Jacques Jean-François

Caffeic Acid, A Versatile Pharmacophore: An Overview

The caffeic acid scaffold, which is abundant in nature, is extremely versatile and is found in a number of biologically active molecules. The purpose of this review is to provide an overview of the pharmacological activity of synthetic caffeic acid analogs including recent reports of anti-inflammatory, anti-cancer, and antiviral activities of these compounds.

Synthesis and Antiradical/Antioxidant Activities of Caffeic Acid Phenethyl Ester and Its Related Propionic, Acetic, and Benzoic Acid Analogues

Caffeic acid phenethyl ester (CAPE) is a bioactive component isolated from propolis. A series of CAPE analogues was synthesized and their antiradical/antioxidant effects analyzed. The effect of the presence of the double bond and of the conjugated system on the antioxidant effect is evaluated with the analogues obtained from 3-(3,4-dihydroxyphenyl) propanoic acid. Those obtained from 2-(3,4-dihydroxyphenyl) acetic acid and 3,4-dihydroxybenzoic acid allow the evaluation of the effect of the presence of two carbons between the carbonyl and aromatic system.

Antiproliferative, antiandrogenic and cytotoxic effects of novel caffeic acid derivatives in LNCaP human androgen-dependent prostate cancer cells.

Caffeic acid and its naturally occurring derivative caffeic acid phenethyl ester (CAPE) have antiproliferative and cytotoxic properties in a variety of cancer cell lines without displaying significant toxicity toward healthy cells, and are considered to be potential anticancer agents. However, little is known about their effects on prostate cancer cells. We synthesized and evaluated the effects of caffeic acid, CAPE (2) and 18 synthetic derivatives on cell viability and androgen-dependent cell proliferation, subcellular localisation and expression of androgen receptor (AR) and secretion of prostate-specific antigen (PSA) in LNCaP human hormone-dependent prostate cancer cells. Several synthetic derivatives of CAPE were strong, concentration-dependent cytotoxic agents in LNCaP cells with IC50 values in the 6.8-26.6 μM range, potencies that were up to five-fold greater than that of CAPE (33.7±4.0 μM). A number of caffeic acid derivatives were inhibitors of androgen-stimulated LNCaP cell proliferation with concomitant inhibition of DHT-stimulated PSA secretion. Compound 24 was the most cytotoxic and antiproliferative caffeic acid derivative (IC50 values of 6.8±0.3 and 2.4±0.8 μM, respectively) inhibiting DHT-stimulated cell proliferation and PSA secretion statistically significantly at concentrations as low as 0.3 μM. Exposure to DHT increased cytoplasmic and nuclear AR levels and co-treatment with increasing concentrations of compound 24 or CAPE (2), notably, further increased these levels. In conclusion, a number of synthetic derivatives of caffeic acid are potent inhibitors of androgen-dependent prostate cancer cell proliferation and viability, acting, at least in part, via an antiandrogenic mechanism that involves increased nuclear accumulation of (presumably inactive) AR.

NMR Metabolomics Analysis of the Effects of 5-Lipoxygenase Inhibitors on Metabolism in Glioblastomas

Changes across metabolic networks are emerging as an integral part of cancer development and progression. Increasing comprehension of the importance of metabolic processes as well as metabolites in cancer is stimulating exploration of novel, targeted treatment options. Arachidonic acid (AA) is a major component of phospholipids. Through the cascade catalyzed by cyclooxygenases and lipoxygenases, AA is also a precursor to cellular signaling molecules as well as molecules associated with a variety of diseases including cancer. 5-Lipoxygenase catalyzes the transformation of AA into leukotrienes (LT), important mediators of inflammation. High-throughput analysis of metabolic profiles was used to investigate the response of glioblastoma cell lines to treatment with 5-lipoxygenase inhibitors. Metabolic profiling of cells following drug treatment provides valuable information about the response and metabolic alterations induced by the drug action and give an indication of both on-target and off-target effects of drugs. Four different 5-lipoxygenase inhibitors and antioxidants were tested including zileuton, caffeic acid, and its analogues caffeic acid phenethyl ester and caffeic acid cyclohexethyl ester. A NMR approach identified metabolic signatures resulting from application of these compounds to glioblastoma cell lines, and metabolic data were used to develop a better understanding of the mode of action of these inhibitors.

CAPE Analogs Induce Growth Arrest and Apoptosis in Breast Cancer Cells

Breast cancer is the second leading cause of death amongst women worldwide. As a result, many have turned their attention to new alternative approaches to treat this disease. Caffeic acid phenylethyl ester (CAPE), a well-known active compound from bee propolis, has been previously identified as a strong antioxidant, anti-inflammatory, antiviral and anticancer molecule. In fact, CAPE is well documented as inducing cell death by inhibiting NFκB and by inducing pro-apoptotic pathways (i.e., p53). With the objective of developing stronger anticancer compounds, we studied 18 recently described CAPE derivatives for their ability to induce apoptosis in breast cancer cell lines. Five of the said compounds, including CAPE, were selected and subsequently characterised for their anticancer mechanism of action. We validated that CAPE is a potent inducer of caspase-dependent apoptosis. Interestingly, some newly synthesized CAPE derivatives also showed greater cell death activity than the lead CAPE structure. Similarly to CAPE, analog compounds elicited p53 activation. Interestingly, one compound in particular, analog 10, induced apoptosis in a p53-mutated cell line. These results suggest that our new CAPE analog compounds may display the capacity to induce breast cancer apoptosis in a p53-dependent and/or independent manner. These CAPE analogs could thus provide new therapeutic approaches for patients with varying genotypic signatures (such as p53 mutations) in a more specific and targeted fashion.

Structure-activity relationship of caffeic acid phenethyl ester analogs as new 5-lipoxygenase inhibitors.

Leukotrienes (LTs) are a class of lipid mediators implicated in numerous inflammatory disorders. Caffeic acid phenethyl ester (CAPE) possesses potent anti‐LTs activity through the inhibition of 5‐lipoxygenase (5‐LO), the key enzyme in the biosynthesis of LTs. In this study, we describe the design and synthesis of CAPE analogs as radical scavengers and 5‐LO inhibitors. Caffeic esters bearing propargyl and allyl linkers between the caffeoyl and aryl moieties (4a–i and 5a–i, respectively) were synthesized by Sonogashira and Heck cross‐coupling reactions to probe the effects of flexibility and aryl substitution on 5‐LO inhibition. Caffeoyl alcohol and ethers (6, 7a–b) as well as caffeoyl aldehyde and ketones (8a–e) were synthesized to elucidate the importance of the ester linkage for inhibitory activity. All tested compounds proved to be good radical scavengers (IC50 of 10–30 μm). After preliminary anti‐LTs activity screening in HEK293 cell models, 5‐LO inhibition potential of selected compounds was determined in human polymorphonuclear leukocytes (PMNL). Most screened compounds outperformed CAPE 3 in concentration‐dependent assays on PMNL, with ester dimers 4i and 5i along with caffeoyl ethers 7a–b being roughly eight‐, seven‐, and 16‐fold more potent than Zileuton, with IC50 values of 0.36, 0.43, and 0.18 μm, respectively.

Clicked Cinnamic/Caffeic Esters and Amides as Radical Scavengers and 5-Lipoxygenase Inhibitors

5-Lipoxygenase (5-LO) is the key enzyme responsible for the conversion of arachidonic acid to leukotrienes, a class of lipid mediators implicated in inflammatory disorders. In this paper, we describe the design, synthesis, and preliminary activity studies of novel clicked caffeic esters and amides as radical scavengers and 5-LO inhibitors. From known 5-LO inhibitor 3 as a lead, cinnamic esters 8a–h and amides 9a–h as well as caffeic esters 15a–h and amides 16a–h were synthesized by Cu(I)-catalyzed [1,3]-dipolar cycloaddition with the appropriate azide precursors and terminal alkynes. All caffeic analogs are proved to be good radical scavengers (IC50: 10–20 μM). Esters 15g and 15f possessed excellent 5-LO inhibition activity in HEK293 cells and were equipotent with the known 5-LO inhibitor CAPE and more potent than Zileuton. Several synthesized esters possess activities rivaling Zileuton in stimulated human polymorphonuclear leukocytes.

Synthesis and Biological Activity of Arylspiroborate Salts Derived from Caffeic Acid Phenethyl Ester

Two novel boron compounds containing caffeic acid phenethyl ester (CAPE) derivatives have been prepared and characterized fully. These new compounds and CAPE have been investigated for potential antioxidant and antimicrobial properties and their ability to inhibit 5-lipoxygenase and whether chelation to boron improves their biological activity. Sodium salt 4 was generally more active than ammonium salt 5 in the biological assays and surpassed the radical scavenging ability of CAPE. Compounds 4 and 5 were more active than CAPE and Zileuton in human polymorphonuclear leukocytes. These results clearly show the effectiveness of the synthesized salts as transporter of CAPE.

Synthesis and In Vitro Characterization of Poly(Ethylene Glycol)–Albumin Hydrogel Microparticles

Abstract High water content hydrogel microparticles based on the cross-linking of albumin with activated poly(ethylene glycol) were synthesized. The influence of different synthesis parameters on the physicochemical characteristics of the microparticles, such as the type of oil and of albumin, and the molecular weight of PEG, was evaluated. The water content of the microparticles ranged from 95 to 98%, increasing with an increase of the molecular weight of PEG. At optimal conditions, microparticles with sizes ranging from 3 to 50 μm were prepared. These microparticles showed a negatively charged surface. They were freely dispersed in PBS buffer and they were stable at 4°C for times varying from 0.5 to 10 months. Initial stirring speed and molecular weight of PEG were the 2 main factors that significantly affected microparticle size. High hydrophilicity, good stability and modulable size make this hydrogel an attractive matrix for protein or cell immobilization for biomedical applications.

Sinapic acid phenethyl ester as a potent selective 5-lipoxygenase inhibitor: Synthesis and structure-activity relationship

Given the hepatotoxicity and an unfavorable pharmacokinetic profile of zileuton (Zyflo®), currently the only approved and clinically used 5‐Lipoxygenase (5‐LO) inhibitor, the search for potent and safe 5‐LO inhibitors is highly demanded. The action of several phenolic acid phenethyl esters as potential 5‐Lipoxygenase (5‐LO) inhibitors has been investigated. For this purpose, a series of 14 phenethyl esters was synthesized and their impact on 5‐LO inhibition was evaluated. The effects of position and number of hydroxyl and methoxy groups on the phenolic acid were investigated. The shortening of the linker between the carbonyl and the catechol moiety as well as the presence of the α,β‐unsaturated carbonyl group was also explored. The sinapic acid phenethyl ester (10), which can be named SAPE (10) by analogy to caffeic acid phenethyl ester (CAPE), inhibited 5‐LO in a concentration‐dependent manner and outperformed both zileuton (1) and CAPE (2). With an IC50 of 0.3 μm, SAPE (10) was threefold more potent than CAPE (2) and 10‐fold more potent than zileuton (1), the only 5‐LO inhibitor approved for clinical use. Unlike CAPE (2), SAPE (10) had no effect on 12‐lipoxygenase (12‐LO) and less effect on cyclooxygenase 1 (COX‐1) which makes it a more selective 5‐LO inhibitor.