Greta Varchi

New Polyfunctional Magnesium Reagents for Organic Synthesis

The iodine-magnesium exchange reaction allows the preparation of polyfunctional aryl, heteroaryl, or alkenyl magnesium reagents at low temperature. These reagents display the typical reactivity of Grignard compounds and undergo various copper-catalyzed reactions such as allylation or 1,4-addition. Using this halogen-metal exchange reaction, it was possible to generate polyfunctional magnesium reagents on the solid phase.

Rapid microwave-assisted deprotection of N-Cbz and N-Bn derivatives

Abstract Catalytic-transfer hydrogenation in iso-propanol under microwave irradiation has been performed to rapidly deprotect N-Cbz and N-Bn derivatives. The method is particularly suitable for the synthesis of short peptides and can also be carried out on supported molecules. The rapid cleavage of chiral molecules derived from (S)-1-phenylethylamine can be very useful for asymmetric synthesis of nitrogen containing compounds.

Mesenchymal stem cells as delivery vehicle of porphyrin loaded nanoparticles: Effective photoinduced in vitro killing of osteosarcoma

Mesenchymal stem cells (MSC) have the unique ability to home and engraft in tumor stroma. These features render them potentially a very useful tool as targeted delivery vehicles which can deliver therapeutic drugs to the tumor stroma. In the present study, we investigate whether fluorescent core-shell PMMA nanoparticles (FNPs) post-loaded with a photosensitizer, namely meso-tetrakis (4-sulfonatophenyl) porphyrin (TPPS) and uploaded by MSC could trigger osteosarcoma (OS) cell death in vitro upon specific photoactivation. In co-culture studies we demonstrate using laser confocal microscopy and time lapse imaging, that only after laser irradiation MSC loaded with photosensitizer-coated fluorescent NPs (TPPS@FNPs) undergo cell death and release reactive oxygen species (ROS) which are sufficient to trigger cell death of all OS cells in the culture. These results encourage further studies aimed at proving the efficacy of this novel tri-component system for PDT applications.

A SMYD3 Small-Molecule Inhibitor Impairing Cancer Cell Growth

SMYD3 is a histone lysine methyltransferase that plays an important role in transcriptional activation as a member of an RNA polymerase complex, and its oncogenic role has been described in different cancer types. We studied the expression and activity of SMYD3 in a preclinical model of colorectal cancer (CRC) and found that it is strongly upregulated throughout tumorigenesis both at the mRNA and protein level. Our results also showed that RNAi‐mediated SMYD3 ablation impairs CRC cell proliferation indicating that SMYD3 is required for proper cancer cell growth. These data, together with the importance of lysine methyltransferases as a target for drug discovery, prompted us to carry out a virtual screening to identify new SMYD3 inhibitors by testing several candidate small molecules. Here we report that one of these compounds (BCI‐121) induces a significant reduction in SMYD3 activity both in vitro and in CRC cells, as suggested by the analysis of global H3K4me2/3 and H4K5me levels. Of note, the extent of cell growth inhibition by BCI‐121 was similar to that observed upon SMYD3 genetic ablation. Most of the results described above were obtained in CRC; however, when we extended our observations to tumor cell lines of different origin, we found that SMYD3 inhibitors are also effective in other cancer types, such as lung, pancreatic, prostate, and ovarian. These results represent the proof of principle that SMYD3 is a druggable target and suggest that new compounds capable of inhibiting its activity may prove useful as novel therapeutic agents in cancer treatment. J. Cell. Physiol. 230: 2447–2460, 2015.

Copper Catalyzed Conjugate Addition of Highly Functionalized Arylmagnesium Compounds to Enones

Abstract Highly functionalized arylmagnesium bromides are readily prepared by an iodine–magnesium exchange reaction. In the presence of catalytic amounts of copper(I) salts and chlorotrimethylsilane, they add to various enones leading to the conjugate addition products in 66–89% yield.

EXTREMELY FACILE FORMATION AND HIGH REACTIVITY OF NEW THIOACYLSILANES CONTAINING THE FERROCENE MOIETY

Abstract Thioacylsilanes containing the ferrocene moiety, easily prepared from the corresponding acylsilanes with Lawessons reagent at room temperature, can be transformed into vinyl silanes, sulfur heterocycles and sulfines.

Synthesis and Reactivities of Enantiomerically Pure β-Hydroxyalkyl and β-Aminoalkyl Ferrocenyl Sulfides

Enantiomerically pure β-hydroxyalkyl and β-aminoalkyl ferrocenyl sulfides have been synthesized in good yields from mercaptoferrocene and amino alcohol derivatives. Primary β-aminoalkyl sulfides allowed the synthesis of tetrahydro-1,4-thiazepines containing the ferrocene moiety with good diastereoselectivity and β-iminoalkyl sulfides. Some of these derivatives have successfully been employed as ligands for palladium-catalyzed allylic substitution, with asymmetric induction of up to 99% ee. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Polymeric nanoparticles enhance the sonodynamic activity of meso-tetrakis (4-sulfonatophenyl) porphyrin in an in vitro neuroblastoma model

Purpose Sonodynamic therapy is a developing noninvasive modality for cancer treatment, based on the selective activation of a sonosensitizer agent by acoustic cavitation. The activated sonosensitizer agent might generate reactive oxygen species leading to cancer cell death. We investigated the potential poly-methyl methacrylate core-shell nanoparticles (NPs) loaded with meso-tetrakis (4-sulfonatophenyl) porphyrin (TPPS) have to function as an innovative sonosensitizing system, ie, TPPS-NPs. Methods Shockwaves (SWs) generated by a piezoelectric device were used to induce acoustic cavitation. The cytotoxic effect of the sonodynamic treatment with TPPS-NPs and SWs was investigated on the human neuroblastoma cell line, SH-SY5Y. Cells were exposed for 12 hours to TPPS-NPs (100 μg/mL) and then to SWs (0.43 mJ/mm2 for 500 impulses, 4 impulses/second). Treatment with SWs, TPPS, and NPs alone or in combination was carried out as control. Results There was a statistically significant decrease in SH-SY5Y cell proliferation after the sonodynamic treatment with TPPS-NPs and SWs. Indeed, there was a significant increase in necrotic (16.91% ± 3.89%) and apoptotic (27.45% ± 3.03%) cells at 48 hours. Moreover, a 15-fold increase in reactive oxygen species production for cells exposed to TPPS-NPs and SWs was observed at 1 hour compared with untreated cells. A statistically significant enhanced mRNA (messenger ribonucleic acid) expression of NRF2 (P<0.001) and a significant downregulation of TIGAR (P<0.05) and MAP3K5 (P<0.05) genes was observed in cells exposed to TPPS-NPs and SWs at 24 hours, along with a statistically significant release of cytochrome c (P<0.01) at 48 hours. Lastly, the sonosensitizing system was also investigated in an in vitro three-dimensional model, and the sonodynamic treatment significantly decreased the neuroblastoma spheroid growth. Conclusion The sonosensitizing properties of TPPS were significantly enhanced once loaded onto NPs, thus enhancing the sonodynamic treatment’s efficacy in an in vitro neuroblastoma model.

Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics

The NAD(+)-dependent sirtuin SIRT6 is highly expressed in human breast, prostate, and skin cancer where it mediates resistance to cytotoxic agents and prevents differentiation. Thus, SIRT6 is an attractive target for the development of new anticancer agents to be used alone or in combination with chemo- or radiotherapy. Here we report on the identification of novel quinazolinedione compounds with inhibitory activity on SIRT6. As predicted based on SIRT6s biological functions, the identified new SIRT6 inhibitors increase histone H3 lysine 9 acetylation, reduce TNF-α production and increase glucose uptake in cultured cells. In addition, these compounds exacerbate DNA damage and cell death in response to the PARP inhibitor olaparib in BRCA2-deficient Capan-1 cells and cooperate with gemcitabine to the killing of pancreatic cancer cells. In conclusion, new SIRT6 inhibitors with a quinazolinedione-based structure have been identified which are active in cells and could potentially find applications in cancer treatment.

Synthesis of Enantiopure β- and γ-Amino Alcohols from Homochiral α- and β-Aminoacylsilanes as Stable Synthetic Equivalents of α- and β-Amino Aldehydes

A practical route is described for the synthesis of enantiopure β- and γ-amino alcohols with two stereocenters, starting from homochiral α- (1 and 5) and β- (13 and 16) -aminoacylsilanes, and involving stereoselective addition of allylmetal compounds and subsequent stereospecific protiodesilylation of the adducts. The degree of diastereoselectivity achieved in the nucleophilic addition step depends on both the nitrogen-protecting group and the reagents used. Diastereomeric excess (de) values equal to or higher than 98% were obtained in the TiCl4-promoted allylation of the N-Pht-aminoacylsilanes 1 and 13 and of the N-Ts-aminoacylsilane 5 with allyltrimethylsilane. Lower de values were obtained in the Sc(OTf)3-catalyzed allylation of 5 with tetraallyltin and in the additions of both allyltrimethylsilane and tetraallyltin to the N-Ts-β-aminoacylsilane 16. Protiodesilylation of the adducts, leading to the β- and γ-amino alcohols, was accomplished with TBAF, except in the case of the adducts obtained from 5. For these, a preliminary removal of the tosyl group was necessary, which was accomplished with simultaneous desilylation by treatment with Na in liquid ammonia.