Colorectal anticancer activity of a novel class of triazolic triarylmethane derivatives.

Triarylmethanes and triazoles constitute privileged structures extensively used in drug discovery programs. In this work, 12 novel triarylmethanes linked to a triazole ring were designed, synthesized, and chemically characterized aiming to target colorectal cancer. The synthetic strategy for triarylmethanes mono- and bi-substituted by a functionalized triazole ring involved a 1,3-dipolar cycloaddition. A preliminary screening in human colorectal cancer cells (HT-29 and HCT116) and murine primary fibroblasts (L929) allowed the selection of the best candidate 9b based on its high inhibition of cancer cell proliferation with an IC50 of 11 µM on HT-29 and 14 µM on HCT116 and its non-cytotoxic effects on murine fibroblasts (<100 µM). A deep mechanistic study on various pathways showed that compound 9b induces caspase-3 cleavage, and its inhibitory effect on PARP activity is correlated with the increase of DNA fragmentation in cancer cells. Moreover, 9b induced apoptosis promoted by the inhibition of anti-apoptotic cell survival signaling pathways demonstrated via the downregulation of phosphorylated Akt and ERK proteins. Finally, the predicted binding modes of compounds 8c and 9b to five potential biological targets (i.e., AKT, ERK-1 and ERK-2, PARP and caspase-3) was evaluated using molecular modeling, and the predictions of the SuperPred webserver identified ERK2 as the most remarkable target. Also predicted in silico, 9b displayed appropriate drug-likeness and good absorption, distribution, metabolism and excretion (ADME) profiles.

Data of the quantification of the influence of DMSO concentration on the kinetic of interaction between TNFα and SPD304.

The data presented here are related to the article entitled "New contributions to the drug profile of TNFα inhibitor SPD304: affinity, selectivity ADMET considerations" published in the European Journal of pharmacology. As DMSO is usually used as a co-solvent to dissolve low aqueous soluble small molecules, such as SPD304, we have investigated the influence of its concentration on the kinetic of interaction between tumor necrosis factor α (TNF-α) and its inhibitor, SPD304. The presented data, acquired using a surface acoustic wave sensor, can be used in further biological studies to compare the kinetic of interaction between proteins/small molecules in general and TNFα/inhibitors in particular. The estimated dissociation constant can be compared to other ones to statute on the degree of affinity between a protein and a given molecule.

New contributions to the drug profile of TNFα inhibitor SPD304: Affinity, selectivity and ADMET considerations.

Tumor necrosis factor alpha (TNFα) is a relevant clinical target for the treatment of chronic inflammatory diseases. Currently, only few small molecules are known as direct inhibitors of TNFα. To date, none of these molecules has shown both an efficient activity and a low toxicity to be considered for clinical trials. The SPD304 is considered as a reference of direct inhibitors of TNFα because of its well demonstrated mechanism (He et al., 2005). Herein, we provide new insights regarding the drug profile, selectivity and absorption, distribution, metabolism, excretion and toxicity (ADMET) considerations of SPD304 to evaluate its potential as a hit for the structure-based design of novel TNFα inhibitors. ELISA experiments confirmed the inhibition of TNFα/TNF receptor 1 binding (IC50 = 12 µM). Cellular-based assays highlighted the cytotoxicity of SPD304, as well as its ability to inhibit TNFα signaling pathways at non-cytotoxic concentrations. A surface acoustic wave (SAW) experiment highlighted only one binding site with a dissociation constant of 6.1 ± 4.7 nM. SPD304 inhibited the binding of the cytokines like interleukins (IL)-4 and IL-13 to their receptors and showed no direct inhibition on proteins involved in the TNFα pathway. Finally, the thermodynamic solubility and Caco-2 cells permeability of SPD304 were experimentally evaluated and ADMET in silico predictions are also discussed. The physicochemical, pharmacological and ADMET studies of SPD304 have shown that is not an ideal hit for a drug optimization program based on its chemical structure.

Plant Occurring Flavonoids as Modulators of the Aryl Hydrocarbon Receptor.

The aryl hydrocarbon receptor (AhR) is a transcription factor deeply implicated in health and diseases. Historically identified as a sensor of xenobiotics and mainly toxic substances, AhR has recently become an emerging pharmacological target in cancer, immunology, inflammatory conditions, and aging. Multiple AhR ligands are recognized, with plant occurring flavonoids being the largest group of natural ligands of AhR in the human diet. The biological implications of the modulatory effects of flavonoids on AhR could be highlighted from a toxicological and environmental concern and for the possible pharmacological applicability. Overall, the possible AhR-mediated harmful and/or beneficial effects of flavonoids need to be further investigated, since in many cases they are contradictory. Similar to other AhR modulators, flavonoids commonly exhibit tissue, organ, and species-specific activities on AhR. Such cellular-context dependency could be probably beneficial in their pharmacotherapeutic use. Flavones, flavonols, flavanones, and isoflavones are the main subclasses of flavonoids reported as AhR modulators. Some of the structural features of these groups of flavonoids that could be influencing their AhR effects are herein summarized. However, limited generalizations, as well as few outright structure-activity relationships can be suggested on the AhR agonism and/or antagonism caused by flavonoids.

Pegylated triarylmethanes: Synthesis, antimicrobial activity, anti-proliferative behavior and in silico studies.

We describe herein the synthesis, characterization and biological studies of novel PEGylated triarylmethanes. Non-symmetrical and symmetrical triarylmethanes series have been synthesized by Friedel-Crafts hydroxyalkylation or directly from bisacodyl respectively followed by a functionalization with PEG fragments in order to increase bioavailability and biological effectiveness. The antimicrobial activity was investigated against Gram-positive and Gram-negative foodborne pathogens and against Candida albicans, an opportunistic pathogenic yeast. The anti-biocidal activity was also studied using Staphylococcus aureus as a reference bacterium. Almost all PEGylated molecules displayed an antifungal activity comparable with fusidic acid with MIC values ranging from 6.25 to 50 µg/mL. Compounds also revealed a promising antibiofilm activity with biofilm eradication percentages values above 80% for the best molecules (compounds 4d and 7). Compounds 7 and 8b showed a modest antiproliferative activity against human colorectal cancer cell lines HT-29. Finally, in silico molecular docking studies revealed DHFR and DNA gyrase B as potential anti-bacterial targets and in silico predictions of ADME suggested adequate drug-likeness profiles for the synthetized triarylmethanes.

Anti-Inflammatory Activity and Cheminformatics Analysis of New Poten t 2-Substituted 1-Methyl-5-Nitroindazolinones.

After the identification of the anti-inflammatory properties of VA5-13l (2-benzyl-1- methyl-5-nitroindazolinone) in previous investigations, some of its analogous compounds were designed, synthesized and evaluated in two anti-inflammatory methods: LPS-enhanced leukocyte migration assay in zebrafish; and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema. The products evaluated (3, 6, 8, 9 and 10) showed the lower values of relative leukocyte migration at 30 µM (0.14, 0.07, 0.10, 0.13 and 0.07, respectively), while in ear edema and myeloperoxidase activity methods, all the compounds reduced inflammation, only 4 and 16 yielded unsatisfactory results. The relationship linking structure and activity (SAR analysis) was determinate by using SARANEA software. The importance of the 5-Nitro group of the indazole ring for the activity was evident, and showed modest reduction when benzyl (Bn) is changed by alkyl group. A substituted Bn moiety at N2 (R) is the best substituent (5-10); nevertheless, if methylene group of Bn is deleted, the activity is affected. Also, introduction of halogen atoms mainly at positions 3 or 4 of the benzyl moiety (6 and 10) leads in general to strong activities. In fact, compounds 7 and 8 (R = 4-FBn or 4-ClBn, respectively) exhibit satisfactory results in in vivo tests and appear promising. The production of IL-6 at all doses assayed was significantly reduced, except with 16. Nonetheless, the production of TNF-α was significantly inhibited only by this chemical (16) at concentration of 50 µM. On the other hand, compound 2 was the one that mostly inhibited the expression of COX-2 and iNOS. From these results, it can be concluded that the inhibition in the release of cytokines can be one of the mechanisms of action responsible for the anti-inflammatory effect for 2-benzyl derivates while other 2-alkyl derivatives can inhibit production of NO. Therefore, nitroindazolinone chemical prototype could be an interesting structural group with anti-inflammatory purposes in the therapeutic.

Fishing Anti-Inflammatories from Known Drugs: In Silico Repurposing, Design, Synthesis and Biological Evaluation of Bisacodyl Analogues.

Herein is described in silico repositioning, design, synthesis, biological evaluation and structure-activity relationship (SAR) of an original class of anti-inflammatory agents based on a polyaromatic pharmacophore structurally related to bisacodyl (BSL) drug used in therapeutic as laxative. We describe the potential of TOMOCOMD-CARDD methods to find out new anti-inflammatory drug-like agents from a diverse series of compounds using the total and local atom based bilinear indices as molecular descriptors. The models obtained were validated by biological studies, identifying BSL as the first anti-inflammatory lead-like using in silico repurposing from commercially available drugs. Several biological in vitro and in vivo assays were performed in order to understand its mechanism of action. A set of analogues of BSL was prepared using low-cost synthetic procedures and further biologically investigated in zebrafish models. Compound 5c and 7e exhibited the best antiinflammatory activities and represent new promising anti-inflammatory agents for further preclinical development.

An efficient and selective microwave-assisted Claisen-Schmidt reaction for the synthesis of functionalized benzalacetones.

A simple and direct method for the Claisen-Schmidt reaction to prepare functionalized α,ß-unsaturated ketones has been developed. Microwave irradiation of aldehydes with acetone produces benzalacetones selectively without self-condensation product in very short reaction times and good yields. Graphical AbstractGraphics for use in the Table of Contents.