An expeditive and green chemo-enzymatic route to diester sinapoyl-l-malate analogues: sustainable bioinspired and biosourced UV filters and molecular heaters.

Sinapoyl malate, naturally present in plants, has proved to be an exceptional UV filter and molecular heater for plants. Although there are nowadays industrially relevant sustainable synthetic routes to sinapoyl malate, its incorporation into certain cosmetic formulations, as well as its adsorption on plant leaves, is limited by its hydrophilicity. To overcome these obstacles, it is important to find a way to effectively control the hydrophilic-lipophilic balance of sinapoyl malate to make it readily compatible with the cosmetic formulations and stick on the waxy cuticle of leaves. To this end, herein, we describe a highly regioselective chemo-enzymatic synthesis of sinapoyl malate analogues possessing fatty aliphatic chains of variable length, enabling the lipophilicity of the compounds to be modulated. The potential toxicity (i.e., mutagenicity, carcinogenicity, endocrine disruption, acute and repeated-dose toxicity), bioaccumulation, persistence and biodegradability potential of these new analogues were evaluated in silico, along with the study of their transient absorption spectroscopy, their photostability as well as their photodegradation products.

Synthesis and biological evaluation of chalcone-polyamine conjugates as novel vectorized agents in colorectal and prostate cancer chemotherapy.

The aim of this study was to synthesize chalcone-polyamine conjugates in order to enhance bioavailability and selectivity of chalcone core towards cancer cells, using polyamine-based vectors. Indeed, it is well-known that polyamine transport system is upregulated in tumor cells. 3',4,4',5'-tetramethoxychalcone was selected as parent chalcone since it was found to be an efficient anti-proliferative agent on various cancer cells. A series of five chalcone-polyamine conjugates was obtained using the 4-bromopropyloxy-3',4',5'-trimethoxychalcone as a key intermediate. Chalcone core and polyamine tails were fused through an amine bond. These conjugates were found to possess a marked in vitro antiproliferative effect against colorectal (HT-29 and HCT-116) and prostate cancer (PC-3 and DU-145) cell lines. The most active conjugate (compound 8b) was then chosen for further biological evaluations to elucidate mechanisms responsible for its antiproliferative activity. Investigations on cell cycle distribution revealed that this conjugate can prevent the proliferation of human colorectal and prostate cancer cells by blocking the cell cycle at the G1 and G2 phase, respectively. Flow cytometry analysis revealed a sub-G1 peak, characteristic of apoptotic cell population and our inquiries highlighted apoptosis induction at early and later stages through several pro-apoptotic markers. Therefore, this chalcone-N1-spermidine conjugate could be considered as a promising agent for colon and prostatic cancer adjuvant therapy.

Enhancement of hydrosolubility and in vitro antiproliferative properties of chalcones following encapsulation into ß-cyclodextrin/cellulose-nanocrystal complexes.

This paper describes the preparation of two chalcone/ß-cyclodextrin/cellulose-nanocrystals complexes and the study of their antiproliferative activities against two colorectal and two prostatic cancer cell lines. The aim of this work was to enhance hydrosolubility of chalcones thanks to the hydrophilic character of cellulose nanocrystals. These latter were linked, through ionic interactions, to a cationic derivative of ß-cyclodextrins whose lipophilic cavity allowed the encapsulation of hydrophobic chalcones: 3-hydroxy-3',4,4',5'-tetramethoxychalcone (1) and 3',4,4',5'-tetramethoxychalcone (2). First, we showed that encapsulation allowed hydrosolubilization of chalcones. Then, chalcone/ß-cyclodextrin/cellulose-nanocrystals complexes demonstrated enhanced in vitro antiproliferative activities, compared to the corresponding free-chalcones.

Determination of eumelanin and pheomelanin in melanomas using solid-phase extraction and high performance liquid chromatography-diode array detection (HPLC-DAD) analysis.

Determination of eumelanin and pheomelanin in melanomas that exhibit different pigmentation was carried using a solid-phase extraction (SPE) preparation method based on weak anion exchange chemistry. This extraction significantly enhanced the chromatographic profile obtained by reverse phase high performance liquid chromatography-diode array detection (RP-HPLC-DAD). The SPE method was developed using aqueous standards of melanin markers: thiazole-2,4,5-tricarboxylic acid (TTCA), thiazole-4,5-dicarboxylic acid (TDCA), pyrrole-2,3-dicarboxylic acid (PDCA) and pyrrole-2,3,5-tricarboxylic acid (PTCA) and non-pigmented cell lines spiked with those markers. An excellent average recovery, above 90%, was obtained for the four markers with a relative standard deviation below 7%. We have also optimized the stationary phase and the mobile phase (phosphate concentration and pH) to improve sensitivity and to reduce the analysis time. Elution of the four markers is achieved in 5 min and total analysis of biological samples is completed in 15 min. The quantification limits for TDCA, TTCA, PDCA and PTCA are 60, 50, 47 and 48 ng/mL respectively. Furthermore, DAD detection improves the marker identification in complex matrices through the analysis of UV spectra. We have successfully applied this method to melanoma tumors and cells. Murine B16BL6 tumor are highly pigmented with mostly eumelanin (98.1% of eumelanin) while human SK-MEL-3 tumor contain about 30% pheomelanin. B16BL6 and B16F10 are eumelanic cells lines and NHEM melanocytes contain about 24% of pheomelanin.

Design and multi-step synthesis of chalcone-polyamine conjugates as potent antiproliferative agents.

The aim of this study is to synthesize chalcone-polyamine conjugates in order to enhance bioavailability and selectivity of chalcone core towards cancer cells, using polyamine-based vectors. 3-hydroxy-3',4,4',5'-tetramethoxychalcone (1) and 3',4,4',5'-tetramethoxychalcone (2) were selected as parent chalcones since they were found to be efficient anti-proliferative agents on various cancer cells. A series of ten chalcone-polyamine conjugates was obtained by reacting carboxychalcones with different polyamine tails. Chalcones 1 and 2 showed a strong cytotoxic activity against two prostatic cancer (PC-3 and DU-145) and two colorectal cancer (HT-29 and HCT-116) cell lines. Then, chalcone-spermine conjugates 7d and 8d were shown to be the most active of the series and could be considered as promising compounds for colon and prostatic cancer adjuvant therapy.

Resistance to 3-HTMC-Induced Apoptosis Through Activation of PI3K/Akt, MEK/ERK, and p38/COX-2/PGE2 Pathways in Human HT-29 and HCT116 Colorectal Cancer Cells.

Increasing incidence and mortality of colorectal cancer brings the necessity to uncover new possibilities in its prevention and treatment. Chalcones have been identified as interesting compounds having chemopreventive and antitumor properties. In this study, we investigated the effects of the synthetic chalcone derivative 3-hydroxy-3',4,4',5'-tetra-methoxy-chalcone (3-HTMC) on proliferation, cell cycle distribution, apoptosis, and its mechanism of action in human colorectal HT-29 (COX-2 sufficient) and HCT116 (COX-2 deficient) cancer cells. We showed that 3-HTMC decreased cell viability in a dose-dependent manner with a more potent antiproliferative effect on HCT116 than HT-29 cells. Flow cytometric analysis revealed G2 /M cell cycle accumulation in HT-29 cells and significant G2 /M arrest in HCT116 cells with a subsequent apoptosis shown by appearance of Sub-G1 peak. We demonstrated that 3-HTMC treatment on both cell lines induced apoptotic process associated with overexpression of death receptor DR5, activation of caspase-8 and -3, PARP cleavage, and DNA fragmentation. In addition, 3-HTMC induced activation of PI3K/Akt and MEK/ERK principal survival pathways which delay 3-HTMC-induced apoptosis in both cell lines. Furthermore, COX-2 overexpression in HT-29 cells contributes to apoptosis resistance which explains the difference of sensitivity between HT-29 and HCT116 cells to 3-HTMC treatment. Even if resistance mechanisms to apoptosis reduced chalcone antitumoral potential, our results suggest that 3-HTMC may be considered as an interesting compound for colorectal cancer therapy or chemoprevention. J. Cell. Biochem. 117: 2875-2885, 2016. © 2016 Wiley Periodicals, Inc.