Chiral Bioactive Molecules in Cosmetics: Advantages and Opportunities

Abstract

Continuous exposure to environmental stressors necessitates the development of novel, effective, and safe cosmetic active ingredients to preserve the skin’s structural integrity and physiological function. In this context, chiral cosmetic actives have emerged as particularly promising candidates owing to their diverse skincare properties. Notably, stereochemistry can markedly influence biological activity, producing enantiomer- or diastereomer-specific differences in efficacy and safety. Herein, we summarize recent advances in the application of chiral bioactive molecules as cosmetic actives, organizing them according to biological activity. We provide a comprehensive discussion of their mechanistic biological activities, the activity differences arising from distinct stereochemical configurations, current limitations, and future prospects.

1. Introduction

The skin, which constitutes the largest organ of the human body, performs a diverse array of vital functions, including protection, thermoregulation, sensory perception, and metabolic processes [1]. However, the skin is continuously exposed to environmental stressors, notably ultraviolet radiation and pollution, leading to oxidative stress, thereby accelerating cutaneous aging and manifesting as wrinkles, reduced elasticity, and hyperpigmentation [2]. If the primary barrier is compromised, the host becomes increasingly susceptible to infection. Consequently, maintaining the skin’s structural integrity and physiological function is essential. To address these challenges, the pursuit of novel, effective, and safe cosmetic active ingredients is highly desirable.

Chiral bioactive molecules are prevalent in cosmetics, pharmaceutical, food, and agricultural industries owing to their distinctive biological functions [3]. In recent years, chiral cosmetic active ingredients have garnered significant research interest owing to their diverse skincare effects, such as anti-melanogenic, anti-aging, antioxidant, anti-inflammatory, and moisturizing activities. Bioactivity relies on molecular recognition by target proteins, which makes stereochemical configuration of a molecule’s chiral centers is of extreme importance on its biological activity [4]. Consequently, enantiomers of the same compound can exhibit markedly different biological activities. This review provides an overview of the current applications and future prospects of chiral bioactive molecules in cosmetic science, with a special focus on differences in biological activity among stereoisomers of the same compound.

2. Anti-Melanogenic Molecules

Melanogenesis refers to the synthesis and distribution of melanin within melanocytes. It is essential for determining the color of skin, hair, and eyes and for protecting the skin from ultraviolet radiation [5]. However, the overproduction of melanin can lead to hyperpigmentation (spots and freckles) and may increase the risk of skin cancer. Therefore, identifying effective and safe anti-melanogenic agents remains a key but challenging objective in the development of skin-whitening products.

Several chiral bioactive molecules, including arbutin, glabridin, and glutathione (referring to β-arbutin, R-glabridin, and D-glutathione), have been incorporated into cosmetic formulations for skin-whitening purposes [6]. Arbutin is a natural glycoside found in plants such as wheat, pear, and bearberry. α-Arbutin is the α-anomeric glycoside isomer of β-arbutin and is typically produced via biotechnological methods. Studies have reported that α-arbutin is more than ten times as effective as β-arbutin in the inhibition of tyrosinase [7]. However, the two anomers display differential cytotoxicity in MCF-7 cells: at low concentrations, α-arbutin appears to be more toxic than β-arbutin [8]. To date, no studies have identified enantioselective differences in the bioactivity of glabridin or glutathione. Nevertheless, nitrosated L-glutathione, synthesized by solid-phase peptide synthesis, is approximately threefold more potent than nitrosated D-glutathione in eliciting relaxation of phenylephrine-induced vascular tone [9].

Plant-derived extracts have recently attracted considerable attention for their anti-melanogenic potential. For example, L-theanine, a natural amino acid present in green tea leaves, has demonstrated anti-melanogenic effects by reducing the intracellular tyrosinase activity of B16F10 murine melanoma cells and by attenuating the expression of melanogenesis-related proteins [5]. D-theanine, prepared from D-pyroglutamic acid and ethylamine, displays a distinct pharmacokinetic profile: studies indicate that L-Theanine undergoes preferential renal reabsorption and metabolism, whereas D-theanine is more rapidly excreted [10]. Additionally, stewartianol and stewartianol-3-O-glucoside, which feature a chiral secondary alcohol and an O-glucoside moiety, respectively, were isolated from Stewartia pseudocamellia and have been shown to inhibit melanogenesis in murine B16 melanoma cells more effectively than arbutin [11]. Apart from naturally extracted chiral molecules, synthetically derived chiral compounds also show promise as effective cosmetic ingredients. For example, N-carbamylglutamate (NCG), an analogue of N-acetylglutamate, has demonstrated multifunctional activities: (1) it exerts an anti-melanogenic effect by reducing melanin production and the expression of melanogenesis-related factors; (2) it markedly decreases UV-induced reactive oxygen species, indicating potent antioxidant activity; (3) it inhibits matrix metalloproteinase activity, thereby preserving collagen integrity and attenuating wrinkle formation; and (4) it suppresses nitric oxide production and downregulates key inflammatory mediators. These findings indicate that NCG is a promising multifunctional cosmetic ingredient with anti-melanogenic, antioxidant, anti-aging, and anti-inflammatory properties [12]. However, the stereoisomeric forms of stewartianol and N-carbamylglutamate have not been reported.

3. Antioxidant Molecules

Skin aging is the most conspicuous manifestation of bodily senescence, characterized by a rough texture, pronounced loss of elasticity, and the development of coarse wrinkles [13]. In this context, oxidative damage from reactive oxygen species generated during cellular metabolism is a principal contributor to accelerated aging [13]. Consequently, the identification of effective antioxidant agents to prevent or mitigate cutaneous aging is both essential and of considerable interest. Natural chiral molecules, including arbutin, ergothioneine (L form), vitamin C (L form), vitamin E, and astaxanthin have been incorporated into cosmetic formulations for anti-aging purposes. For example, arbutin can lower intracellular ROS by directly scavenging free radicals and enhance cellular antioxidant capacity [6]. By contrast, the enantiomers of these natural products do not exhibit equivalent levels of biological activity, for instance, D-ergothioneine shows poor cellular uptake and negligible antioxidant activity in vivo. Similarly, D-vitamin C and 2S-stereoisomers of vitamin E (S configuration at the pyran ring) is rapidly metabolized and excreted, whereas L-vitamin C and 2R-stereoisomers of vitamin E persist for several days [14,15,16]. In addition, studies showed that S-astaxanthin has a higher affinity for cluster of differentiation 36 (CD36), and exhibits superior absorption and permeability compared with R-astaxanthin [17]. Pro-xylane, a synthetic derivative of xylose, has been widely incorporated into anti-aging cosmetic formulations [18]. Importantly, the β-C-glycosidic linkage is essential to retain activity compared with the α-C-glycosidic isomer. Furthermore, the stereochemistry of the hydroxyl group in the aglycone affects activity, with the S-configuration showing superior performance.

Flavonoids are phenolic compounds isolated from a wide array of vascular plants, many of which possess chiral architectures—for example, Silymarin, Salidroside and Liquiritigenin [19,20,21]. Numerous studies have shown that these molecules exhibit diverse biological activities, including antioxidant, anti-inflammatory, and anti-allergic effects. Silymarin with the 2R, 3R, 10S, 11S stereochemical configuration exhibited a tenfold increase in oral bioavailability and was more readily absorbed than the 2R, 3R, 10R, 11R configuration [22]. R-liquiritigenin had approximately threefold higher bioavailability than S-liquiritigenin [23]. Furthermore, studies have indicated that synthetically derived amino-acid derivatives and peptides hold promise as antioxidant and anti-aging agents [24,25,26]. However, no reports have described the stereoisomeric forms of salidroside or of the aforementioned synthetically derived amino-acid derivatives and peptides.

4. Anti-Inflammatory Molecules

Anti-inflammatory cosmetic active ingredients are widely employed owing to their capacity to mitigate cutaneous inflammation, calm skin hypersensitivity, and facilitate epidermal repair [27]. As noted above, chiral natural products bearing a flavan scaffold have been reported to exhibit broad anti-inflammatory activity [20]. Moreover, synthetically derived chiral flavan analogues have demonstrated potential as inflammation inhibitors [28]. Notably, enantioenriched flavanols consistently exhibit greater inhibition of IL-1β secretion than their corresponding enantiomers and racemic mixtures, indicating that chirality plays an important role in target recognition by these bioactive molecules [28]. (−)-α-Bisabolol, an unsaturated monocyclic sesquiterpene chiral alcohol predominantly extracted from chamomile, is a widely used anti-inflammatory active ingredient [29]. The ED₅₀ of (+)-epi-α-bisabolol was lower than that of racemic α-bisabolol, indicating greater cicatrizant activity; however, (+)-epi-α-bisabolol also exhibited increased cytotoxicity against 3T3 mouse fibroblasts [30]. (+)-Ectoine, a chiral cyclic amino-acid derivative produced by halophilic bacteria, has been shown to increase skin hydration, improve barrier function, and attenuate inflammation, thereby alleviating the symptoms of atopic dermatitis, underscoring its anti-inflammatory and moisturizing properties [31]. (±)-Ectoine was prepared in a six-step synthesis. However, comparative studies of its biological activity have not yet been reported [32]. Furthermore, studies have indicated that synthetically derived amino-acid derivatives [33], chiral spirocyclic scaffolds [34], and pyrazolo-isoquinoline derivatives [27] possess anti-inflammatory activities; however, comparative activity data for their stereoisomers are lacking.

5. Molecules with Moisturizing Effects

An adequate level of skin hydration is essential for preserving epidermal barrier function and supporting the normal physiological activities of skin tissues, a role largely attributable to the structure of the stratum corneum, the outermost epidermal layer [35]. Ceramides, the principal lipid constituents of the stratum corneum, play a critical role in maintaining skin hydration and barrier integrity [36,37]. All four stereoisomers of sphingosine were efficiently prepared by solid-phase activated resin ester and further converted into distinct chiral ceramides. Biological evaluation revealed that stereochemistry caused up to a tenfold difference in inhibitory activity against sphingomyelin synthase [38]. In addition, chiral compounds such as amino acids and polysaccharides have demonstrated moisturizing effects, examples include arginine and hyaluronic acid. Arginine has been shown to increase skin urea content in patients with atopic dermatitis and in elderly skin, thereby helping the stratum corneum retain moisture [35]. Despite these findings, stereoisomer-specific comparative activity data for arginine and hyaluronic acid are absent.

6. Conclusions and Outlook

In summary, various chiral bioactive molecules have been demonstrated to exhibit skincare benefits, encompassing anti-melanogenic, anti-aging, antioxidant, anti-inflammatory and moisturizing activities. In particular, a wide range of chiral structures derived from peptides, glycosides, amino acids, and dihydroflavonoids have attracted considerable attention due to their multifaceted skincare effects. Compounds such as arbutin, pro-xylane, hyaluronic acid, and ceramide have already been widely incorporated into commercial cosmetic formulations, underscoring the promising potential of chiral bioactive molecules in the cosmetic field. Importantly, numerous examples—including arbutin, theanine, ergothioneine, vitamin C, vitamin E, astaxanthin, Pro-xylane, silymarin, liquiritigenin, flavanols, α-bisabolol, ceramides—demonstrate that stereoisomers of the same compound often exhibit significantly different biological activities, underscoring the critical role of chirality in biological function.

Despite these achievements, limitations and challenges remain regarding their further application in human skin. Although preliminary activity studies of some compounds in cell-based models have provided valuable insights, critical formulation aspects such as safety, stability, enantiomeric purity and skin permeation still require urgent evaluation. In addition, activity differences between stereoisomers of certain chiral compounds remain unstudied. On the other hand, predicting skincare activities in silico from chemical structures can substantially reduce the time and resources required to screen cosmetic active ingredients. Consequently, concerted efforts to elucidate the structure–property relationships of chiral bioactive molecules are essential to guide the rational screening and synthesis of more effective cosmetic actives. We expect that significant progress in this field will be achieved in the near future through the expanded application of chiral bioactive molecules in cosmetic formulations.