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| 2.11 | The title is: Structural Diversity, Biosynthesis, and Multifaceted Biological Activities of Caffeic Acid and Its Derivatives: Focus on Anticancer, Antileishmanial, and Anti-Inflammatory Properties |
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Title: Structural Diversity, Biosynthesis, and Multifaceted Biological Activities of Caffeic Acid and Its Derivatives: Focus on Anticancer, Antileishmanial, and Anti-Inflammatory Properties
Structural Diversity and Biosynthesis of Caffeic Acid and Its Derivatives
Caffeic acid derivatives exhibit structural diversity, with examples including caffeic acid bornyl ester (CABE)—a rare natural product with notable biological properties [1]—and prenylated caffeic acid derivatives. Enzymatic-catalyzed synthesis is a promising green pathway for CABE production, with lipases being the most commonly used enzymes for ester synthesis reactions (e.g., esterification, transesterification, interesterification) in nonaqueous solvents; their versatility in such media makes them important biocatalysts for industrial applications [1]. Prenylation of caffeic acid can be catalyzed by the enzyme NovQ, which appends two dimethylallyl groups to form 3-O,4-O-di-(dimethylallyl) caffeic acid at a high yield (63.4%) [2]. In plant systems, caffeic acid acts as a chemical inhibitor of 4-coumarate:CoA ligase (4CL) in the phenylpropanoid pathway; treatment of Taxus chinensis suspension cultures with 100 µM caffeic acid affects phenylalanine ammonia-lyase (PAL) activity and expression, though effects are decoupled in some cases (e.g., increased PAL activity without changes in expression) [3].
Chemical Synthesis and Natural Isolation of Caffeic Acid Derivatives
| Process Type | Target Derivatives | Key Steps | Citations |
|---|---|---|---|
| Chemical synthesis | Phenylpropenoid esters | Steglich procedure: esterification with terpene alcohols (argon, room temp, CDI/DMAP catalysts) + BSTFA derivatization for GC/MS analysis | [4] |
| Natural isolation | Caffeic acid derivatives | Extraction with diethyl ether, column chromatography fractionation, GC/MS analysis of derivatized fractions (from birch buds: Betula pubescens and B. litwinowii) | [4] |
Antileishmanial Activity and Structure-Activity Relationships of Caffeic Acid Bornyl Esters
Caffeic acid bornyl ester (CABE) is a rare caffeic acid derivative and natural product with antileishmanial activity [1]. Caffeic Acid (−)-bornyl Ester (1) was isolated from a polar sub-fraction of the crude chloroform extract of V. wallichii rhizomes; the sub-fraction exhibited an IC₅₀ of 11.8 µg/mL against L. major promastigotes, while the pure compound 1 had an IC₅₀ of 48.8 µM against the same parasite and high cytotoxicity (8.3 µM) against the J774.1 cell line [5]. To optimize antileishmanial activity and reduce cytotoxicity, a library of derivatives of 1 was synthesized, using the caffeoyl-skeleton as a key antiprotozoal pharmacophore [5]. The bornyl moiety was critical for preserving antileishmanial activity, with borneol identified as the most advantageous substituent due to its bulkiness [5]. The catechol moiety (3,4-hydroxyl groups on the aromatic ring) in compound 1 is prone to oxidation into an o-quinone that reacts with protein amino groups; modifying this structure yielded derivatives with improved profiles. A non-substituted aromatic ring was found advantageous for activity against both Leishmania species [5], and removing the Michael moiety (replacing it with a simple carbonyl group) maintained activity while eliminating cytotoxicity [5]. When active compounds were screened against L. major amastigotes, compound 15 remained the most active, with its IC₅₀ (33.0 μM) falling within the range of the clinical drug miltefosine [5].
Antileishmanial Activity and Cytotoxicity of CABE Derivatives
| Compound | Modification | IC₅₀ (µM) against L. major Promastigotes | IC₅₀ (µM) against L. donovani Promastigotes | Cytotoxicity (µM) against J774.1 Cell Line | Notes [5] |
|---|---|---|---|---|---|
| 1 | N/A (parent) | 48.8 | — | 8.3 | — |
| 15 | Omitted catechol hydroxyl groups (cinnamic acid bornyl ester) | 39.6 | 15.6 | ~41.5 (fivefold lower than 1) | Activity within clinical drug range; most promising compound |
| 28 | Acetylated catechol structure | Slightly increased (not specified) | — | Single-digit micromolar | — |
| 27 | Replaced Michael moiety with simple carbonyl group | Matched 15 | — | None | — |
| 15 | N/A (screened against amastigotes) | — (amastigotes: 33.0) | — | — | Activity within miltefosine range |
Multifaceted Biological Activities of Caffeic Acid and Its Derivatives: Anticancer, Anti-Inflammatory, and Algal Inhibition Effects
Caffeic acid (CA) and its derivatives exhibit diverse biological activities relevant to anticancer, anti-inflammatory, and algal inhibition effects. Caffeic acid bornyl ester (CABE), a rare derivative, demonstrates anticancer activity via apoptosis induction in breast cancer cells, alongside anti-inflammatory, antibacterial, and leishmaniasis treatment properties [1]. CA is also a key active ingredient in Qingchangbaidu decoction (QBD), binding to therapeutic targets PIK3CA and MAPK1 (linked to chronic liver diseases) with high docking scores indicating strong binding activity [6].
Biological Activity Data for Caffeic Acid (CA)
| Activity Category | Specific Assay/Model | Key Metrics & Observations | Citation |
|---|---|---|---|
| Anticancer (Tumor Explants) | Patient A (100 μg/mL CA) | Reduced tumor viability to 67.2% | [7] |
| Anticancer (Tumor Explants) | Patient B (100 μg/mL CA) | Reduced tumor viability to 32.5% | [7] |
| Anticancer (Tumor Explants) | Patient A (CA + paclitaxel) | Further reduced viability to 17.1% | [7] |
| Anticancer (Tumor Explants) | Patient B (CA + paclitaxel) | Further reduced viability to 20.2% | [7] |
| Anticancer (Tumor Explants) | CA + paclitaxel (Patient A) | 1.42-fold increase in LDH release (enhanced cytotoxicity) | [7] |
| Anticancer (Tumor Explants) | CA + paclitaxel (Patient B) | 1.80-fold increase in LDH release (enhanced cytotoxicity) | [7] |
| Antiproliferative (In Vitro) | HCT-116 colorectal cancer cells (300 μM CA) | Some antiproliferative effects observed | [8] |
| Antiproliferative (In Vitro) | SW-480 colorectal cancer cells (300 μM CA) | Some antiproliferative effects observed | [8] |
| Antiproliferative (In Vitro) | MCF-7 breast cancer cells (300 μM CA) | No antiproliferative effects observed | [8] |
| Anti-Inflammatory | Whole blood phagocytes (IC₅₀) | IC₅₀ <3.1 μg/mL (potent inhibition) | [9] |
| Anti-Inflammatory | Isolated PMNs (IC₅₀) | IC₅₀ <3.1 μg/mL (potent inhibition) | [9] |
| Anti-Inflammatory | T-cells (anti-proliferative IC₅₀) | IC₅₀ <3.1 μg/mL (notable effects) | [9] |
| Algal Inhibition | 96 h-EC₅₀ against algae | 5.8 mg/L (outperformed analogs: cinnamic acid, p-coumaric acid, 3-hydroxycinnamic acid, ferulic acid, isoferulic acid, which showed weak/no effects at 5–100 mg/L) | [10] |
The table above consolidates quantitative and qualitative data on CA’s biological activities, spanning anticancer effects in tumor explants and cell lines, anti-inflammatory potency against immune cells, and robust algal inhibition relative to structural analogs. Collectively, these findings highlight CA’s multifunctional therapeutic potential across multiple disease-relevant pathways.
Genotoxicity and Antigenotoxicity Potential of Caffeic Acid and Its Derivatives in Plant Extracts
Polyphenols—including caffeic acid and its derivatives—are key phytochemicals in various plant extracts, with their presence linked to both genotoxic and antigenotoxic effects [11]. The antigenotoxic action of essential oils and methanolic extracts has been attributed to hydroxycinnamic acid derivatives, a major class of these polyphenols [11]. Notably, plant extracts with qualitatively similar polyphenolic and flavonoid compositions (where caffeic acid and quercetin are the most common phytochemicals) may exhibit genotoxic effects, suggested to stem from individual or synergistic interactions of these phenolic and flavonoid mixtures [11]. Additionally, caffeic acid, alongside secoiridoid oleuropein, triterpenes, flavonoids, and tannins, may contribute to specific biological effects [11].
Polyphenolic and Flavonoid Constituents of Plant Extracts and Parts
| Plant Source | Identified Phytochemicals | Citation |
|---|---|---|
| Moringa oleifera Lam leaves (powder and infusion) | Cinnamic derivatives, caffeic acid, chlorogenic acid, rutin | [11] |
| Flowering aerial parts (methanol extracts) | Hydroxycinnamic acid derivatives (chlorogenic, feruloylquinic, rosmarinic acids), caffeoyl pentoside | [11] |
| Aerial parts of certain plants | Hydroxycinnamic acids (rosmarinic, caffeic acids), flavonoids (apigenin, luteolin, quercetin, diosmetin, kaempferol, acacetin, agastachioside, salvigenin) | [11] |
| Plant leaves | Caffeic acid, ferulic acid, flavonoids | [11] |
References
[1] Harun Kamaruddin, A.H.; Mohd Yusof, N.N.; Gonawan, F.N.; Basir, N.I., Lipase-catalyzed synthesis of caffeic acid bornyl ester, 2019, Horiz. in Biopr. Engin.
[2] Ozaki, T.; Mishima, S.; Nishiyama, M.; Kuzuyama, T., NovQ is a prenyltransferase capable of catalyzing the addition of a dimethylallyl group to both phenylpropanoids and flavonoids, 2009, Journal of Antibiotics
[3] Brzycki Newton C, Young EM, Roberts SC., Targeted control of supporting pathways in paclitaxel biosynthesis with CRISPR-guided methylation, 2023, Front Bioeng Biotechnol
[4] Szczepaniak, Lech; Walejko, Piotr; Isidorov, Valery A., Gas Chromatographic and Mass Spectrometric Characterization of Trimethylsilyl Derivatives of Some Terpene Alcohol Phenylpropenoids, 2013, ANALYTICAL SCIENCES
[5] Glaser, Jan; Schultheis, Martina; Hazra, Sudipta; Hazra, Banasri; Moll, Heidrun; Schurigt, Uta; Holzgrabe, Ulrike, Antileishmanial Lead Structures from Nature: Analysis of Structure-Activity Relationships of a Compound Library Derived from Caffeic Acid Bornyl Ester, 2014, MOLECULES
[6] Cheng X, Han ZX, Su ZJ, Zhang FL, Li BP, Jiang ZR, Tang L, Yang JS., Network Pharmacology-Based Exploration on the Intervention of Qinghao Biejia Decoction on the Inflammation-Carcinoma Transformation Process of Chronic Liver Disease via MAPK and PI3k/AKT Pathway, 2022, Biomed Res Int
[7] Carranza-Torres IE, Guzmán-Delgado NE, Coronado-Martínez C, Bañuelos-García JI, Viveros-Valdez E, Morán-Martínez J, Carranza-Rosales P., Organotypic Culture of Breast Tumor Explants as a Multicellular System for the Screening of Natural Compounds with Antineoplastic Potential, 2015, Biomed Res Int
[8] Wang, Chong-Zhi; Zhang, Zhiyu; Huang, Wei-Hua; Du, Guang-Jian; Wen, Xiao-Dong; Calway, Tyler; Yu, Chunhao; Nass, Rachael; Zhao, Jing; Du, Wei; Li, Shao-Ping; Yuan, Chun-Su, Identification of potential anticancer compounds from Oplopanax horridus, 2013, PHYTOMEDICINE
[9] Orhan, Ilkay Erdogan; Mesaik, M. Ahmed; Jabeen, Almas; Kan, Yuksel, Immunomodulatory properties of various natural compounds and essential oils through modulation of human cellular immune response, 2016, INDUSTRIAL CROPS AND PRODUCTS
[10] Li, Min; Wang, Yayao; Xiao, Jianxing; Yan, Xingfu; Liu, Bingru, Allelopathic inhibition effects and mechanism of phenolic acids to Microcystis aeruginosa, 2023, ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH
[11] Al-Naqeb G, Kalmpourtzidou A, Giampieri F, De Giuseppe R, Cena H., Genotoxic and antigenotoxic medicinal plant extracts and their main phytochemicals: “A review”, 2024, Front Pharmacol