Polyamine conjugation of curcumin analogues toward the discovery of mitochondria-directed neuroprotective agents

Article abstract of DOI:10.1021/jm100637k

Mitochondria-directed antioxidants 2-5 were designed by conjugating curcumin congeners with different polyamine motifs as vehicle tools. The conjugates emerged as efficient antioxidants in mitochondria and fibroblasts and also exerted a protecting role through heme oxygenase-1 activation. Notably, the insertion of a polyamine function into the curcumin-like moiety allowed an efficient intracellular uptake and mitochondria targeting. It also resulted in a significant decrease in the cytotoxicity effects. 2-5 are therefore promising molecules for neuroprotectant lead discovery.

Full text of DOI:10.1021/jm100637k

7264 J. Med. Chem. 2010, 53, 7264–7268
DOI: 10.1021/jm100637k
Polyamine Conjugation of Curcumin Analogues toward the Discovery of Mitochondria-Directed
Neuroprotective Agents†
Elena Simoni,‡ Christian Bergamini,§ Romana Fato,§ Andrea Tarozzi, Sandip Bains,# Roberto Motterlini,#,^
Andrea Cavalli,^,‡ Maria Laura Bolognesi,‡ Anna Minarini,‡ Patrizia Hrelia, Giorgio Lenaz,§ Michela Rosini,*,‡ and
Carlo Melchiorre*,‡
‡Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy, §Departments of Biochemistry, and
Pharmacology, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy, ^Department of Drug Discovery and Development, Italian Institute of
Technology, Via Morego 30, 16163 Genova, Italy, and #Nortwhick Park Institute for Medical Research, Harrow, U.K.
Received May 26, 2010
Mitochondria-directed antioxidants 2-5 were designed by conjugating curcumin congeners with
different polyamine motifs as vehicle tools. The conjugates emerged as efficient antioxidants in
mitochondria and fibroblasts and also exerted a protecting role through heme oxygenase-1 activation.
Notably, the insertion of a polyamine function into the curcumin-like moiety allowed an efficient
intracellular uptake and mitochondria targeting. It also resulted in a significant decrease in the
cytotoxicity effects. 2-5 are therefore promising molecules for neuroprotectant lead discovery.
Introduction
with multiple molecular targets and biological activities. In
addition to anti-inflammatory, antiviral, and neuroprotective
actions,9 it possesses direct primary10 and indirect secondary
antioxidant activity.11 It also asserts antiproliferative and/or
apoptotic effects in cancer cells targeting cell cycle regulatory
molecules.12,13 Despite its broad effects on the biological
functions of cells, the potential use of 1 as a therapeutic agent
is severely affected by its low water solubility, poor in vivo bio-
availability, and rapid metabolism.14 In recent years, its structure
has been widely modified, focusing mainly on changes in the
β-diketone structure and aryl substitution pattern of the mole-
cule. Among the obtained compounds, the 3,5-dibenzylide-
nepiperidin-4-one (DBP) framework attracted our attention
because of its higher antioxidant and antiproliferative actions
with respect to 115-17 and the possibility for the amino group
to be easily functionalized. This moiety may also offer the
chance of an improved pharmacokinetic profile.18
In this context, the aim of the present study is to selectively
direct the above-mentioned moiety into the mitochondrion,
which is the cellular compartment where ROS production and
apoptosis modulation mainly occur. This should contribute to
the development of effective drugs for therapeutic interven-
tion in pathologies, such as cancer and neurodegenerative
diseases, where these processes are strongly compromised.
So far, most research effort in developing mitochondria-
directed molecules has been based on two distinct mitochon-
drial features: the organelle’s protein import machinery and
the high membrane potential across the inner membrane.19 In
particular, the latter offers a unique chemical opportunity for
selectively targeting the mitochondrion, as verified for several
lipophilic cations that efficiently accumulate into this subcel-
lular compartment in a gradient-dependent manner.3 On this
basis and also because polyamine chains have already been
used to improve the cellular import of drug molecules,20,21 we
selected a polyamine scaffold, protonated at physiological
pH, because it could direct the bioactive functionality into
Mitochondria undertake essential and diverse roles in the
physiology of eukaryotic cells.1 In addition to being the major
source of ATP, they participate in numerous metabolic reac-
tions and regulate a variety of cellular functions including
proliferation, differentiation, and apoptosis. Mitochondria
are both a major site of production and a primary target of
reactive oxygen species (ROSa). ROS act as signaling mole-
cules, but can cause damage if produced excessively. It is
therefore not surprising that mitochondrial dysfunctions are
associated with a wide variety of human pathologies ranging
from neurodegenerative and neuromuscular diseases to dia-
betes and cancer.1
The unique structural and functional characteristics of
mitochondria prompted researchers to design drugs able to
selectively modulate the function of this organelle for ther-
apeutic gain. This has led to the emergence of “mitochondria-
directed therapeutics” as a new field of biomedical research.2,3
Inparticular, inrecent years, much attention has beendevoted
to identifying purposely designed mitochondria-directed anti-
oxidants. This has led to innovative therapeutic molecules,
some of which are now undergoing phase II clinical trials for
neurodegenerative diseases.3-5 In addition, because of their
proapoptotic potential, mitochondria have recently emerged
as intriguing targets for anticancer drugs.6-8
Curcumin (1) is a polyphenolic compound isolated from the
rhizomes of the Curcuma longa plant. It is a pleiotropic agent
†Dedicated to Professor Goffredo Rosini on the occasion of his 70th
birthday.
*To whom correspondence should be addressed. For M.R.: phone,
þ39 0512099722; fax, þ39 0512099734; e-mail, michela.rosini@unibo.
it. For C.M.: phone, þ39 0512099706; fax, þ39 0512099734; e-mail,
carlo.melchiorre@unibo.it .
a Abbreviations: ROS, reactive oxygen species; DBP, 3,5-dibenzyli-
denepiperidin-4-one; PPAA, propylphosphonic anhydride; SMP, sub-
mitochondrial particles; HO-1, heme oxygenase-1; BAEC, bovine aortic
endothelial cells; CCCP, carbonyl cyanide m-chlorophenylhydrazone.
r
pubs.acs.org/jmc
Published on Web 09/10/2010
2010 American Chemical Society

Brief Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 19 7265
Figure 1. Design strategy for compounds 2-5.
mitochondria passing through cell and mitochondria mem-
branes. We synthesized a series of polyamine-based deriva-
tives, conjugating differently substituted DBP scaffolds with
spermine and norspermidine chains (2-5) (Figure 1), which
were then biologically investigated to assess their antioxidant
and antiproliferative effects. We synthesized the fluorescent
probe 6 to validate whether or not the synthesized compounds
were preferentially taken up by mitochondria.
Information). Owing to its cytotoxicity, the antioxidant effi-
cacy of the lonely polyphenolic moiety14 could not be verified
in the conditions used for 2-5. The replacement of the
methoxy function of 1 with an ethoxy function, meant to
modulate the stability of the phenoxy free radical, did not
effectively result insignificant improvement of the antioxidant
activity. Moreover, as expected, inserting different polyamine
chains did not influence the antioxidant efficacy.
1 not only exhibits free radical scavenging properties but
also protects against oxidative stress by means of indirect anti-
oxidant mechanisms such as heme oxygenase-1 (HO-1) induc-
tion.11 HO-1 exerts its protective role by degrading the intra-
cellular levels of pro-oxidant heme and by producing biliverdin,
the precursor of bilirubin, this latter being an endogenous
molecule with powerful antioxidant features.26 For this reason,
14 and polyamines 2 and 4, which carry the synthone 14, were
assayed as HO-1 modulators in bovine aortic endothelial cells
(BAEC) using 10 μM of each compound incubated for 6 h.
Interestingly, 14 turned out to be more efficacious than 1 in
activating HO-1. Including a spermine tail in the constrained
polyphenolic nucleus only slightly affected its efficacy (Figure 3).
This promising result suggests that the synthesized compounds
are, like 1, multimodal antioxidants able to raise cell defenses by
means of direct and indirect mechanisms. To verify how diffe-
rent substituents on the two aromatic rings can tune the profile
of the DBP moiety in relation to its ability to increase HO-1
activity, a detailed structure-activity relationships study is in
progress and will be published in due course.
Results and Discussion
2-5 were synthesized following the convergent synthetic
approach depicted in Scheme 1. To incorporate a polyamine
backbone into the polyphenolic moiety, partially protected
spermine 7,22 norspermidine 8,23 and 9 having only one free
aminefunction were first provided withanacidic functionality
through reaction with succinic anhydride to afford 11-13.
Compound 9 was obtained by reductive amination of 7 with
the commercially available 4-(benzothiazol-2-yl)benzaldehyde
(10). Then (3E,5E)-3,5-bis-(-4-hydroxy-3-methoxybenzyl-
idene)piperidin-4-one (14) and (3E,5E)-3,5-bis-(-4-hydroxy-
3-ethoxybenzylidene)piperidin-4-one (15), synthesized by follo-
wing reported procedures,24 were condensed with 11-13 in
the presence of propylphosphonic anhydride (PPAA) to give
16-20. This protocol for amidation via mixed phosphoric
anhydrides allowed an excellent selectivity for N- versus
O-(phenolic) acylation, making hydroxyl protection unneces-
sary.25 Removal of BOC groups with trifluoroacetic acid
in CH2Cl2 gave the targets 2-6 as trifluoroacetate salts
(Scheme 1).
The antioxidant activity was first tested on submitochondrial
particles (SMP) of bovine heart mitochondria. Addition of
antimycin A to SMP treated with NADH induced a strong
increase in ROS production, which was detected by the fluoro-
genic probe DCFDA. At 10 μM, 2-5 significantly decreased
ROS production, similar to the reference compound 1. Con-
versely, the unexpected very low fluorescence detected in the
presence of 14 and antimycin A suggested that this compound
could interfere with the electron transport chain. The ROS
decrease could be explained by two different mechanisms: the
compound may act directly on the sites of ROS production or it
may have a strong scavenger activity (Figure 2).
The reported antitumoral efficacy of the DBP nucleus,15-17,27
together with the high degree of cytotoxicity verified for 14 in
the T67 cell line, prompted us to further explore the anti-
proliferative effect of this series of compounds. To verify their
effect on tumor and normal cell proliferation, 2-5 and
reference compounds 1 and 14 were assayed in human colonic
carcinoma Caco-2, human neuroblastoma SH-SY5Y, rat
glioma C6, and human prostate cancer LNCaP cell lines,
mouse embryo BALB/c 3T3 fibroblasts line, and murine
hippocampal neuronal HT22 cell lines. Antiproliferative
activities were determined after 72 h of treatment with various
concentrations (0.1-30 μM) of the tested compound. Cell
proliferation was measured by MTT assay, the results being
expressed as IC50 (concentration of compound resulting in
50% inhibition of cell proliferation). As depicted in Table 1,
2-5 showed antiproliferative effects similar to that of 1, while
14was significantly morecytotoxic. Inparticular, the different
efficacy of the polyamine derivatives and 14 is highlighted in
Figure 4, where the cell proliferation of normal (a) and cancer
To further explore the antioxidant potential of the synthe-
sized compounds, their activity against oxidative insults was
assayed in human fibroblasts, following treatment with tert-
butyl hydroperoxide. Interestingly, 2-5 at 10 μM decreased
ROS production by 38-45% (see Table 3SI in Supporting

7266 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 19
Simoni et al.
Scheme 1a
a Reaction conditions: (a) toluene, reflux, 2 h, and then ethanol, NaBH4, room temp, overnight; (b) succinic anhydride, Et3N, CH2Cl2, room temp,
24 h; (c) PPAA, Et3N, dry DMF, room temp, 3-4 h; (d) TFA, CH2Cl2, room temp, 4 h.
Figure 3. Effect of 1, 2, 4, and 14 on HO-1 activity in endothelial
cells. Bovine aortic endothelial cells were exposed to 10 μM com-
pound, and HO-1 activity was measured after 6 h of incubation as
described in the Experimental Section. Each bar represents the
average of three independent experiments, and results are expressed
as (pmol of bilirubin/mg of protein)/h. The control group (CON) is
represented by cells exposed to medium alone: (/) p < 0.05 vs
Figure 2. Effect of 1-5 and 14 on ROS production in submito-
chondrial particles induced by 2 μM antimycin A using NADH as
control (CON).
substrate. 1.8 μM mucidin is used as a negative control.
Therefore, inserting a polyamine into the DBP nucleus (with
the intention of conveying the compound into mitochondria)
(b) cells is reported for 14 and 2, as examples. In agreement
with that observed in T67 glioma cells, 10 μM 14 exerted a
strong inhibition of the cell proliferation at all the tested cell
lines. Conversely, at the same concentration of 2, the decrease
of cell proliferation was about 40% in cancer cell lines and
about 10% in normal ones. Compared to healthy cells, this
suggests that cancer cells have a differential sensitivity to poly-
amine derivatives. This has already been reported for 1.13
significantly reduced the antiproliferative potency of the poly-
phenolic moiety, with the antioxidant efficacy being pre-
served. In particular, we were intrigued to find that 10 μM
2-5 significantly reduced ROS formation in fibroblasts with-
out causing considerable cytotoxic effects at the studied
healthy cell lines. This prompted us to regard these com-
pounds as useful pharmacological tools for developing valid
neuroprotective agents.

Brief Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 19 7267
Table 1. Antiproliferative Effects of 1-5 and 14 on Tumor and Normal
Cell Lines
IC50 (μM)a
tumor cell line
SH-SY5Y
normal cell line
compd
Caco-2
C6
HT22
HaCaT
3T3
1
15.0
11.9
14.4
16.5
16.2
0.2
12.8
14.2
20.8
17.8
14.6
2.1
16.1
13.9
14.2
19.9
14.5
3.9
20.4
19.8
18.4
24.5
18.9
3.1
21.9
15.6
15.7
17.7
15.5
3.0
14.2
18.4
16.8
14.1
15.3
4.2
2
3
4
5
14
a Concentration of compound resulting in 50% inhibition of tumor
and normal cell proliferation. The cell proliferation was determined by
the MTT assay (as described in the Experimental Section) after 72 h of
incubation with the tested compound (0.1-30 μM). The values are
reported as the mean of two independent experiments.
Figure 5. Fluorescence images of T67 cells treated with 10 μM 6 in
the absence (a) and in the presence (b) of 20 μM CCCP.
hypothesis, we performed fluorimetric measurement in intact
cells following 6’s fluorescence in the presence of different
amounts of CCCP, until complete mitochondrial depolariza-
tion. Our data show that the leaking of 6 follows the gradient
dissipation induced by the uncoupler in a dose-dependent
manner (see Figure 1SI in Supporting Information). The resi-
dual fluorescence observed after CCCP treatment (Figure 5b)
is related to the partial distribution of 6 in the lipid phase as
confirmed by the results obtained titrating 6’s fluorescence in
the presence of increasing amounts of liposomes (see Figure
2SI in Supporting Information). Moreover, CCCP pretreated
cells were not able to accumulate 6 (Figure 3SI in Supporting
Information).
In conclusion, this study suggests that 2-5 are efficient
multimodal antioxidants able to penetrate cells and locate
themselves inside the mitochondria. In particular, polyamines,
already identified as excellent vectors for the polyamine
transport system mediated cell import process, also emerged
for their ability to specifically convey a bioactive functionality
into mitochondria, taking advantage of electrostatic forces.
Even more intriguing is the finding that, in addition to
representing a promising tool in the considerable challenge
of targeted drug delivery, polyamines might also be able to
finely tune the bioactivity of a compound. In particular, in the
present study, the well-retained antioxidant activity observed
for DBP-polyamine conjugates with respect to 14 is accom-
panied by a significant loss of cytotoxicity, suggesting that
Figure 4. Antiproliferative effects of 2 and 14 on tumor (a) and
normal (b) cell lines. The cell proliferation was determined by the
MTT assay (as described in the Experimental Section) after 72 h
of incubation with compounds (0.1-30 μM). The results were
expressed as percentage of control cells. The values are reported
as the mean of two independent experiments.
On the basis of these promising results, we wanted to verify
if the synthesized compounds enabled efficient intracellular
uptake and mitochondria targeting in a cellular context. To
this end, mitochondria delivery was preliminarily assessed by
inverted fluorescence microscopy using 6 as the fluorescent
probe. To verify the direct involvement of mitochondrial
membrane potential in polyamine localization, T67 glioma
cells were pretreated with 10 μM 6 and 1 mg/mL oligomycin,
an ATP-synthase inhibitor that enhances the mitochondrial
potential favoring proton accumulation within the intermem-
brane space. Fluorescence images were obtained after 30 min
of incubation in the presence (Figure 5a) and absence
(Figure 5b) of the mitochondrial uncoupler carbonyl cyanide
m-chlorophenylhydrazone (CCCP). The high fluorescence
intensity measured in the former case is consistent with an
active cellular uptake of 6, while the loss of fluorescence
observed in the presence of CCCP strongly suggests that the
uptake is driven by the mitochondrial potential. To test this

7268 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 19
Simoni et al.
these compounds may represent promising molecules for
neuroprotectant lead discovery. This thesis is further corro-
borated by the finding that naturally occurring polyamines
have been covalently linked to CNS active therapeutic agents
to significantly increase their permeability through the blood-
brain barrier.28
(7) Kang, B. H.; Plescia, J.; Song, H. Y.; Meli, M.; Colombo, G.;
Beebe, K.; Scroggins, B.; Neckers, L.; Altieri, D. C. Combinatorial
drug design targeting multiple cancer signaling networks controlled
by mitochondrial Hsp90. J. Clin. Invest. 2009, 119, 454–464.
(8) Lim, S. H.; Wu, L.; Burgess, K.; Lee, H. B. New cytotoxic rosamine
derivatives selectively accumulate in the mitochondria of cancer
cells. Anti-Cancer Drugs 2009, 20, 461–468.
(9) Sun, A. Y.; Wang, Q.; Simonyi, A.; Sun, G. Y. Botanical phenolics
and brain health. NeuroMol. Med. 2008, 10, 259–274.
Experimental Section
(10) Weber, W. M.; Hunsaker, L. A.; Abcouwer, S. F.; Deck, L. M.;
Vander Jagt, D. L. Anti-oxidant activities of curcumin and related
enones. Bioorg. Med. Chem. 2005, 13, 3811–3820.
(11) Motterlini, R.; Foresti, R.; Bassi, R.; Green, C. J. Curcumin, an
antioxidant and anti-inflammatory agent, induces heme oxyge-
nase-1 and protects endothelial cells against oxidative stress. Free
Radical Biol. Med. 2000, 28, 1303–1312.
(12) Anand, P.; Sundaram, C.; Jhurani, S.; Kunnumakkara, A. B.;
Aggarwal, B. B. Curcumin and cancer: an “old-age” disease with an
“age-old” solution. Cancer Lett. 2008, 267, 133–164.
General Information. Chemical reagents were purchased from
Sigma Aldrich, Fluka and Lancaster (Italy). CH2Cl2 was distilled
from calcium chloride. TLC experiments were performed on 0.20
mm silica gel 60 F254 plates (Merck, Germany). Nuclear magnetic
resonance spectra (NMR) were recorded at 200 and 400 MHz on
Varian VXR 200 and 400 spectrometers and reported in parts per
million. Direct infusion ESI mass spectra were recorded on a
Waters ZQ 4000 apparatus. The purity of compounds was deter-
mined as >95% by HPLC and elemental analyses.
(13) Sa, G.; Das, T. Anti cancer effects of curcumin: cycle of life and
death. Cell Div. 2008, 3, 14.
(14) Padhye, S.; Chavan, D.; Pandey, S.; Deshpande, J.; Swamy, K. V.;
Sarkar, F. H. Perspectives on chemopreventive and therapeutic
potential of curcumin analogs in medicinal chemistry. Mini-Rev.
Med. Chem. 2010, 10, 372–387.
(15) Youssef, K. M.; El-Sherbeny, M. A.; El-Shafie, F. S.; Farag, H. A.;
Al-Deeb, O. A.; Awadalla, S. A. Synthesis of curcumin analogues
as potential antioxidant, cancer chemopreventive agents. Arch.
Pharm. (Weinheim, Ger.) 2004, 337, 42–54.
(16) Pati, H. N.; Das, U.; Quail, J. W.; Kawase, M.; Sakagami, H.;
Dimmock, J. R. Cytotoxic 3,5-bis(benzylidene)piperidin-4-ones
and N-acyl analogs displaying selective toxicity for malignant cells.
Eur. J. Med. Chem. 2008, 43, 1–7.
(17) Dimmock, J. R.; Arora, V. K.; Duffy, M. J.; Reid, R. S.; Allen,
T. M.; Kao, G. Y. Evaluation of some N-acyl analogues of 3,5-
bis(arylidene)-4-piperidones for cytotoxic activity. Drug Des. Dis-
covery 1992, 8, 291–299.
(18) Dimmock, J. R.; Arora, V. K.; Chen, M.; Allen, T. M.; Kao, G. Y.
Cytotoxic evaluation of some N-acyl and N-acyloxy analogues of
3,5-bis(arylidene)-4-piperidones. Drug Des. Discovery 1994, 12, 19–28.
(19) Weissig, V.; Cheng, S. M.; D’Souza, G. G. Mitochondrial phar-
maceutics. Mitochondrion 2004, 3, 229–244.
(20) Casero, R. A., Jr.; Woster, P. M. Recent advances in the develop-
ment of polyamine analogues as antitumor agents. J. Med. Chem.
2009, 52, 4551–4573.
(21) Bolognesi,M.L.;Calonghi,N.;Mangano,C.;Masotti,L.;Melchiorre,
C. Parallel synthesis and cytotoxicity evaluation of a polyamine-
quinone conjugates library. J. Med. Chem. 2008, 51, 5463–5467.
(22) Wellendorph, P.; Jaroszewski, J. W.; Hansen, S. H.; Franzyk, H. A
sequential high-yielding large-scale solution-method for synthesis
of philanthotoxin analogues. Eur. J. Med. Chem. 2003, 38, 117–122.
(23) Nagarajan, M.; Xiao, X.; Antony, S.; Kohlhagen, G.; Pommier,
Y.; Cushman, M. Design, synthesis, and biological evaluation of
indenoisoquinoline topoisomerase I inhibitors featuring poly-
amine side chains on the lactam nitrogen. J. Med. Chem. 2003,
46, 5712–5724.
General Procedure for 11-13. Succinic anhydride (1 equiv)
and Et3N (2 equiv) were added to a solution of the appropriate
Boc-protected polyamine (7-9) (1 equiv) in dry CH2Cl2. After
being stirred at room temperature for 24 h, the mixture was
worked up by washing with NaHCO3. Then the aqueous layer
was acidified using KHSO4, extracted with CH2Cl2, and dried
over Na2SO4. Removal of the solvent gave oily compounds that
were used in the next step without further purification.
General Procedure for 16-20. The appropriate amine hydro-
chloride (14, 15) (1 equiv) was added to a stirred solution of
the corresponding acid (11-13) (1 equiv) in dry DMF, PPAA
(2 equiv), and Et3N (3 equiv). After the mixture was stirred at
room temperature for 3-4 h, the solvent was evaporated and the
crude product purified by flash chromatography on silica gel.
General Procedure for 2-6. Trifluoroacetic acid (30% in
DCM) was carefully added to a stirred solution of the appro-
priate Boc-compound (16-20) in CH2Cl2 at 0 ꢀC and was
allowed to stir at room temperature for 4 h. The solvent was
evaporated under reduced pressure, adding heptane for the
azeotropic removal of trifluoroacetic acid traces. The trifluor-
oacetate salts were washed with ether to obtain 2-6 in quanti-
tative yield.
For the chemical characterization of 2-6, 9, 11-13, and
16-20, see Supporting Information.
Acknowledgment. This research was supported by grants
from the University of Bologna, Italy, and MIUR (Grant
PRIN 20073EWPF9_003).
(24) Artico, M.; Di Santo, R.; Costi, R.; Novellino, E.; Greco, G.; Massa,
S.; Tramontano, E.; Marongiu, M. E.; De Montis, A.; La Colla, P.
Geometrically and conformationally restrained cinnamoyl com-
pounds as inhibitors of HIV-1 integrase: synthesis, biological evalua-
tion, and molecular modeling. J. Med. Chem. 1998, 41, 3948–3960.
(25) Appendino, G.; Minassi, A.; Morello, A. S.; De Petrocellis, L.; Di
Marzo, V. N-Acylvanillamides: development of an expeditious
synthesis and discovery of new acyl templates for powerful activa-
tion of the vanilloid receptor. J. Med. Chem. 2002, 45, 3739–3745.
(26) Clark, J. E.; Foresti, R.; Green, C. J.; Motterlini, R. Dynamics of
haem oxygenase-1 expression and bilirubin production in cellular
protection against oxidative stress. Biochem. J. 2000, 348 (Part 3),
615–619.
(27) Adams, B. K.; Ferstl, E. M.; Davis, M. C.; Herold, M.; Kurtkaya,
S.; Camalier, R. F.; Hollingshead, M. G.; Kaur, G.; Sausville,
E. A.; Rickles, F. R.; Snyder, J. P.; Liotta, D. C.; Shoji, M.
Synthesis and biological evaluation of novel curcumin analogs as
anti-cancer and anti-angiogenesis agents. Bioorg. Med. Chem.
2004, 12, 3871–3883.
Supporting Information Available: Synthesis of intermediate
and final compounds, results from elemental and HPLC ana-
lyses, and biological methods. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) Johannsen, D. L.; Ravussin, E. The role of mitochondria in health
and disease. Curr. Opin. Pharmacol. 2009, 9, 780–786.
(2) Armstrong, J. S. Mitochondria-directed therapeutics. Antioxid.
Redox Signaling 2008, 10, 575–578.
(3) Hoye, A. T.; Davoren, J. E.; Wipf, P.; Fink, M. P.; Kagan, V. E.
Targeting mitochondria. Acc. Chem. Res. 2008, 41, 87–97.
(4) Moreira, P. I.; Zhu, X.; Wang, X.; Lee, H. G.; Nunomura, A.;
Petersen, R. B.; Perry, G.; Smith, M. A. Mitochondria: a thera-
peutic target in neurodegeneration. Biochim. Biophys. Acta 2010,
1802, 212–220.
(5) Tauskela, J. S. MitoQ, a mitochondria-targeted antioxidant.
IDrugs 2007, 10, 399–412.
(6) Ralph, S. J.; Neuzil, J. Mitochondria as targets for cancer therapy.
Mol. Nutr. Food Res. 2009, 53, 9–28.
(28) Poduslo, J. F.; Curran, G. L. Polyamine modification increases the
permeability of proteins at the blood-nerve and blood-brain
barriers. J. Neurochem. 1996, 66, 1599–1609.