Evaluation of the In vitro cytotoxic activity of caffeic acid derivatives and liposomal formulation against pancreatic cancer cell lines

Pancreatic cancer belongs to the most aggressive group of cancers, with very poor prognosis. Therefore, there is an important need to find more potent drugs that could deliver an improved therapeutic approach. In the current study we searched for selective and effective caffeic acid derivatives. For this purpose, we analyzed twelve compounds and evaluated their in vitro cytotoxic activity against two human pancreatic cancer cell lines, along with a control, normal fibroblast cell line, by the classic MTT assay. Six out of twelve tested caffeic acid derivatives showed a desirable effect. To improve the therapeutic efficacy of such active compounds, we developed a formulation where caffeic acid derivative (7) was encapsulated into liposomes composed of soybean phosphatidylcholine and DSPE-PEG2000. Subsequently, we analyzed the properties of this formulation in terms of basic physical parameters (such as size, zeta potential, stability at 4 °C and morphology), hemolytic and cytotoxic activity and cellular uptake. Overall, the liposomal formulation was found to be stable, non-hemolytic and had activity against pancreatic cancer cells (IC50 19.44 µM and 24.3 µM, towards AsPC1 and BxPC3 cells, respectively) with less toxicity against normal fibroblasts. This could represent a promising alternative to currently available treatment options

Synergistic Cytotoxicity of Methyl 4-Hydroxycinnamate and Carnosic Acid to Acute Myeloid Leukemia Cells via Calcium-Dependent Apoptosis Induction

Acute myeloid leukemia (AML) is a malignant hematopoietic disease with poor prognosis for most patients. Conventional chemotherapy has been the standard treatment approach for AML in the past 40 years with limited success. Although, several targeted drugs were recently approved, their long-term impact on survival of patients with AML is yet to be determined. Thus, it is still necessary to develop alternative therapeutic approaches for this disease. We have previously shown a marked synergistic anti-leukemic effect of two polyphenols, curcumin (CUR) and carnosic acid (CA), on AML cells in-vitro and in-vivo. In this study, we identified another phenolic compound, methyl 4-hydroxycinnamate (MHC), which among several tested phytochemicals could uniquely cooperate with CA in killing AML cells, but not normal peripheral blood mononuclear cells. Notably, our data revealed striking phenotypical and mechanistic similarities in the apoptotic effects of MHC+CA and CUR+CA on AML cells. Yet, we show that MHC is a non-fluorescent molecule, which is an important technical advantage over CUR that can interfere in various fluorescence-based assays. Collectively, we demonstrated for the first time the antileukemic activity of MHC in combination with another phenolic compound. This type of synergistically acting combinations may represent prototypes for novel antileukemic therapy

Synthesis and Antioxidant Activity of Caffeic Acid Derivatives

A series of caffeic acid derivatives were synthesized via a modified Wittig reaction which is a very important tool in organic chemistry for the construction of unsaturated carbon–carbon bonds. All reactions were performed in water medium at 90 °C. The aqueous Wittig reaction worked best when one unprotected hydroxyl group was present in the phenyl ring. The olefinations in the aqueous conditions were also conducted with good yields in the presence of two unprotected hydroxyl groups. When the number of the hydroxyl groups was increased to three, the reaction yields were worse, and the derivatives 12, 13, and 18 were obtained with 74%, 37%, and 70% yields, respectively. Nevertheless, the Wittig reaction using water as the essential medium is an elegant one-pot synthesis and a greener method, which can be a safe alternative for implementation in organic chemistry. The obtained compounds were tested for their antioxidant activity, and 12, 13, and 18 showed the highest activities. Moreover, all synthesized compounds displayed no cytotoxicity, and can therefore be used in the pharmaceutical or cosmetic industry

Synthesis and Antioxidant Activity of Caffeic Acid Derivatives

A series of caffeic acid derivatives were synthesized via a modified Wittig reaction which is a very important tool in organic chemistry for the construction of unsaturated carbon–carbon bonds. All reactions were performed in water medium at 90 °C. The aqueous Wittig reaction worked best when one unprotected hydroxyl group was present in the phenyl ring. The olefinations in the aqueous conditions were also conducted with good yields in the presence of two unprotected hydroxyl groups. When the number of the hydroxyl groups was increased to three, the reaction yields were worse, and the derivatives 12, 13, and 18 were obtained with 74%, 37%, and 70% yields, respectively. Nevertheless, the Wittig reaction using water as the essential medium is an elegant one-pot synthesis and a greener method, which can be a safe alternative for implementation in organic chemistry. The obtained compounds were tested for their antioxidant activity, and 12, 13, and 18 showed the highest activities. Moreover, all synthesized compounds displayed no cytotoxicity, and can therefore be used in the pharmaceutical or cosmetic industry

Design of Therapeutic Self-Assembled Monolayers of Thiolated Abiraterone

The aim of our work was to synthetize of a new analogue of abiraterone—thiolated abiraterone (HS-AB) and design a gold surface monolayer, bearing in mind recent advances in tuning monolayer structures and using them as efficient drug delivery systems. Therapeutic self-assembled monolayers (TSAMs) were prepared by chemically attaching HS-AB to gold surfaces. Their properties were studied by voltammetry and atomic force microscopy (AFM). A gold electrode with immobilized thioglycolic acid (HS-GA) was used for comparison. The surface concentration of HS-AB on the gold surface was 0.572 nmol/cm2, determined from the area of the voltammetric reduction peaks (desorption process). The area per one molecule estimated from the voltammetry experiments was 0.291 nmol/cm2. The capacity of thus prepared electrode was also tested. The calculated capacity for the HS-AB modified electrode is 2.90 μF/cm2. The obtained value indicates that the monolayer on the gold electrode is quite well ordered and well-packed. AFM images show the formation of gold nanoparticles as a result of immersing the HS-AB modified gold electrode in an aqueous solution containing 1 mM HAuCl4·3H2O. These structures arise as a result of the interaction between the HS-AB compound adsorbed on the electrode and the AuCl4− ions. The voltammetric experiments also confirm the formation of gold structures with specific catalytic properties in the process of oxygen reduction

Anti-cancer and electrochemical properties of thiogenistein : new biologically active compound

Pharmacological and nutraceutical effects of isoflavones, which include genistein (GE), are attributed to their antioxidant activity protecting cells against carcinogenesis. The knowledge of the oxidation mechanisms of an active substance is crucial to determine its pharmacological properties. The aim of the present work was to explain complex oxidation processes that have been simulated during voltammetric experiments for our new thiolated genistein analog (TGE) that formed the self-assembled monolayer (SAM) on the gold electrode. The thiol linker assured a strong interaction of sulfur nucleophiles with the gold surface. The research comprised of the study of TGE oxidative properties, IR-ATR, and MALDI-TOF measurements of SAM before and after electrochemical oxidation. TGE has been shown to be electrochemically active. It undergoes one irreversible oxidation reaction and one quasi-reversible oxidation reaction in PBS buffer at pH 7.4. The oxidation of TGE results in electroactive products composed likely from TGE conjugates (e.g., trimers) as part of polymer. The electroactive centers of TGE and its oxidation mechanism were discussed using IR supported by quantum chemical and molecular mechanics calculations. Preliminary in-vitro studies indicate that TGE exhibits higher cytotoxic activity towards DU145 human prostate cancer cells and is safer for normal prostate epithelial cells (PNT2) than genistein itself

Design and Molecular Modeling of Abiraterone-Functionalized Gold Nanoparticles

The aim of our work was the synthesis and physicochemical characterization of a unique conjugate consisting of gold nanoparticles (AuNPs) and a pharmacologically active anticancer substance abiraterone (AB). The direct coupling of AB with gold constitutes an essential feature of the unique AuNPs–AB conjugate that creates a promising platform for applications in nanomedicine. In this work, we present a multidisciplinary, basic study of the obtained AuNPs–AB conjugate. Theoretical modeling based on the density functional theory (DFT) predicted that the Aun clusters would interact with abiraterone preferably at the N-side. A sharp, intense band at 1028 cm−1 was observed in the Raman spectra of the nanoparticles. The shift of this band in comparison to AB itself agrees well with the theoretical model. AB in the nanoparticles was identified by means of electrochemistry and NMR spectroscopy. The sizes of the Au crystallites measured by XRPD were about 9 and 17 nm for the nanoparticles obtained in pH 7.4 and 3.6, respectively. The size of the particles as measured by TEM was 24 and 30 nm for the nanoparticles obtained in pH 7.4 and pH 3.6, respectively. The DLS measurements revealed stable, negatively charged nanoparticles

Synthesis of Thiol Derivatives of Biological Active Compounds for Nanotechnology Application

An efficient method of thiol group introduction to the structure of common natural products and synthetic active compounds with recognized biological efficacy such genistein (1), 5,11-dimethyl-5H-indolo[2,3-b]quinolin (2), capecitabine (3), diosgenin (4), tigogenin (5), flumethasone (6), fluticasone propionate (7), ursolic acid methyl ester (8), and β-sitosterol (9) was developed. In most cases, the desired compounds were obtained easily via two-step processes involving esterification reaction employing S-trityl protected thioacetic acid and the corresponding hydoxy-derivative, followed by removal of the trityl-protecting group to obtain the final compounds. The results of our preliminary experiments forced us to change the strategy in the case of genistein (1), and the derivatization of diosgenin (4), tigogenin (5), and capecitabine (3) resulted in obtaining different compounds from those designed. Nevertheless, in all above cases we were able to obtain thiol-containing derivatives of selected biological active compounds. Moreover, a modelling study for the two-step thiolation of genistein and some of its derivatives was accomplished using the density functional theory (B3LP). A hypothesis on a possible reason for the unsuccessful deprotection of the thiolated genistein is also presented based on the semiempirical (PM7) calculations. The developed methodology gives access to new sulphur derivatives, which might find a potential therapeutic benefit