and 6 (500 lM) as a function of time. The rate of uptake (amol of Pt
cellÀ1 hÀ1) was found to be 16.0 0.56 and 64.9 1.4 for cells treated with 6 and
C mutant cells.21 This effect is believed to be due to the internali-
zation of cyclodextrin in the cells through fluid phase pinocyto-
sis.21,29,30 To validate the internalization of bCD in SK-N-SH cells,
we synthesized fluorescein isothiocynate (FITC) tagged cyclodex-
trin.31 Confocal fluorescence images showed that all SK-N-SH cells
treated with FITC-tagged bCD exhibited green fluorescence (Fig. 4),
suggesting that FITC-tagged bCD were efficiently internalized into
the cancer cells. Interestingly, the FITC-tagged bCD appeared to be
localized around the nucleus of the cells.
Because 6 is more cytotoxic than carboplatin towards SK-N-SH
cells, we examined the uptake rate at which both compounds enter
the cells using inductively coupled plasma mass spectrometry
(ICP-MS).14,32 Six-well plates with each well containing 3.5 Â 105
of SK-N-SH cells suspended in culture medium were incubated at
37 °C for 24 h to allow the cells to adhere to the surface of the well.
The number of viable cells in the wells was measured by light
carboplatin, respectively.
microscopy using a hemocytometer and trypan blue. The cells in
the wells were treated with 500 lM of 6 or carboplatin for differ-
ent incubation times of 0, 1, 2, 3, and 4 h. The cells were trypsini-
zed, pelleted by centrifugation, and the pellets were washed twice
with phosphate buffered saline (PBS, 10 mM). The cells were lysed
in 70% nitric acid at 50 °C for 48 h and the cell lysate was analyzed
for platinum by ICP-MS. The uptake rate was determined by calcu-
lating the amount of platinum taken up by the cell in units of atto-
moles (10À18) of platinum which was plotted versus incubation
time (Fig. 5). The uptake rate of platinum per cell, in attomoles
(10À18) per hour, was calculated from the total number of viable
cells (number of viable cells in each well in the 6-well plates, be-
fore treatment with 6 and carboplatin were 2.04 Â 105 and
3.85 Â 105, respectively) and the number of moles of platinum that
Figure 4. (A) Structure of FITC-tagged bCD, (B) confocal fluorescence image of SK-N-SH cells incubated with 150 nM of FITC-tagged bCD.

7424
D. Prashar et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7421–7425
Figure 6. Agarose gel electrophoresis image of pBR322 DNA (33.3
l
M base pairs) after incubation with 6 or carboplatin in 10 mM HEPES, pH 7.4 for 24 h. Lanes 2 through 11
contained 30, 35, 40, 45, 50, 60, 70, 80, 90, and 100
only pBR322 DNA.
l
M of 6, and lanes 12 through 18 contained 30, 40, 50, 70, 80, 90 and 100 M of carboplatin. Lane 1 (control) contained
l
each cell took up from the culture medium per hour.14 The uptake
rates of 6 and carboplatin at 500 M by SK-N-SH cells were found
6 binds DNA than in the case for carboplatin. For example, the DNA
in lane 11 (6 at 100 M) migrated less than in lane 18 (carboplatin
at 100 M). As shown in Figure 6, carboplatin and 6 have little ef-
fect on the mobility of the nicked circular, Form II DNA (no super-
coiling) in the gel. We note that bCD alone does not show any
binding to pBR322 DNA (see the Supplementary data).
l
l
to be 16.0 0.56 and 64.9 1.4 amol of Pt cellÀ1 hÀ1, respectively.
Comparing the uptake of platinum (Fig. 5) and the survival (%) of
SK-N-SH cells (Fig. 3) after 4 h incubation shows that while the up-
take of carboplatin was ꢀ4.4 times higher than that of 6, there was
a decrease of ꢀ6% in the survival of SK-N-SH cells treated with 6,
and no observable decrease of survival for cells treated with
carboplatin.
l
Collectively, the results of this study suggest that, when com-
pared to carboplatin, the higher cytotoxicity of 6 towards neuro-
blastoma cells is not related to the amount of platinum that
enters the cell, but perhaps to the more effective transport of 6
to the nucleus via the appended bCD moiety followed by efficient
binding to nuclear DNA. Other than binding nuclear DNA, platinum
based complexes have demonstrated the potency for targeting and
inhibiting protein activities.37–41 For example, a number of plati-
num(II) complexes have been reported to inhibit human thiore-
doxin reductase,39 mammalian topoisomerases40 and matrix
metalloproteinase (MMP-3),41 by undergoing ligand-substitution
reactions with reactive amino acid residues. Studies of these agents
in vivo including binding to DNA as well as to potential protein tar-
gets will further decipher the mechanism of the cytotoxicity of
these bCD hosted agents.
This work reports the synthesis of a bCD encapsulated ada-
mantane–platinum host–guest complex, 6. Confocal fluorescence
indicated the internalization of bCD at locations close to nuclei
of cells. The cytotoxicity assays showed that 6 was more toxic
than carboplatin toward neuroblastoma (SK-N-SH) cells. Agarose
gel electrophoresis confirmed the binding of 6 to pBR322 DNA,
while bCD alone does not bind DNA, and showed that 6 exhibited
a higher level of binding than carboplatin. Interestingly, the ICP-
MS measurement indicated that carboplatin had a higher uptake
rate than 6 into the cells. These results suggest that factors such
as intracellular transport, receptor binding, and heterogeneous
distributions of agents inside the cells likely play more important
roles than just the cellular uptake for cytotoxic effects. This work
suggests that using deliberate host-guest chemistry can be a pow-
erful strategy to influence the binding activities and other phar-
These data indicate that the uptake rate of carboplatin by neu-
roblastoma cells is ꢀ4 times higher than 6, while the cytotoxicity
experiments show that 6 is more cytotoxic than carboplatin. Hence
the amount of platinum entering the cell alone cannot be the basis
for the different cytotoxic effects of the compounds. However, con-
sidering that the main target for the platinum agents is believed to
be DNA, carboplatin could be more susceptible to reaction with,
and inactivation by, components in the cytosol than is the case
for 6.
Because binding to DNA is believed to be a key element for plat-
inum-based therapeutic agents,33 we examined and compared the
binding of carboplatin and 6 to plasmid pBR322 DNA using agarose
gel electrophoresis.34–36
Plasmid DNA (pBR322) exists in different chemical forms—
covalently closed, nicked and linear. Form I DNA is a supercoiled
closed circular DNA, and Form II DNA is a nicked circular DNA
without supercoiling, and thus have different mobilities in an aga-
rose gel. Form I DNA is wound into a compact structure, and hence
is the fastest moving conformation of the plasmid. Once the plas-
mid DNA is treated with the platinum agents, binding and unwind-
ing of Form I DNA will cause a decrease in the mobility of Form I
DNA.33 After incubating pBR322 for 24 h with different concentra-
tions (30–100 lM) of 6 or carboplatin, the image of the agarose gel
(Fig. 6) shows that the mobility of closed circular Form I DNA de-
creased with an increase in concentrations of 6 and carboplatin,
but decrease in mobility of Form I with 6 is greater than the case
for carboplatin.
Since the leaving ligands for both compounds are expected to be
the dicarboxylate, the DNA binding unit in both cases is most likely
cis-{Pt(NH3)2}+2 which, in comparison to cisplatin, would bind to
and unwind supercoiled Form I closed circular DNA (negative
writhe) through the formation of a 1,2 intrastrand crosslink.6 For
cisplatin, platinum binding unwinds Form I DNA, which reduces
the supercoiling (writhe approaches zero), causing the closed cir-
cular DNA to become more open and ‘doughnut-like’ in nature,
and hence causing a decrease in the electrophoretic mobility of
the platinated DNA in the gel. Since mobility is approximately in-
versely proportional to platinum loading on the DNA, Figure 6 sug-
gests that, during the 24 h incubation period, more platinum from
maco-properties of a therapeutic agent. We believe that
noncovalent modification can be integrated into drug design, for-
mulation, as well as other functions such as targeted delivery and
combined drug therapy, rather than treating them as separate
topics.
Acknowledgments
We thank NSF–CAREER (# 0845686), and Syracuse Center of
Excellence for CARTI award supported by the U.S. Environmental
Protection Agency (grants Nos.: X-83232501-0) for financial
support.

D. Prashar et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7421–7425
7425
19. Krause-Heuer, A. M.; Wheate, N. J.; Tilby, M. J.; Pearson, D. G.; Ottley, C. J.;
Aldrich-Wright, J. R. Inorg. Chem. 2008, 47, 6880.
Supplementary data
20. Wheate, N. J. J. Inorg. Biochem. 2008, 102, 2060.
21. Rosenbaum, A. I.; Zhang, G.; Warren, D. J.; Maxfield, F. R. Proc. Natl. Acad. Sci.
U.S.A. 2010, 107, 5477.
22. Wennekes, T.; Van den Berg, R. J. B. H. N.; Donker, W.; van der Marel, G. A.;
Strijland, A.; Aerts, J. M. F. G.; Overkleeft, H. S. J. Org. Chem. 2007, 72, 1088.
23. Boreham, C. J.; Broomhead, J. A.; Fairlie, D. P. Aust. J. Chem. 1981, 34, 659.
24. Di Pasqua, A. J.; Goodisman, J.; Kerwood, D. J.; Toms, B. B.; Dubowy, R. L.;
Dabrowiak, J. C. Chem. Res. Toxicol. 2006, 19, 139.
25. Shi, Y.; Toms, B. B.; Dixit, N.; Kumari, N.; Mishra, L.; Goodisman, J.; Dabrowiak,
J. C. Chem. Res. Toxicol. 2010, 23, 1417.
26. Ishiyama, M.; Tominaga, H.; Shiga, M.; Sasamoto, K.; Ohkura, Y.; Ueno, K. Biol.
Pharm. Bull. 1996, 19, 1518.
27. O’Toole, S. A.; Sheppard, B. L.; McGuinness, E. P. J.; Gleeson, N. C.; Yoneda, M.;
Bonnar, J. Cancer Detect. Prev. 2003, 27, 47.
28. Di Pasqua, A. J.; Kerwood, D. J.; Shi, Y.; Goodisman, J.; Dabrowiak, J. C. Dalton
Trans. 2011, 40, 4821.
29. Rodal, S. K.; Skretting, G.; Garred, O.; Vilhardt, F.; Van Deurs, B.; Sandvig, K. Mol.
Biol. Cell 1999, 10, 961.
30. Mukherjee, S.; Ghosh, R. N.; Maxfield, F. R. Physiol. Rev. 1997, 77, 759.
31. Teranishi, K.; Nishiguchi, T. Anal. Biochem. 2004, 325, 185.
32. Ghezzi, A.; Aceto, M.; Cassino, C.; Gabano, E.; Osella, D. J. Inorg. Biochem. 2004,
98, 73.
33. Cohen, G. L.; Bauer, W. R.; Barton, J. K.; Lippard, S. J. Science 1979, 203, 1014.
34. Scovell, W. M.; Collart, F. Nucleic Acids Res. 1985, 13, 2881.
35. Keck, M. V.; Lippard, S. J. J. Am. Chem. Soc. 1992, 114, 3386.
36. Sorokanich, R. S.; Di Pasqua, A. J.; Geier, M.; Dabrowiak, J. C. Chem. Biodiversity
2008, 5, 1540.
37. Che, C.-M.; Siu, F.-M. Curr. Opin. Chem. Biol. 2010, 14, 255.
38. Benedetti, B. T.; Peterson, E. J.; Kabolizadeh, P.; Martinez, A.; Kipping, R.;
Farrell, N. P. Mol. Pharm. 2011, 8, 940.
39. Becker, K.; Herold-Mende, C.; Park, J. J.; Lowe, G.; Schirmer, R. H. J. Med. Chem.
2001, 44, 2784.
40. Lo, Y.-C.; Ko, T.-P.; Su, W.-C.; Su, T.-L.; Wang, A. H. J. J. Inorg. Biochem. 2009, 103,
1082.
41. Arnesano, F.; Boccarelli, A.; Cornacchia, D.; Nushi, F.; Sasanelli, R.; Coluccia, M.;
Natile, G. J. Med. Chem. 2009, 52, 7847.
Supplementary data (details of synthesis and characterization
of synthetic products and other experimental details) associated
with this article can be found, in the online version, at
doi:10.1016/j.bmcl.2011.10.006.
References and notes
1. Otero-Espinar, F. J.; Torres-Labandeira, J. J.; Alvarez-Lorenzo, C.; Blanco-
Mendez, J. J. Drug Delivery Sci. Technol. 2010, 20, 289.
2. Davis, M. E.; Brewster, M. E. Nat. Rev. Drug Discovery 2004, 3, 1023.
3. Loftsson, T.; Brewster, M. E. J. Pharm. Sci. 1996, 85, 1017.
4. Uekama, K.; Hirayama, F.; Irie, T. Chem. Rev. 1998, 98, 2045.
5. Szejtli, J. Chem. Rev. 1998, 98, 1743.
6. Dabrowiak, J. C. Metals in Medicine, 1st ed.; Wiley & Sons: Chichester, 2009.
7. Rosenberg, B.; VanCamp, L.; Trosko, J. E.; Mansour, V. H. Nature 1969, 222, 385.
8. Kelland, L. Nat. Rev. Cancer 2007, 7, 573.
9. Hall, M. D.; Okabe, M.; Shen, D.-W.; Liang, X.-J.; Gottesman, M. M. Annu. Rev.
Pharmacol. Toxicol. 2008, 48, 495.
10. Krause-Heuer, A. M.; Gruenert, R.; Kuehne, S.; Buczkowska, M.; Wheate, N. J.;
Le Pevelen, D. D.; Boag, L. R.; Fisher, D. M.; Kasparkova, J.; Malina, J.; Bednarski,
P. J.; Brabec, V.; Aldrich-Wright, J. R. J. Med. Chem. 2009, 52, 5474.
11. Abu-Surrah Adnan, S. Mini-Rev. Med. Chem. 2007, 7, 203.
12. Reedijk, J. Pure Appl. Chem. 1987, 59, 181.
13. Centerwall, C. R.; Goodisman, J.; Kerwood, D. J.; Dabrowiak, J. C. J. Am. Chem.
Soc. 2005, 127, 12768.
14. Di Pasqua, A. J.; Goodisman, J.; Kerwood, D. J.; Toms, B. B.; Dubowy, R. L.;
Dabrowiak, J. C. Chem. Res. Toxicol. 2007, 20, 896.
15. Wang, D.; Lippard, S. J. Nat. Rev. Drug Discovery 2005, 4, 307.
16. Halamikova, A.; Heringova, P.; Kasparkova, J.; Intini, F. P.; Natile, G.;
Nemirovski, A.; Gibson, D.; Brabec, V. J. Inorg. Biochem. 2008, 102, 1077.
17. Zhang, J.; Wang, X.; Tu, C.; Lin, J.; Ding, J.; Lin, L.; Wang, Z.; He, C.; Yan, C.; You,
X.; Guo, Z. J. Med. Chem. 2003, 46, 3502.
18. Komeda, S.; Moulaei, T.; Woods, K. K.; Chikuma, M.; Farrell, N. P.; Williams, L.
D. J. Am. Chem. Soc. 2006, 128, 16092.