Naturally Occurring Cinnamic Acid Sugar Ester Derivatives

Abstract

Cinnamic acid sugar ester derivatives (CASEDs) are a class of natural product with one or several phenylacrylic moieties linked with the non-anomeric carbon of a glycosyl skeleton part through ester bonds. Their notable anti-depressant and brains protective activities have made them a topic of great interest over the past several decades. In particular the compound 3 ,6-disinapoylsucrose, the index component of Yuanzhi (a well-known Traditional Chinese Medicine or TCM), presents antidepressant effects at a molecular level, and has become a hotspot of research on new lead drug compounds. Several other similar cinnamic acid sugar ester derivatives are reported in traditional medicine as compounds to calm the nerves and display anti-depression and neuroprotective activity. Interestingly, more than one third of CASEDs are distributed in the family Polygalaceae. This overview discusses the isolation of cinnamic acid sugar ester derivatives from plants, together with a systematic discussion of their distribution, chemical structures and properties and pharmacological activities, with the hope of providing references for natural product researchers and draw attention to these interesting compounds.

Cinnamic Acid Conjugates in the Rescuing and Repurposing of Classical Antimalarial Drugs

“…Remarkably, despite antileishmanial activity being more often associated to 8-aminoquinolines, like sitamaquine [82] or tafenoquine [83], conjugates 8, which embed a 4-aminoquinoline moiety, were significantly more active in vitro than the primaquine-derived conjugates 9 against promastigotes (3.1 < IC50 < 21 μM for compounds 8 versus 16 < IC50 < 53 μM for compounds 9) of L. infantum. Moreover, compounds 8 were comparable (1.2 < IC50 < 9.3 μM) to the reference antileishmanial drug miltefosine (IC50 = 4.1 μM) against intracellular amastigotes, while having low-to-mild toxicity against Building on the antiproliferative activity of the antimalarial drug artemisinin (5) and its derivatives [76,77]…”

“…In view of this, reports have emerged over the past decade where conjugation to CA was proposed as a useful strategy for the rescuing of known antimalarials [53][54][55]. The structures of these compounds are depicted in Figure 1 and include from classical agents such as chloroquine (2), primaquine (3), or mepacrine (4), to current first-line drugs like artemisinin (5). This strategy was hoped to deliver more efficient antimalarials that might be devoid of the resistance, pharmacokinetics, and/or pharmacodynamics liabilities associated with the parent antimalarial drug.…”

“…For instance, the simplest natural CA, trans-cinnamic acid ((2E)-3-phenylprop-2-enoic acid), can be found in the bark of several tree species from the genus Cinnamomum [1], or in the resinous exudates of trees from the genus Liquidamber [2], whereas hydroxycinnamic acids (phenolic acids) like p-coumaric, caffeic, ferulic, and sinapic acids, as well as derived compounds, are present in many different parts of a wide panoply of plants, including fruits, leaves, flowers, and others [1][2][3][4]. These acids are frequently found in a conjugated form, constituting key building blocks of complex polyphenols, such as acylated derivatives of flavonoid glycosides [5], and they have a number of biological roles in plants, from protection against microbes long been explored for their potential therapeutic applications, most of which related to their antioxidant, antimicrobial, and antineoplastic properties [4,[7][8][9][10][11][12][13][14]. The potential of CA-based compounds as therapeutic agents for other conditions, including Alzheimer's Disease [15], other nervous system disorders [16,17], acute pain [18], inflammation [19], diabetes [20,21], viral infections [22], tuberculosis [23][24][25][26], and malaria [26][27][28][29], among others, has also been addressed.…”

“…Antiproliferative primaquine-CA conjugates developed by Zorc et al[74,75].Building on the antiproliferative activity of the antimalarial drug artemisinin(5) and its derivatives[76,77], Xu et al have synthesized dihydroartemisinin-CA conjugates 18 and 19 (Figure 8), and evaluated their activity against one normal (L-02) and four cancer (PC-3, SGC-7901, A549, and MDA-MB-435) cell lines. One of the conjugates (19, where R 1 = R 4 = R 5 = H, and R 2 = R 3 = OMe) was found to have strong and selective activity against the lung cancer cell line A549 (GI 50 = 0.20 µM), likely associated with the compound's ability to induce increased levels of intracellular ferrous ions, and oxidative stress leading to apoptosis [78].…”

Antidepressant Potential of Cinnamic Acids: Mechanisms of Action and Perspectives in Drug Development

“…This finding is in accordance with a previous study performed by Oglodek (2017), in which it was identified that major depressive disorders, associated Reports of antidepressant activity on these compounds indicate that they may be an alternative treatment option for depression [17]. Cinnamic acids are a group of aromatic carboxylic acids with carbonic skeleton C6-C3 ( Figure 2) found in a variety of plants and foods, for which the biosynthetic route can generate several secondary metabolites such as coumarins, lignans, isoflavonoids, flavonoids, and others natural products [18].Cinnamic acids and their derivatives have attracted the attention of researchers due to their wide distribution in nature, low toxicity, structural diversity, and pharmacological actions [19], as anti-inflammatory [20], antioxidant [21], antitumor [22], hypoglycemic [23], antidepressant [24], and cytoprotective actions of neuroinflammation in neurodegenerative diseases [25]. Considering the importance of cinnamic acids as bioactive substances and their presence in various foods and medicinal plants, this review discusses the antidepressant action mechanisms of these compounds, demonstrating their therapeutic potential for depressive disorders.…”