Introduction of Canthaxanthin
Canthaxanthin, a prominent member of the carotenoid family, has garnered attention for its vibrant red-orange hue and diverse applications in various industries. This naturally occurring pigment is found in certain plants, algae, and bacteria, but it is also synthesized chemically for commercial purposes.
Canthaxanthin's structural intricacies and isomerism contribute to its diverse properties. Structurally, carotenoids follow a geometric pattern, connected by a double bond, forming either the E or Z form. Isomers exhibit variations in melting points, stability, solubility, absorption affinity, color, and color intensity. A canthaxanthin molecule, composed of a 40-carbon polyene chain with double bonds and terminal hydroxyls, features an extended double-bond system centrally. Modification through processes like cyclization, rearrangement, and dehydrogenation generates diverse structures. The β-rings form dihedral angles, and keto groups are approximately 2.7 nm apart.
Canthaxanthin's solubility in water, lipids, or organic solvent-water mixtures allows molecular aggregation. In nature, various isomers, including all-trans-canthaxanthin, 9-cis, and 13-cis, exist. HPLC separates and quantifies isomers, while HPLC-APCI-MS confirms canthaxanthin presence. Isomerization, influenced by temperature, acid, and ions, is crucial. High temperature and light induce carotenoid isomerization, altering their functions. Separation of 13 canthaxanthin isomers, and identification through 1H-NMR, reveals unique properties. Modern methods employ C30 and Si60-HPLC-APCI-MS with DAD for efficient separation, identifying isomers like 9,13'-di-cis and 15-cis-canthaxanthin. Proapoptotic activity varies among isomers, with 9-cis-canthaxanthin exhibiting higher activity. Advances in analytical techniques continue to enhance our understanding of canthaxanthin's structural complexity and functional diversity.
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Chemical Synthesis of Canthaxanthin
Given the increasing demand for canthaxanthin in various industries, chemical synthesis has become a key approach for large-scale production. Several methodologies have been developed, each with its unique advantages and challenges.
One notable chemical synthesis method involves the Wittig olefination, where 6-oxo-isophorone is transformed into a key intermediate, C15-Wittig salt. The subsequent steps include a double Wittig olefination to produce Z/E-canthaxanthin, with the isomers separated by crystallization. However, challenges arise, such as the formation of by-products like triphenylphosphine oxide, making the process atom-inefficient and separation difficult.
An alternative route utilizes sulfone intermediates, circumventing the need for triphenylphosphine. This approach involves a coupling reaction, allylic oxidation, Ramberg-Bäcklund reaction, and dehydrosulfonation to yield canthaxanthin. Though it addresses some challenges of the Wittig olefination, each synthetic route has its intricacies and considerations.
Fig. 1 Scheme of the synthesis of canthaxanthin (Rebelo B. A., et al. 2020).
Recent advancements have introduced a novel route for total canthaxanthin synthesis, involving epoxidation, condensation, and oxidation reactions. This method, proposed by Pi et al., demonstrates the continuous evolution in synthetic strategies, aiming for improved efficiency and reduced by-products.
Biosynthesis of Canthaxanthin
Addressing environmental concerns and health-related issues linked to synthetic carotenoids, the focus is shifting towards natural alternatives. Microbial synthesis offers a sustainable method for canthaxanthin production. Microorganisms like Chlorella zofingiensis and Gordonia jacobea are employed, emphasizing a more eco-friendly approach. Genetic engineering of noncarotenogenic microbes like Blakeslea trispora and Saccharomyces cerevisiae enhances carotenoid production. Canthaxanthin, an isoprenoid compound, results from the conversion of isoprene compounds through a biosynthetic pathway. Enzymes such as β-carotene ketolase and β-carotene hydroxylase play pivotal roles in these conversions. High-yielding microalgae like Chlorella zofingiensis serve as excellent sources of canthaxanthin due to their well-characterized biosynthetic pathways. The biosynthesis involves the conversion of β-carotene to canthaxanthin or zeaxanthin through specific enzymatic reactions. This microbial synthesis provides a promising avenue for sustainable and health-conscious canthaxanthin production.
The Role of Canthaxanthin
Canthaxanthin plays a pivotal role in various biological processes, offering a spectrum of benefits in different realms such as antioxidant activity, lipid metabolism, cancer prevention, neuroprotection, immunomodulation, and growth enhancement in marine animals.
One of the key attributes of canthaxanthin is its potent antioxidant capabilities. Research indicates that canthaxanthin possesses anti-aging properties by scavenging free radicals, combating oxidative stress, and bolstering endogenous antioxidant defenses. The keto-carotenoid exhibits higher antioxidant and free radical scavenging capacities compared to other carotenoids, attributed to the stability provided by the conjugation of the keto group with the polyene backbone. Studies have shown that canthaxanthin acts as a robust antioxidant, reacting with phenoxyl radicals and countering photo-oxidation by dissipating energy.
The antioxidant potential of canthaxanthin has been compared to other carotenoids, and it has been found to exhibit significant radical scavenging ability. Notably, its stability and ability to stabilize carbon-centered radicals contribute to its effectiveness. Furthermore, 9-cis isomers of canthaxanthin have been identified to possess higher antioxidant activity than the all-trans form. The source of canthaxanthin, whether microbial or synthetic, can impact its antioxidant activity.
Beyond its antioxidant role, canthaxanthin influences lipid metabolism and exhibits effects on lipid membranes. It can alter the thermotropic phase transition of lipid bilayers, particularly in the gel phase, and modify the surface of lipid membranes. In terms of atherosclerosis prevention, canthaxanthin-incorporated low-density lipoprotein has demonstrated efficacy in inhibiting atherosclerosis compared to other carotenoids.
Canthaxanthin's involvement in cancer prevention is noteworthy, showing antimutagenic and anticarcinogenic effects. Studies have revealed its inhibitory action on various cancers, such as mammary cancer, melanomas, and prostate cancer cells. However, its effects on different types of cancers vary, indicating the need for further exploration.
The keto-carotenoid also exhibits partial neuroprotective activity, particularly in chemically induced rat adrenal medulla cell deaths. Its impact on the gap junction system, which plays a role in cell communication, suggests potential neuroprotective effects. Additionally, canthaxanthin has shown immunomodulatory activities by enhancing the proliferation and activity of immunocompetent cells.
In the realm of marine animal growth, canthaxanthin, when added as a dietary complement, has been associated with increased growth, survival, and improved utilization of nutrients. The addition of canthaxanthin-loaded liposomes has shown positive effects on growth aspects and canthaxanthin accumulation in rainbow trout fillets.
While canthaxanthin holds immense promise, challenges exist in its production methods, with chemical synthesis still dominating the market. The development of new transgenic strains and advancements in genetic engineering are contributing to increased canthaxanthin production, aiming for competitiveness with synthetic methods.
In conclusion, canthaxanthin emerges as a multifaceted compound with implications across diverse fields. From its role as a potent antioxidant to its influence on lipid metabolism, cancer prevention, neuroprotection, immunomodulation, and growth enhancement in marine animals, canthaxanthin's versatility underscores its significance. Further research is crucial to unravel its molecular targets, biological functions, and potential applications, paving the way for a deeper understanding of this intriguing keto-carotenoid.
References
- Esatbeyoglu T. Rimbach G. Canthaxanthin: From molecule to function. Molecular Nutrition & Food Research. 2017, 61(6): 1600469.
- Rebelo B. A., et al. Canthaxanthin, a red-hot carotenoid: Applications, synthesis, and biosynthetic evolution. Plants. 2020, 9(8): 1039.
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