**1. Introduction**

In the human body, the skin is the outermost and largest organ with three basic functions, i.e*.* protecting from various stresses and hazards, regulating some physiological aspects, and sensing any conditional changes in the environment. While conducting its functions, the skin works with other internal systems and forms a rigid network with nervous, immune, and endocrine systems [1]. On the other hand, the skin also interacts with the environment around [2] such as microorganisms living on the skin surface [3] to maintain the function of the human body. Any imbalances between these factors often lead to various multifactorial skin disorders [4]. Based on their main cause, skin disorders can be classified into six groups including tumor and cancer, trauma, pigmentation disorders, microbial (viral, bacterial, fungal, and parasitic) infections, rashes, and miscellaneous conditions [5]. Therefore, treatment of skin disorders requires systematic attention in the medical field.

The treatment of skin disorders is usually conducted in topical, systematic, or combinatorial modes using bioactive compounds to relieve any formed defects in nervous, immune, and endocrine systems. Various bioactive compounds have been evaluated through a long clinical assay [6]. In the development process of these compounds, many parameters should be considered such as economical aspect, bioavailability, stability, toxicity, and metabolism of drug molecules in both topical and systematic therapies [7].

Chalcone is a class of organic compounds with 1,3-diaryl-2-propen-1-one (**Figure 1**) as the backbone structure that is obtained either through an isolation and purification process from natural samples [8], semisynthesis process from existing natural products [9], or total synthesis process [10]. Chalcone is considered

**Figure 1.** *Backbone structure of chalcones.*

as privileged scaffold since it exhibits broad biological activities [10]. Many pieces of study have used chalcone as a lead compound to find more potent drugs for diseases due to the ease and convenience in synthesizing and functionalizing chalcone structure. In treating skin disorders, the efficacy of chalcone derivatives is related to several biological activities including antioxidant [11], anti-inflammation [12], immunomodulation [13], anti-angiogenesis [14], antimicrobial [15], and enzyme modulator [16]. The usage of chalcone derivatives in dermatology has been developed over the past several years to obtain the most active ingredient in either for maintaining skin health or treating skin disorders. Licochalcone A, isoliquiritigenin, and xanthohumol are examples of well-known chalcone derivatives with low toxicity and side effects on treating skin disorders and disease. In this chapter, these applications are described and discussed to provide a broad and comprehensive perspective regarding the role of chalcones in the dermatology field.

#### **2. Dangerous impacts of ultraviolet irradiation**

The ultraviolet (UV) light is the electromagnetic radiation with a wavelength range from 200 to 400 nm. In general, based on the wavelength range, UV radiation is divided into four regions including UVC, UVB, UVA2, and UVA1 at 200–280, 280–320, 320–340, and 340–400 nm, respectively. This hazardous radiation causes various acute and chronic negative effects on the human skin. Clinical manifestations that occur usually depend on the wavelength and intensity of UV radiation, part of the body exposed, and type of skin (based on Fitzpatrick's classification of skin). Acute effects of UV radiations, in general, involve various forms of inflammations such as erythema, local immunosuppression, phototanning, and epidermis thickening [17]. Mechanistically, acute effects are initiated by suitable interactions between several chromophores (either on the epidermis or dermis layers) and UV irradiation [18]. These interactions trigger the structural changes that modulate various biochemical and immunological processes [19] such as releasing several pro-inflammatory cytokines, damaging various cell biomolecules [20], generating various reactive oxygen species (ROS) [21], and producing several inflammatory mediators such as prostaglandins, histamine, and leukotrienes [22, 23]. Meanwhile, chronic effects usually lead to photoadaptation or photoprotection effects through the formation of photoaging, immunosuppression, and photocarcinogenesis [17].

#### **2.1 Chalcones as sunscreen active ingredients**

Chalcone has been found as one of the bioactive compounds that is able to reduce negative effects from UV radiation such as hesperidin methyl chalcone, licochalcone A, etc. Chalcones as antioxidant and anti-inflammatory agents are

#### *Chalcones in Dermatology DOI: http://dx.doi.org/10.5772/intechopen.91145*

used in topical or systemic methods, while the sunscreen agent is used in topical applications. In general, the sunscreen activity of chalcones is generated by high UV absorbance on the UVB-UVA region [24], which corresponds to n → π\* and π → π\* electronic transition from HOMO to LUMO energy levels in chalcones' conjugated electronic system. The absorbance region of chalcones can be shifted by introducing electron-donor substituents (bathochromic shift) or electron-withdrawing substituents (hypsochromic shift) in both of the chalcone aromatic rings. However, the effects of these groups are more significant if present in A ring compared to B ring [25].

The main problem in using chalcone derivatives as sunscreen active compound is relatively poor photostability and transformations into various by-products [26–28]. Several reports have investigated the utilization of chalcone derivatives as sunscreen active compounds and also prepared sunscreen formulations with high compatibility on the skin. However, the photostability of chalcone derivatives used has not been evaluated yet [25, 26].

### **2.2 Chalcones as photoprotective agents**

Several chalcones exhibit strong protection on UV-induced deleterious effects such as *trans*-chalcone, butein, monspermoside, licochalcone A, phloretin, and hesperidin derivatives. Unsubstituted *trans*-chalcones showed a potential activity in reducing inflammation effect and oxidative stress in mice [27, 28]. A formulation containing 1% unsubstituted *trans*-chalcone has been applied to protect the skin from UVB radiation by inhibiting inflammation through reducing tumor necrosis factor alpha (TNF-α) levels and improving antioxidant and detoxification systems through enhancing heme oxygenase 1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) messenger ribonucleic acid (mRNA) expressions [28]. Systemic administration of *trans*-chalcone could inhibit UVB-induced skin inflammation and prevented oxidative stress by targeting nicotinamide adenine dinucleotide phosphate H (NADPH) oxidase and cytokine production [27]. Butein and monspermoside compounds were also used as photostabilizer for UVA-absorbing compounds such as dibenzoylmethane [29].

Licochalcone A, isolated from *Glycyrrhiza inflata*, is the most well-studied chalcone derivative related to its activity as UV photoprotector. Either in vitro or in vivo studies showed that licochalcone A had a strong protective effect against UVB-induced oxidative stress and inflammation. Licochalcone A attenuated UVBinduced inflammation by inhibiting prostaglandin E2 (PGE2), cyclooxygenase (COX-2), lipoxygenase, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and Nrf2 [30–32], while in vivo assay showed that topical formulation containing licochalcone A caused a significant reduction in UV-induced erythema, irritation, and oxidative process in the skin [31–33].

Similar to their flavanone analog, hesperidin [34], hesperidin methyl chalcone, and hydrolyzed methylhesperidin compounds as semisynthetic products also exhibit high UV protective effect. Topical and systematic administration of hesperidin methyl chalcone in hairless mice inhibited UVB-induced oxidative stress by reducing free radicals and ROS, enhanced endogenous antioxidant systems, and inhibited inflammation by reducing the production of cytokines [35]. The hydrolysis product of methylhesperidin, 4′,6′-dihydroxy-3,4,2′-trimethoxychalcone and 4′-hydroxy-3,4,2′,6′-tetramethoxychalcone compounds, also induced cytoprotective gene expression and reduced oxidative stress by promoting Nrf2 nuclear translocation and antioxidant response element (ARE) luciferase activity in UVBirradiated keratinocytes [36].

Phloretin is a natural dihydrochalcone that exhibited a strong inhibition of several matrix metalloproteinases. The isolated 3-hydroxyphloretin and phloretin from *Malus doumeri* var. *formosana* showed high inhibition of MMP-1 production in fibroblast cells [37]. A combination of phloretin, ferulic acid, and vitamin C as antioxidants had a high protective effect on UV damage in the human skin by preventing erythema formation and inhibiting MMP-9 and thymine dimerization reaction. In this case, phloretin acted as an antioxidant and synergized with other antioxidants by stabilizing and enhancing the bioavailability of ferulic acid and vitamin C in the skin [38].

### **3. Pigmentation disorders**

Melanogenesis is a complex process of production and distribution of melanin by melanocytes. In this process, melanins (in form of eumelanin, pheomelanin, or trichochrome) are synthesized and stored in melanosomes (an organelle in melanocytes) and then transported to nearby keratinocytes to act as photoprotector in the skin and lead to chronic pigmentations [39]. The synthesis of melanin involves several reaction steps and is catalyzed by phenylalanine hydroxylase (PAH), tyrosinase (TYR), tyrosine hydroxylase isoform I (THI), tyrosinaserelated protein 1 (TRYP1), and tyrosinase-related protein 2 (TRYP2) [40] enzymes. The rate-determining step of this process is hydroxylation of L-tyrosine to L-dopaquinone catalyzed by tyrosinase enzyme [41]. The final products of this process include black-brown eumelanin, yellow-reddish brown pheomelanin, and trichochrome [42].

There are many internal (endocrine, immune, inflammatory, and central nervous systems) and external (ultraviolet radiation and drugs) factors that affect the melanogenesis process [41]. Any disruptions from these factors will cause different types of pigmentation disorders including various skin conditions with strange melanocyte density, melanin concentration, or both that change pigmentations in the skin [43]. In general, pigmentation disorders can be divided into two main groups including hyperpigmentation and hypopigmentation that related to the amount of changes of normal melanin pigmentation, respectively. Both of these groups include several diseases with different clinical manifestations, but the most common forms of these are melasma (hyperpigmentations) and vitiligo (hypopigmentations) [42, 43].

#### **3.1 Melasma**

Melasma is a multifactorial skin disease indicated by the presence of symmetrical hyperpigmented area in a certain part of the face including centrofacial, malar, and mandibular parts. This disease is affected by UV, visible, and infrared exposure, by inducing reactive oxygen species and promoting melanogenesis [44], hormonal conditions [45], and genetics [46]. Chalcone derivatives are extensively used in medical therapy as photoprotective described in Sections 2.1 and 2.2, and hypopigmenting agents. Various studies showed that either natural or synthetic chalcones exhibited strong activity in inhibiting cellular tyrosinase and reducing cellular melanin formation [47]. However, the action mode of chalcone derivatives in this study is unknown since most of these studies used mushroom tyrosinase that is different from human tyrosinase [48]. Other studies conducted by Kim and coworkers showed similar results with additional parameters. In these studies, chalcones containing cyclohexylmethoxy group not only attenuated cellular melanin production and tyrosinase activity, but also reduced the expressions of

#### *Chalcones in Dermatology DOI: http://dx.doi.org/10.5772/intechopen.91145*

several melanogenesis-related genes (transcriptional activity of tyrosinase and microphthalmia-associated transcription factor/MITF) and proteins (TRP1, TRP2, and MITF) [49, 50].

**Table 1** shows several in vitro assays that use Murine B16 melanoma cell lines (B16F10), melanoma cells, and human melanocyte (G361) cells in determining chalcone derivatives' efficacy for hypopigmenting agent. In vivo studies also showed that licochalcone A and isoliquiritigenin-containing licorice extract cream can improve melasma and increase skin brightness [51]. Loading the licorice extract into solid lipid nanoparticles has been formulated and applied in a clinical trial for melisma [52].
