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In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/methods Page 1 of 9 Analytical Methods 1 2 Analytical Methods RSC Publishing 3 4 5 MINIREVIEW 6 7 8 Cite this: DOI: 9 Caffeic Acid: a review of its potential use for 10 11 medications and cosmetics 12 Received a a a a 13 Accepted C. Magnani, V.L.B. Isaac, M.A. Correa and H.R.N. Salgado 14 DOI: 15 Besides powerful antioxidant activity, increasing collagen production and prevent premature 16 www.rsc.org/ aging, caffeic acid has demonstrated antimicrobial activity and may be promising in the 17 treatment of dermal diseases. The relevance of this study is based on the use of caffeic acid 18 increasingly common in humans. Thus, studies that demonstrate and clarify the functions of 19 this substance are very important. 20 21 Manuscript 22 Introduction 23 24 Characteristics of caffeic acid 25 26 Phenolic compounds occur universally in the plant kingdom 27 and are part of a large and complex group of organic 28 substances. Higher plants synthesize and accumulate a wide 29 variety of phenolic compounds, which confer protection against the attacks of free radicals, which are by products from the 30 1 process of photosynthesis and against tissue injuries. The Fig. 2 Chemical structure of the main cinnamic acids. Cinnamic 31 phenolic compounds can be classified into two groups: group of Accepted acid R1 = R2 = R3 = R4 = H, o-coumaric acid: R2 = OH, p- 32 simple phenolic compounds and group of polyphenolic 33 compounds which can be observed through the frame shown in coumaric acid: R3 = OH; caffeic acid: R2 = R3 = OH; ferulic 34 Figure 1. 2,3 acid: R2 = OCH3 and R3 = OH. 35 36 Phenolic Compounds Modern consumers increasingly demand products and foods 37 with high quality. Cosmetics may not have as many health 38 implications as pharmaceutical products or food, but they are 39 polyphenols simple chemical products that people use daily and apply on skin, hair, phenolics 4 40 nails and even teeth or mouth. Allied to this, legislation is Methods 41 increasingly strict about quality and safety, which has 5 42 tannins flavonoids phenolic coumarins challenged the industries. For this reason, natural antimicrobial 43 acids compounds, such as polyphenols 6 are being widely used. 44 Caffeic acid (3,4-dihydroxycinnamic) is one of the hydroxy- 45 cinnamate and phenylpropanoids metabolites more widely 46 hydroxybenzoic hydroxycinnamic distributed in plant tissues. This polyphenol is present in many acid acid 47 food sources, including coffee drinks, blueberries, apples and 48 Fig. 1 Chemical classification of phenolic compounds. cider 7. Besides food, caffeic acid is present in several 49 medications of popular use, in the majority, based on propolis. 8 50 9,10 Cinnamic acid derivatives, also called phenylpropanoids are Besides acting as a carcinogenic inhibitor , is also known as Analytical 51 nine carbon structures (Figure 2). Caffeic acid (3,4- an antioxidant and antibacterial in vitro, and can contribute to 52 dihydroxycinnamic) is representative of this group. the prevention of atherosclerosis and other cardiovascular 53 11-13 a UNESP - Universidade Estadual Paulista, Faculdade de Ciências diseases . 54 55 Farmacêuticas, Departamento de Fármacos e Medicamentos– . 56 Araraquara, SP, Brasil 57 58 59 60 This journal is © The Royal Society of Chemistry 2013 Anal. Methods , 2013, 00 , 1-3 | 1 Analytical Methods Page 2 of 9 ARTICLE Journal Name 1 Antioxidant Activity derived from both normal metabolic processes and essential 2 metabolic processes to the body (endogenous), and they can be 3 4 Antioxidants are compounds that act by inhibiting or derived from exposure to environmental factors (exogenous) 5 reducing the effects triggered by free radicals and oxidizing such as pollution, radiation, pesticides tobacco, among others. compounds. 14 Free radicals can cause beneficial or deleterious effects to 6 28-30 7 The phenolic antioxidants act as free radical scavengers and health. 8 sometimes as metal chelators. They act both in the initiation The importance of reactive oxygen species (ROS) and free 9 step such as on the propagation of the oxidative process. The radicals has attracted increasing attention over the last decade. 10 products are relatively stable due to the resonance of the ROS, which include free radicals such as superoxide anion •- • 11 aromatic ring shown by these substances. The phenolic acids radicals (O 2 ), hydroxyl radicals (OH ) and reactive oxygen 12 are characterized by the presence of a benzene ring, a species such as H 2O2 and singlet oxygen (1O 2). These 13 carboxylic acid grouping and one or more hydroxyl or methoxy molecules exacerbate factors of cell damage and aging. 31,32 14 groups of the molecule, which confers antioxidant properties. 15 ROS are continuously produced during normal physiologic 15 The phenylpropanoids act as antioxidants by eliminating events and they can easily initiate the peroxidation of 16 oxygen free radicals 16,17 and chelating pro-oxidant metal ions, membrane lipids, leading to the accumulation of lipid 17 especially iron. 18,19 The hydroxyl groups of these molecules peroxides. 33,34 However antioxidants cells have developed 18 confer antioxidant activity, but they are not the only factors in mechanisms to protect themselves from free radical toxicity. 19 determining the potency of their activities. There is a single The agents considered antioxidants include: catalytic enzymes 20 hydroxyl group para -substituted in an aromatic ring that is that remove radicals such as superoxide dismutase (SOD); 21 linked to a side chain conjugate in the case of ferulic acid. This proteins which minimizes the availability of pro-oxidants, such Manuscript 22 substitution allows the phenoxy radical free electrons to as iron ions and copper ions, for example, transferrins, ferritins, 23 become delocalized over the entire molecule, and therefore metallothionein and haptoglobines; low molecular weight 24 stable. 20 The ortho substitution to the methoxy group, an molecules that have the ability to capture reactive oxygen 25 electron donor, is also a contributing factor to the stability of species through autoxidation such as, for example, those with 26 the phenoxy radical and thus increases the efficiency glutathione and thiol group (SH) or vitamins such as α- 27 antioxidant. 21,22 The presence of a second hydroxyl group in the tocopherol, ascorbic acid and β-carotene. 35,36 28 ortho position, besides the para position is known to increase When there is an imbalance between pro and antioxidant 29 the antioxidant activity due to a additional resonance system, with a predominance of oxidants, the oxidative stress 30 stabilization and formation of o-quinone (Figure 3). 20,21,23 This occurs 37,38 . This stress can be associated with damage to lipids, 31 characteristic can be used to explain the fact that the efficiency proteins and gens and it imply a great variety of human diseases Accepted 32 of antioxidants such as caffeic acid is greater than that of ferulic as well as in the aging process. 39 33 acid. The free radicals also act on the skin tissue, which originate 34 mainly by exogenous actions, such as ultraviolet radiation. 35 Depending on the dose, exposure time, wavelength and area 36 exposed, the ultraviolet radiation can cause skin burns, 37 premature skin aging and even skin cell DNA damage and skin 38 cancer. 40,41 39 Thus, the natural aging of the skin associated with the 40 Methods 41 action of free radicals causes a reduction in skin hydration, 42 pigmentation, fine wrinkles, signals from sagging and increased Fig. 3 Chemical structure of caffeic acid and formation of ortho - possibility of the occurrence of neoplasm diseases. Another 43 quinone. 44 change is the reduction of dermal collagen that makes the skin 45 Caffeic acid has been shown to be a α-tocopherol protective thinner. These changes are even more evident after menopause, 46 in low-density lipoprotein (LDL). 24 Furthermore, their in which there is a rapid decrease in the levels of collagen in 47 combination with other products, such as with chlorogenic and skin and bone, suggesting that estrogen influences the collagen 42 48 caftaric acids showed more potent antioxidant activity in a synthesis in the skin as much bone mass. 49 variety of different systems. 17,25 In order to maintain the skin healthier and younger-looking, 50 Natural phenolic antioxidants including caffeic and ferulic thereby mitigating the effects of aging, more strategies have Analytical 51 acids, gained remarkable attention as promising photoprotective been suggested. 30 The use of natural or synthetic antioxidants in 52 agents 26,27 and also have been present in skin care products for foods, cosmetics, beverages and also medicine is one of the 53 its antioxidant activity. However the literature shows little defence mechanisms against free radicals.43-45 54 evidence about the usefulness of hydroxycinnamic acids to Photoaging of the skin is one of the most common 55 protect the skin from photo-oxidative damage.