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Journal of Inorganic Biochemistry
Volume 88, Issues 3–4,
February 2002
, Pages 295-304
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Abstract
Several bis-β-cyclodextrin porphyrins have been prepared as supramolecular receptors of carotenoids. The binding constants of carotenoids to receptors were determined by quenching the fluorescence of the porphyrins on hydrophobic binding of carotenoids within the cavities of cyclodextrins. Ka=8.3×106 M−1 was calculated for binding of β,β-carotene to bis-β-cyclodextrin Zn porphyrin. The corresponding Ru complex catalyzes the central cleavage of carotenoids in the presence of tert-butyl hydroperoxide in a biphasic system.
Introduction
Carotenoids, the ‘orange pigments of life’, are biosynthesized de novo in higher plants, algae, fungi and bacteria. Animals and humans, however rely on extraction from their diet [1], [2], [3]. The general significance of carotenoids to animal and human nutrition is undisputed, in particular two biological functions are well established: (i) the ability of carotenoids to quench 1O2 and (ii) its antioxidant activity depending on oxygen partial pressure [4]. Thus it seems that carotenoids are complementary to tocopherols (vitamin E) preventing lipid peroxidation by a radical chain-braking mechanism [5], [6]. The other major function of β,β-carotene 1 derives from its metabolites which are produced by oxidative cleavage providing retinal 2 (provitamin A) and retinoic acid 3. Though it has been known since 1930 that retinol 4 (vitamin A) derives in vivo from 1, the enzymatic origin of central cleavage of β,β-carotene was only shown in 1965 when Olson and Hayaishi reported the identification of in vitro activity of an enzyme from rat intestine [7]. Later an alternative pathway, the excentric cleavage of 1, was discovered yielding apocarotenals, such as 5 which are subsequently degraded to 2 [8], [9], [10], [11] (Fig. 1).
During the last 35 years many groups have tried unsuccessfully to purify the enzyme catalyzing the central cleavage of 1 and quite a number of investigations failed to provide a conclusive answer on the mechanism of this enzymatic transformation, i.e. it has been impossible to distinguish between a dioxygenase and a monooxygenase mechanism. Nevertheless the enzyme was termed β,β-carotene 15,15′-dioxygenase (EC 1.13.11.21) and was often referred to as being an iron dioxygenase. Recently, however, we have been able for the first time to identify the protein which catalyzes the central cleavage of 1 [12]. We have developed a purification protocol for the enzyme from chicken intestinal mucosa (M. Leuenberger, C. Engeloch-Jarret, W.-D. Woggon, unpublished results) and overexpressed the functional 60.3-kDa protein in Escherichia coli and BHK (baby hamster kidney) cell lines [13]. At about the same time another research group published on the expression of the enzyme derived from Drosophila melanogaster [14]. We also investigated the substrate specificity [15] and the reaction mechanism employing a non-symmetric carotenoid and highly enriched 17O2 and H218O [16]. Accordingly the enzyme is not a dioxygenase but operates by monooxygenase mechanism in which the first step is an epoxidation of the central 15,15′ double bond. The nature of the metal complex involved in O2 cleavage remains to be elucidated by X-ray (A. Wyss, U. Baumann, W.-D. Woggon, unpublished results). A metal porphyrin can be excluded with certainty because the corresponding chromophore is absent.
Parallel to our investigations of the native protein we designed and synthesized an enzyme model for the regioselective cleavage of carotenoids; details of this work are reported here.
Section snippets
General
All non-aqueous reactions were carried out under an inert argon atmosphere using flame dried glassware. Reagents were used as received from Fluka (Buchs, Switzerland) and Aldrich Chemie (Buchs, Switzerland) unless otherwise stated. Retinal 2 and apocarotenals for HPLC reference were obtained as a gift from F. Hoffman-La Roche. Solvents were dried under standard conditions and freshly distilled prior to use. Thin layer chromatography (TLC) was performed on precoated glass plates (silica gel 60 F
Results and discussion
The fact that β,β-carotene 15,15′-monooxygenase controls the regiospecific cleavage of one C=C bond out of a possible six within the substrate is an intriguing and challenging one. In order to mimic such a regioselective system the following strategy was employed: (i) synthesis of a receptor for 1 in which the binding constant, Ka, for 1 is orders of magnitude greater than that for retinal 2, in order to prevent product inhibition; (ii) introduction of a reactive metal complex which is capable
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Cited by (35)
The ‘Visualized’ macrocycles: Chemistry and application of fluorophore tagged cyclodextrins
2017, International Journal of Pharmaceutics
Citation Excerpt :
Another interesting Por-CD system in which four β-CD rings were connected through the Por moiety was investigated by Breslow et al. as artificial catalytic site for hydroxylation of inactivated carbons in steroid substrates (Breslow et al. 1996, 1997a,b; Yang et al., 2002). French et al. studied and applied Por-linked β-CD dimer for the selective cleavage of double bonds in the molecule of β,β-carotene (French et al., 2000, 2002). Thanks to the cooperative binding effect of fixed CD rings, these supramolecular enzyme mimics showed remarkable regio- and stereoselectivity and good catalytic turnovers.
Cyclodextrins are macrocyclic molecules able to form host-guest complexes due to their hydrophobic cavity. Because of their carbohydrate nature they do not absorb light in the UV–vis region (200–800nm), but they can be converted into spectroscopically active compounds via modification with a chromophore unit. Among the chromophores, the group of fluorophores can provide high sensitivity in analytical applications (chemosensing) and low detection limit in optical imaging methods (fluorescent microscopy). Fluorophore-tagged cyclodextrins therefore combine interesting spectroscopic properties with promising supramolecular features which make these conjugates widely applicable in various pharmaceutical fields. The aim of this work is to review the various types of fluorophores which have been used for cyclodextrin tagging, to discuss the synthetic strategies used for the conjugation and to summarize the pharmaceutical applications of these ‘visualized’ macrocycles including their use in photodynamic therapy. The recent achievements in studying how the fluorophore-appended cyclodextrin derivatives cross biological barriers are also reviewed.
Functionality stored in the structures of cyclodextrin-porphyrinoid systems
2015, Coordination Chemistry Reviews
Citation Excerpt :
This time, the catalytic cleavage reaction occurred only at the central double-bond and resulted in equal amounts of aldehydes 23 and 27. The results suggest that the stronger binding of an aromatic end-group stabilized the carotene-catalyst complex and prevented movements within the CD cavity [28]. Superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase are important enzymes protecting cells from oxidative stress.
The binding of cyclodextrins and porphyrinoids (including porphyrins, phthalocyanines and chlorins) is carried out by both covalent linking or inclusion complexation. Many of the resulting structures possess intrinsic biomimetic functionality. Therefore, they have been investigated as biomimetics, which imitate some biochemical processes occurring in nature, such as carotene cleavage, cytochrome P450-mediated hydroxylation, oxygen binding by hemoglobin, or as components of multichromophoric arrays in light harvesting antenna systems. Interestingly enough, cyclodextrins improve porphyrinoids photosensitizing properties by increasing the values of singlet oxygen generation quantum yield which is of immense value for applications in photodynamic therapy. Noteworthy is the great potential for medical applications, revealed recently in the construction of sophisticated systems consisting of covalently linked cyclodextrins and photosensitizers that were considered as carriers for multimodal anticancer therapy.
Cyclodextrin-[RuCl<inf>2</inf>(Arene)]<inf>2</inf> conjugates: Another way to enhance the enantioselectivity of aromatic ketones reduction by aromatic ligands' volume
2013, Tetrahedron
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In the artificial enzymes and artificial metalloenzymes based on CDs, the CDs units can function as the hydrophobic pockets in enzymes and form inclusion complex with the substrate molecule, thus the substrate molecule would be immobilized near the modifying groups of CDs, which play the role of catalytic active center. Hence, enhanced catalytic activity, obvious acceleration in reaction rate, and excellent regioselectivity can usually be achieved in the organic reaction catalyzed by the artificial enzymes and artificial metalloenzymes based on CDs, such as the cytochrome P-450 oxidase mimics reported by Breslow and co-workers,15–18 the carotene dioxygenases mimics reported by French and co-workers,19,20 the glutathione peroxidase mimics reported by Liu and Jin21–25 and the hydrolase mimics reported by Mao.26–30 However, when applied in the asymmetric organic reaction, the artificial enzymes and artificial metalloenzymes based on CDs usually could not give so satisfactory results, such as the artificial metalloenzymes in the asymmetric oxidation of thioanisole reported by Bonchio and Sakuraba,31,32 the ee just being 50–60%.
Eight amino alcohol-modified β-CDs CD-1–CD-8 have been synthesized in acceptable yields and were employed to form artificial metalloenzymes with [RuCl2(Benzene)]2 and [RuCl2(Mesitylene)]2, respectively. All the conformations of CD-1–CD-8, the complexes between CD-1–CD-8 and [RuCl2(Arene)]2, and the inclusion complexes between CD-1–CD-8 and acetophenone were characterized by UV, 1H NMR, 1H ROESY NMR, and quantum calculation. The catalytic activity of the formed artificial metalloenzymes in the asymmetric hydrogenation of aromatic ketones, especially the effect of the aromatic ligands' volume on the enantioselectivity were investigated in detail, in which it was obvious that the enantioselectivity increased as the increase in the aromatic ligands' volume. For the best artificial metalloenzyme constructed from the complex between CD-8 and [RuCl2(Mesitylene)]2, which not only exhibits a good tolerance to a wide range of substrates but also demonstrates some substrate selectivity, 76.39% ee was obtained for acetophenone and 79.67% ee for 2-acetylnaphthalene. A strategy to improve the enantioselectivity in the asymmetric reactions catalyzed by the artificial metalloenzymes based on CDs has been provided.
Biomimetic asymmetric aldol reactions catalyzed by proline derivatives attached to β-cyclodextrin in water
2012, Tetrahedron Letters
Two proline derivatives, (S)-2-aminomethylpyrrolidine and (R)-2-aminomethylpyrrolidine modified β-CD (CD-1, CD-2) were synthesized in the yields of 31% and 14%. Their self-inclusion conformations were characterized by 1H ROESY NMR studies and quantum calculation. When CD-1 was applied to asymmetric aldol reactions, up to 94% ee was obtained. Substrate selectivity was also observed in these asymmetric aldol reactions.
Amino alcohol-modified β-cyclodextrin inducing biomimetic asymmetric oxidation of thioanisole in water
2012, Carbohydrate Research
Citation Excerpt :
Their work demonstrated that metalloporphyrins possessing two or four β-CD units could oxidize and hydroxylate substrates bound in the cavity of β-CD with excellent regioselectivity in the presence of more reactive functional groups.16–21 French et al.22,23 also reported metalloporphyrins with two β-CD units mimicking the carotene dioxygenases, catalyzed the central cleavage of carotenoids in 15,15′ double bond regioselectively. The origin of these excellent regioselectivity should be attributed to that β-CD units immobilize substrates in a reactive conformation, in which reaction is directed to certain substrate atoms.
Inspired by β-CD, a macrocyclic oligomers of d-(+)-glucopyranose and a renewable material, which could be obtained from starch, that can promote a lot of organic reactions in water, a green solvent, several amino alcohol-modified β-CDs CD-1 to CD-7 were synthesized in the yields of 36–61%. Their conformations in vacuum and in aqueous solution were optimized by quantum calculation. Their complexes with sodium molybdate prepared in situ were characterized by 1H NMR and were applied in the asymmetric oxidation of thioanisole. Their performance in inducing enantioselectivity was investigated in detail. For the optimal one, CD-1, moderate enantioselectivity (56% ee) was achieved in aqueous CH3COONa–HCl buffer solution (pH 7.0). The abilities of CD-1 to CD-7 to induce asymmetry are highly dependent on the pH value of the reaction medium and the structure of the modifying group. The origin of the moderate enantioselectivity and the reaction mechanism were investigated with the aid of 1H ROESY NMR studies and quantum calculation. The moderate enantioselectivity was attributed to the two different binding models between CD-1 and thioanisole, which could be defined as intramolecular catalysis and intermolecular catalysis, in which intramolecular catalysis gave (S)-methyl phenyl sulfoxide and intermolecular catalysis gave (R,S)-methyl phenyl sulfoxide.
β-Cyclodextrin-linked Ru complexes for oxidations and reductions
2008, Advances in Inorganic Chemistry
Citation Excerpt :
Even artificial substrates such as 27 and 30, lacking one methyl group in the polyene, are cleaved at the central double bond (Fig. 11) (17). However, we observed two exceptions from the rule (18). The synthetic carotenoids 31 and 32, originally designed as inhibitors, turned out to be substrates being cleaved at the C14′–C15′ double bond (Fig. 11).
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