Hydrophilic carotenoids: Recent progress

Article abstract of DOI:10.3390/molecules17055003

Carotenoids are substantially hydrophobic antioxidants. Hydrophobicity is this context is rather a disadvantage, because their utilization in medicine as antioxidants or in food chemistry as colorants would require some water dispersibility for their effe

Full text of DOI:10.3390/molecules17055003

Molecules 2012, 17, 5003-5012; doi:10.3390/molecules17055003
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Review
Hydrophilic Carotenoids: Recent Progress
Magdolna Háda, Veronika Nagy, József Deli and Attila Agócs *
Department of Biochemistry and Medical Chemistry, University of Pécs, Medical School,
Szigeti út 12, H-7624 Pécs, Hungary
* Author to whom correspondence should be addressed; E-Mail: attila.agocs@aok.pte.hu;
Tel.: +36-72-536001 (ext. 31864); Fax: +36-72-536225.
Received: 22 March 2012; in revised form: 17 April 2012 / Accepted: 19 April 2012 /
Published: 30 April 2012
Abstract: Carotenoids are substantially hydrophobic antioxidants. Hydrophobicity is this
context is rather a disadvantage, because their utilization in medicine as antioxidants or in
food chemistry as colorants would require some water dispersibility for their effective
uptake or use in many other ways. In the past 15 years several attempts were made to
synthetize partially hydrophilic carotenoids. This review compiles the recently synthetized
hydrophilic carotenoid derivatives.
Keywords: carotenoids; hydrophilic; esterification; PEG conjugates; cycloaddition
1. Introduction
There are substantially two reasons for the synthesis of carotenoids with increased hydrophilic
character: their possible use in medicine because of the altered or enchanced biological activity of the
new compounds or their use in food (or feed) industry. Only a few hydrophilic carotenoids can be
found in Nature, and among them the abundantly occuring crocin shows true water-solubility.
Several methods have been published (mostly patented) for enhancing the hydrophilicity of
carotenoids. These formulations are typically obtained by physical methods, like polyethyleneglycol
(PEG) dispersions. In this review only chemical derivatization including complexation is covered. The
most important questions that arise in connection of the new derivatives—besides the extent of
hydrophilicity—are whether they have at least the same antioxidant effect as the unmodified
carotenoids and what are their toxicological and pharmacokinetic properties; the latter questions
should be answered in the future for most of the following compounds. The antioxidant activity of

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some hydrophilic carotenoids increased in water when compared to the antioxidant activity of the
hydrophobic parent compounds in organic solvents, as shown by Sliwka et al. [1].
2. Hydrophilic Salts of Carotenoid Esters
It seems quite obvious that transformation of a carotenoid into a hydrophilic derivative can be
achieved by the synthesis of charged salt-like compounds or molecules that contain very polar groups
(i.e., the COOH groups of bixin or crocetin makes them at least slightly water-dispersible). In fact such
compounds have been synthesized in the past few years, mainly by Lockwood et al. and Sliwka et al.
The astaxanthin disuccinate disodium salt 2 (Figure 1) [2,3], which has moderate water
dispersibility, was one of the first hydrophilic carotenoid derivatives synthetized and it has already had
a significant career as a powerful antioxidant. It is now in the clinical trials phase as a potential
cardioprotective drug under the name Cardax [4–6]. Other derivatives like diphosphate 1 [7,8] and
dilysinate 3 [9–11] are more hydrophilic for being more ionized (Figure 1). Compounds 1
(29.27 mg/mL) and 2 showed moderate water dispersibility (2.85 mg/mL), whereas 3 (181.6 mg/mL)
is the first synthetic truly water-soluble carotenoid. Very recently Sliwka et al. synthetized some new
cationic carotenoid lipids, where a quaternary ammonium moiety is responsible for the amphipatic
character of the molecules [12,13].
Figure 1. Hydrophilic carotenoid salts.

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Sliwka et al. also synthetized and studied thoroughly remarkable phospholipid derivatized
carotenoids like 4 [14–16], and also investigated the physicochemical properties of natural hydrophilic
carotenoids such as bixin and crocin [17–19]. Recently, they have synthetized aldoxime and ketoxime
hydrochlorides from oxo carotenoids, which showed moderate water dispersibility [20]. The
antioxidant and aggregation properties of all these compounds were extensively studied in the above
mentioned articles [21].
3. Complexation with Cyclodextrins
Cyclodextrins (CD) are known biocompatible oligosaccharides of truncated cone shape, that have
been applied in many fields of chromatography, environmental chemistry and also as food additives
and complexing agents. Until the year 2000 there were no studies in connection with carotenoids that
would reveal the real interaction between CDs and carotenoids. CDs were used as solubilizing agent,
simply mixed with carotenoids in different proportions [22–25]. Later it was found that carotenoids
without cyclic end groups at least on one end (e.g., lycopene or bixin) could form 1:1 inclusion
complexes which are more stable than the native carotenoids [26–31]. We have found that cyclic
end-groups cannot enter the relatively apolar cavity of CDs because of their size, but 3-4 CD
molecules surround each end-group and are bound there through secondary interactions. A lot of CD
derivatives were tested with various carotenoids and the most successful formulations were the
randomly methylated -CD (RAMEB) complexes of capsanthin, capsorubin and lutein [32]. The major
drawback of these nanocapsulated carotenoids is that they contain a relatively high percent (95%) of
CD which is required to maintain their complexation ability and the water solubility of the complexes.
The aqueous solutions of these complexes are stable over months, so no aggregation can be observed,
and the complexation is not pH dependent. The RAMEB-lutein complex has been recently found to
facilitate the incorporation of lutein in neurons [33].
4. Glycosides
Carotenoid glycosides occur in Nature as constituents of cell membranes of certain heat-resistant
microorganisms. These compounds, also called thermoxanthins, are slightly more hydrophilic than
simple carotenoids, however, their amphiphilic structure is noteworthy. The length of the thermoxanthins
is equal to the width of the phospholipid bilayer, and they are incorporated into the cell membrane
modifying its properties. This particular behaviour of thermoxanthins is believed to be partially
responsible for the heat resistance of the Thermus species [34].
Only a few methods have been published for the chemical synthesis of carotenoid glycosides: direct
glycosylation of carotenoid alcohols using the classical Königs-Knorr procedure [35,36] and total
synthesis starting from 3-hydroxy-β-ionone [37,38]. Glycosides of astaxanthin were also prepared by a
biosynthetic process [39].
Mimetics of natural thermoxanthins were prepared by the generation of dications from -carotene
or isozeaxanthin, which were treated with appropriate sugar derivatives as nucleophiles to make mono-
and dithioglycosides [40]. The most successful reaction, to synthesize a thioglycoside in this case, can
be seen in Scheme 1. After deprotection partially water-soluble thermoxanthin mimetics could be
obtained. With this method CDs could be also coupled to carotenoids in the future.

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Scheme 1. Synthesis of thermoxanthin mimetics.
BzO
O
BzO
OBz
OBz
OH
S
3'
4'
1
4'
7
15
15'
1. CF3COOH
CH2Cl2, -15 °C, N2
6
5
2
3
8
10
4
2. 3 equiv.
OH
O
S
O
SH
BzO
BzO
BzO
BzO
isozeaxanthin
5a: 4R,4'S 51%
OBz
OBz
5b: 4S,4'S
18%
OBz
OBz
5c: 4R,4'R
4
O
S
BzO
BzO
OBz
6
6%
BzO
In a similar way sulphur-containing amino acids can be coupled to carotenoids in good yields. With
N-acetylcysteine as a nucleophile the products obtained are carotenoid-cysteine conjugates in which
the amino acid moiety binds the carotenoid via sulphur (compound 7, Figure 2). The water-dispersibility
of the products can be increased by deprotection of the amino group to obtain compounds like 8 [41].
Figure 2. Cysteine conjugates of carotenoids.
5. PEGylated Carotenoids
Polyethyleneglycol (PEG) conjugates of a wide range of biomolecules (especially peptides) are
known [42,43], however, no covalently-bound PEG-carotenoid conjugates have been synthesized
before. The hydrophilic PEG conjugates usually have better pharmacokinetic behaviour and, in
general, are more efficient in drug targeting. There are examples of carotenoid-PEG dispersions in the
literature which enhance the bioavailability of carotenoids [44]. PEG conjugates change the osmotic
homeostasis much less than ionic compounds (such in those mentioned in Section 2). Furthermore, the
water-solubility of PEG conjugates is independent of pH. If the PEG moiety is connected to the

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carotenoid through a relatively labile bond, which can be cleaved under physiological conditions, the
PEG will serve solely as an indifferent, polar carrier for carotenoids.
Carotenoid-PEG esters and diesters were synthesized from several carotenoid succinates [45] with
polyethyleneglycols of different chain length [tetraethyleneglycol (TEG), octaethyleneglycol (OEG),
PEG-550 monomethyl ether (mPEG-550), Scheme 2] [46]. The same way carotenoid dimers and trimers
that have a PEG spacer between the carotenoids were synthetized in good yields (Scheme 3) [47].
Scheme 2. Synthesis of TEG- and OEG conjugates from mono- and disuccinates (Car = Carotenoid).
Scheme 3. Trimers with OEG spacer.

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The water dispersibility of the products was compared and found, as expected, to be proportional
with the PEG content of the conjugates. Although the conjugation via ester bond makes these
compounds susceptible to hydrolysis (e.g., by pancreatic secretions), it might as well be an advantage
that they are regenerated to the parent hydroxy-carotenoids under physiological conditions.
Preliminary studies showed elevated antioxidant activity of some PEG-carotenoid ester conjugates
(Scheme 2) in H2O2 induced oxidative stress.
Recently, we introduced azide-alkyne click chemistry to the field of carotenoid synthesis. After
optimization of the reaction conditions, PEG azides could be coupled to carotenoid derivatives bearing
an alkyne moiety [48]. This method seems to work well with carotenoids (Scheme 4), so it could be
used in the future to synthesize not only carotenoid-PEG conjugates but conjugates with other,
bioactive molecules.
Scheme 4. Synthesis of carotenoid-PEG conjugates via click-reaction.
6. Conclusions
Intensive research into hydrophilic carotenoid formulations of any kind commenced less than 15
years ago. In the past few years some attempts were made to make the carotenoids water dispersible
via derivatization. As the example of Cardax shows, water-dispersible carotenoids can be more
effective antioxidants and can display new properties in comparision with the parent carotenoids.
Although some physiological and antioxidant studies were made on almost all of the compounds of
this review, there is still a long way to go until the understanding of the action of hydrophilic
carotenoids in contrast to native carotenoids.
Acknowledgements
The authors would like to thank for the grants OTKA PD 77467 and OTKA K 83898 (Hungarian
National Research Foundation) and SROP-4.2.2/B-10/1-2010-0029, Supporting Scientific Training of
Talented Youth at the University of Pécs.

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Sample Availability: Samples of the compounds 5-24 are available from the authors.
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