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We report the implementation of our in silico/synthesis pipeline by targeting the glutathione-dependent enzyme mPGES-1, a valuable macromolecular target in both cancer therapy and inflammation therapy. Specifically, by using a virtual fragment screening approach of aromatic bromides, straightforwardly modifiable by the Suzuki-Miyaura reaction, we identified 3-phenylpropanoic acid and 2-(thiophen-2-yl)acetic acid to be suitable chemical platforms to develop tighter mPGES-1 inhibitors. Among these, compounds 1c and 2c showed selective inhibitory activity against mPGES-1 in the low micromolar range in accordance with molecular modeling calculations. Moreover, 1c and 2c exhibited interesting IC50 values on A549 cell lines compared to CAY10526, selected as reference compound. The most promising compound 2c induced the cycle arrest in the G0/G1 phase at 24 h of exposure, whereas at 48 and 72 h, it caused an increase of subG0/G1 fraction, suggesting an apoptosis/necrosis effect.

[Image: see text] Microsomal prostaglandin E(2) synthase-1 (mPGES-1), the terminal enzyme responsible for the production of inducible prostaglandin E(2), has become an attractive target for the treatment of inflammation and cancer pathologies. Starting from an aminobenzothiazole scaffold, used as an unprecedented chemical core for mPGES-1 inhibition, a Combinatorial Virtual Screening campaign was conducted, using the X-ray crystal structure of human mPGES-1. Two combinatorial libraries (6 × 10(4)) were obtained by decorating the aminobenzothiazole scaffold with all acyl chlorides and boronates available at the Merck database. The scientific multidisciplinary approach included virtual screening workflow, synthesis, and biological evaluation and led to the identification of three novel aminobenzothiazoles 1, 3, and 13 acting as mPGES-1 inhibitors. The three disclosed hits are able to inhibit mPGES-1 in a cell-free system (IC(50) = 1.4 ± 0.2, 0.7 ± 0.1, and 1.7 ± 0.2 μM, respectively), and all are endowed with antitumoral properties against A549 human cancer cell lines at micromolar concentrations (28.5 ± 1.1, 18.1 ± 0.8, and 19.2 ± 1.3 μM, respectively).

The identification of inhibitors of Hsp90 is currently a primary goal in the development of more effective drugs for the treatment of various types of multidrug resistant malignancies. In an attempt to identify new small molecules modulating the activity of Hsp90, we screened a small library of tetranortriterpenes. A high-affinity interaction with Hsp90 inducible form was uncovered for eight of these compounds, five of which are described here for the first time. By monitoring the ATPase activity and the citrate synthase thermal induced aggregation, compound 1 (cedrelosin A), 3 (7α-limonylacetate), and 5 (cedrelosin B), containing a limonol moiety, were found to be the most effective in compromising the Hsp90α chaperone activity. Consistent with these findings, the three compounds caused a depletion of c-Raf and pAkt Hsp90 client proteins in HeLa and MCF/7 cell lines. Induced fit docking protocol and molecular dynamics were used to rationalize the structural basis of the biological activity of the limonol derivatives. Taken together, these results point to limonol-derivatives as promising scaffolds for the design of novel Hsp90α inhibitors.

Two new glucopyranosylbianthrones (1 and 2) were isolated from the aerial part of the plant Asphodelus tenuifolius, collected in Southwest Algeria. The 2D structures of 1 and 2 were defined by NMR analysis, HRESIMS data, and comparison with literature data. The comparison of experimental and calculated electronic circular dichroism and NMR data led to characterization of the (M) and (P) atropisomeric forms of the glucopyranosylbianthrones, asphodelins (1) and (2), respectively. The in vitro activities of these two metabolites were evaluated in human melanoma A375 cells, and both the compounds inhibited cell proliferation in a concentration-dependent manner, with IC50 values of 20.6 ± 0.8 and 23.2 ± 1.1 μM, respectively. Considering their biological profile, an inverse virtual screening approach was employed to identify and suggest putative anticancer interacting targets.

BAG3 protein has emerged as a key regulator of important cellular processes and its expression is increased in some tumor types; however, despite its potential value for future chemotherapeutics, no selective BAG3 modulators have been yet reported. Here we report the 2,4-thiazolidinedione derivative 28 as the first BAG3 protein modulator.

Heat shock protein 90 (Hsp90) is an ATP dependent molecular chaperone deeply involved in the complex network of cellular signaling governing some key functions, such as cell proliferation and survival, invasion and angiogenesis. Over the past years the N-terminal protein domain has been fully investigated as attractive strategy against cancer, but despite the many efforts lavished in the field, none of the N-terminal binders (termed “classical inhibitors”), currently in clinical trials, have yet successfully reached the market, because of the detrimental heat shock response (HSR) that showed to induce; thus, recently, the selective inhibition of Hsp90 C-terminal domain has powerfully emerged as a more promising alternative strategy for anti-cancer therapy, not eliciting this cell rescue cascade. However, the structural complexity of the target protein and, mostly, the lack of a co-crystal structure of C-terminal domain-ligand, essential to drive the identification of new hits, represent the largest hurdles in the development of new selective C-terminal inhibitors. Continuing our investigations on the identification of new anticancer drug candidates, by using an orthogonal screening approach, here we describe two new potent C-terminal inhibitors able to induce cancer cell death and a considerable down-regulation of Hsp90 client oncoproteins, without triggering the undesired heat shock response.

The natural product magnolol (1) and a selection of its bioinspired derivatives 2-5, were investigated by Inverse Virtual Screening in order to identify putative biological targets from a panel of 308 proteins involved in cancer processes. By this in silico analysis we selected tankyrase-2 (TNKS2), casein kinase 2 (CK2) and bromodomain 9 (Brd9) as potential targets for experimental evaluations. The Surface Plasmon Resonance assay revealed that 3-5 present a good affinity for tankyrase-2, and, in particular, 3 showed an antiproliferative activity on A549 cells higher than the well-known tankyrase-2 inhibitor XAV939 used as reference compound.

Here, we report a procedure to obtain novel artificial materials using either fungal or isolated tobacco cells in association with different percentages of carbon nanotubes. The electrical, mechanical, and optical properties of these materials have been determined. The produced bio-nano-composite materials have linear electrical characteristics, high temperature stability up to 180 °C, linear increase of the electrical conductivity with increasing temperature and, in one case, also optical transparency. Using tobacco cells, we obtained a material with low mass density and mechanical properties suitable for structural applications along with high electrical conductivity. We also present theoretical models both for their mechanical and electrical behavior. These findings report a procedure for the next generation bio-nano-composite materials.

Cyclic peptoids have recently emerged as important examples of peptidomimetics for their interesting complexing properties and innate ability to permeate biological barriers. In the present contribution, experimental and theoretical data evidence the intricate conformational and stereochemical properties of five novel hexameric peptoids decorated with N-isopropyl, N-isobutyl, and N-benzyl substituents. Complexation studies by NMR, in the presence of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaTFPB), theoretical calculations, and single-crystal X-ray analyses indicate that the conformationally stable host/guest metal adducts display architectural ordering comparable to that of the enniatins and beauvericin mycotoxins. Similarly to the natural depsipeptides, the synthetic oligolactam analogues show a correlation between ion transport abilities in artificial liposomes and cytotoxic activity on human cancer cell lines. The reported results demonstrate that the versatile cyclic peptoid scaffold, for its remarkable conformational and complexing properties, can morphologically mimic related natural products and elicit powerful biological activities.

Hsp90 C-terminal ligands are potential new anti-cancer drugs alternative to the more studied N-terminal inhibitors. Here we report the identification of a new dihydropyrimidinone binding the C-terminus, which is not structurally related to other well-known natural and nature-inspired inhibitors of this second druggable Hsp90 site.

Besides its function in normal cellular growth, the molecular chaperone heat shock protein 90 (Hsp90) binds to a large number of client proteins required for promoting cancer cell growth and/or survival. In an effort to discover new small molecules able to inhibit the Hsp90 ATPase and chaperoning activities, we screened, by a surface plasmon resonance assay, a small library including different plant polyphenols. The ellagitannin geraniin, was identified as the most promising molecule, showing a binding affinity to Hsp90α similar to that of 17-(allylamino)-17-demethoxygeldanamycin (17AGG). Geraniin was able to inhibit in vitro the Hsp90α ATPase activity in a dose−dependent manner, with an inhibitory efficiency comparable to that measured for 17-AAG. In addition, this compound compromised the chaperone activity of Hsp90α, monitored by the citrate synthase thermal induced aggregation assay. Geraniin decreased the viability of HeLa and Jurkat cell lines and caused an arrest in G2/M phase. We also proved that following exposure to different concentrations of geraniin, the level of expression of the client proteins c-Raf, pAkt, and EGFR was strongly down−regulated in both the cell lines. These results, along with the finding that geraniin did not exert any appreciable cytotoxicity on normal cells, encourage further studies on this compound as a promising chemical scaffold for the design of new Hsp90 inhibitors.