Biotage Initiator

Indole 2-carboxylates are very important scaffolds that are widely investigated for their activities and are used as key intermediates of biologically active molecules. Herein, we report a new procedure for the preparation of this class of derivatives, via Fischer indole synthesis, starting from β-nitroacrylates and arylhydrazines. The protocol permits the production of the title targets in satisfactory overall yields, avoids any wasteful aqueous work-up, and has with evident advantages from a sustainability point of view.

undefined Gabrielli, undefined Panmand, undefined Ballini, undefined Palmieri. Applied Sciences, 9 (23), 5168, 2019.

Prostate cancer represents the most common malignancy diagnosed in men, and is the second-leading cause of cancer death in this population. In spite of dedicated efforts, the current therapies are rarely curative, requiring the development of novel approaches based on innovative molecular targets. In this work, we validated aldehyde dehydrogenase 1A1 and 1A3 isoform expressions in different prostatic tissue-derived cell lines (normal, benign and malignant) and patient-derived primary prostate tumor epithelial cells, demonstrating their potential for therapeutic intervention using a small library of aldehyde dehydrogenase inhibitors. Compound 3b, 6-(4-fluorophenyl)-2-phenylimidazo [1,2-a]pyridine exhibited not only antiproliferative activity in the nanomolar range against the P4E6 cell line, derived from localized prostate cancer, and PC3 cell lines, derived from prostate cancer bone metastasis, but also inhibitory efficacy against PC3 colony-forming efficiency. Considering its concomitant reduced activity against normal prostate cells, 3b has the potential as a lead compound to treat prostate cancer by means of a still untapped molecular target.

Luca Quattrini, Maria Sadiq, Giovanni Petrarolo, Norman J. Maitland, Fiona M. Frame, Klaus Pors, Concettina La Motta. Biomedicines, 8 (12), 569, 2020.

The peptide hormone hepcidin is one of the key regulators of iron absorption, plasma iron levels, and tissue iron distribution. Hepcidin functions by binding to and inducing the internalisation and subsequent lysosomal degradation of ferroportin, which reduces both iron absorption in the gut and export of iron from storage to ultimately decrease systemic iron levels. The key interaction motif in hepcidin has been localised to the highly conserved N-terminal region, comprising the first nine amino acid residues, and has led to the development of mini-hepcidin analogs that induce ferroportin internalisation and have improved drug-like properties. In this work, we have investigated the use of head-to-tail cyclisation and N-methylation of mini-hepcidin as a strategy to increase oral bioavailability by reducing proteolytic degradation and enhancing membrane permeability. We found that backbone cyclisation and N-methylation was well-tolerated in the mini-hepcidin analogues, with the macrocylic analogues often surpassing their linear counterparts in potency. Both macrocyclisation and backbone N-methylation were found to improve the stability of the mini-hepcidins, however, there was no effect on membrane-permeabilizing activity.

Daniela Goncalves Monteiro, Johannes W. A. van Dijk, Randy Aliyanto, Eileen Fung, Elizabeta Nemeth, Tomas Ganz, Johan Rosengren, Richard J. Clark. Biomedicines, 9 (2), 164, 2021.

Affibody-mediated PNA-based pretargeting is a promising approach to radionuclide therapy of HER2-expressing tumors. In this study, we test the hypothesis that shortening the PNA pretargeting probes would increase the tumor-to-kidney dose ratio. The primary probe ZHER2:342-SR-HP15 and the complementary secondary probes HP16, HP17, and HP18, containing 9, 12, and 15 nucleobases, respectively, and carrying a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator were designed, synthesized, characterized in vitro, and labeled with 177Lu. In vitro pretargeting was studied in HER2-expressing SKOV3 and BT474 cell lines. The biodistribution of these novel probes was evaluated in immunodeficient mice bearing SKOV3 xenografts and compared to the previously studied [177Lu]Lu-HP2. Characterization confirmed the formation of high-affinity duplexes between HP15 and the secondary probes, with the affinity correlating with the length of the complementary PNA sequences. All the PNA-based probes were bound specifically to HER2-expressing cells in vitro. In vivo studies demonstrated HER2-specific uptake of all 177Lu-labeled probes in xenografts in a pretargeting setting. The ratio of cumulated radioactivity in the tumor to the radioactivity in kidneys was dependent on the secondary probe’s size and decreased with an increased number of nucleobases. The shortest PNA probe, [177Lu]Lu-HP16, showed the highest tumor-to-kidney ratio. [177Lu]Lu-HP16 is the most promising secondary probe for affibody-mediated tumor pretargeting.

Hanna Tano, Maryam Oroujeni, Anzhelika Vorobyeva, Kristina Westerlund, Yongsheng Liu, Tianqi Xu, Daniel Vasconcelos, Anna Orlova, Amelie Eriksson Karlström, Vladimir Tolmachev. Cancers, 13 (3), 500, 2021.

In this study, conversion of xylose to furfural was studied using lignin-based activated carbon-supported iron catalysts. First, three activated carbon supports were prepared from hydrolysis lignin with different activation methods. The supports were modified with different metal precursors and metal concentrations into five iron catalysts. The prepared catalysts were studied in furfural production from xylose using different reaction temperatures and times. The best results were achieved with a 4 wt% iron-containing catalyst, 5Fe-ACs, which produced a 57% furfural yield, 92% xylose conversion and 65% reaction selectivity at 170 °C in 3 h. The amount of Fe in 5Fe-ACs was only 3.6 µmol and using this amount of homogeneous FeCl3 as a catalyst, reduced the furfural yield, xylose conversion and selectivity. Good catalytic activity of 5Fe-ACs could be associated with iron oxide and hydroxyl groups on the catalyst surface. Based on the recycling experiments, the prepared catalyst needs some improvements to increase its stability but it is a feasible alternative to homogeneous FeCl3.

Annu Rusanen, Riikka Kupila, Katja Lappalainen, Johanna Kärkkäinen, Tao Hu, Ulla Lassi. Catalysts, 10 (8), 821, 2020.

Selectively targeted nanoscale drug delivery systems have recently emerged as promising intravenously therapeutic option for most chronic joint diseases. Here, a newly synthetized dodecapeptide (GE11)-polylactide-co-glycolide (PLGA)-based conjugate was used to prepare smart nanoparticles (NPs) intended for intra-articular administration and for selectively targeting Epidermal Growth Factor Receptor (EGFR). GE11-PLGA conjugate-based NPs are specifically uptaken by EGFR-overexpressed fibroblast; such as synoviocytes; which are the primarily cellular component involved in the development of destructive joint inflammation. The selective uptake could help to tune drug effectiveness in joints and to decrease local and systemic side effects. Dexamethasone (DXM) is a glucorticoid drug commonly used in joint disease treatment for both systemic and local administration route. In the present research; DXM was efficiently loaded into GE11-PLGA conjugate-based NPs through an eco-friendly nanoprecipitation method set up for this purpose. DXM loaded GE11-PLGA conjugate-based NPs revealed satisfactory ex vivo cytocompatibility; with proper size (≤150 nm) and good dimensional stability in synovial fluid. Intra-articular formulation was developed embedding DXM loaded GE11-PLGA conjugate-based NPs into thermosetting chitosan-based hydrogel; forming a biocompatible composite hydrogel able to quickly turn from liquid state into gel state at physiological temperature; within 15 min. Moreover; the use of thermosetting chitosan-based hydrogel extends the local release of active agent; DXM.

Enrica Chiesa, Silvia Pisani, Barbara Colzani, Rossella Dorati, Bice Conti, Tiziana Modena, Kevin Braekmans, Ida Genta. International Journal of Molecular Sciences, 19 (8), 2304, 2018.

Identification of molecules able to promote neuroprotective mechanisms can represent a promising therapeutic approach to neurodegenerative disorders including Huntington’s disease. Curcumin is an antioxidant and neuroprotective agent, even though its efficacy is limited by its poor absorption, rapid metabolism, systemic elimination, and limited blood–brain barrier (BBB) permeability. Herein, we report on novel biodegradable curcumin-containing nanoparticles to favor the compound delivery and potentially enhance its brain bioavailability. The prepared hyaluronan-based materials able to self-assemble in stable spherical nanoparticles, consist of natural fatty acids chemically conjugated to the natural polysaccharide. The aim of this study is to provide a possible effective delivery system for curcumin with the expectation that, after having released the drug at the specific site, the biopolymer can degrade to nontoxic fragments before renal excretion, since all the starting materials are provided by natural resource. Our findings demonstrate that curcumin-encapsulated nanoparticles enter the cells and reduce their susceptibility to apoptosis in an in vitro model of Huntington’s disease.

Giuseppe Pepe, Enrica Calce, Valentina Verdoliva, Michele Saviano, Vittorio Maglione, Alba Di Pardo, Stefania De Luca. International Journal of Molecular Sciences, 21 (22), 8846, 2020.

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. Their inhibitory activity was assessed against the cytosolic human isoforms hCA I, hCA II and the transmembrane hCA IX and XII. Several of the investigated derivatives showed interesting inhibition activity towards the tumor associate isoforms hCA IX and hCA XII. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds, within the active site of hCA IX.

Andrea Angeli, Victor Kartsev, Anthi Petrou, Mariana Pinteala, Volodymyr Brovarets, Sergii Slyvchuk, Stepan Pilyo, Athina Geronikaki, Claudiu T. Supuran. International Journal of Molecular Sciences, 22 (10), 5082, 2021.

A silica-bound C-butylpyrogallol[4]arene chromatographic stationary phase was prepared and characterised by thermogravimetric analysis, scanning electron microscopy, NMR and mass spectrometry. The chromatographic performance was investigated by using C60 and C70 fullerenes in reverse phase mode via flash column and high-pressure liquid chromatography (HPLC). The resulting new stationary phase was observed to demonstrate size-selective molecular recognition as postulated from our in-silico studies. The silica-bound C-butylpyrogallol[4]arene flash and HPLC stationary phases were able to separate a C60- and C70-fullerene mixture more effectively than an RP-C18 stationary phase. The presence of toluene in the mobile phase plays a significant role in achieving symmetrical peaks in flash column chromatography.

Subbareddy Mekapothula, A. D. Dinga Wonanke, Matthew A. Addicoat, David J. Boocock, John D. Wallis, Gareth W. V. Cave. International Journal of Molecular Sciences, 22 (11), 5726, 2021.

The syntheses and characterizations of the chelating ligand 6-chloro-6′-methyl-2,2′-bipyridine (6-Cl-6′-Mebpy) and of the copper(I) compounds [Cu(POP)(6-Cl-6′-Mebpy)][PF6] and [Cu(xantphos)(6-Cl-6′-Mebpy)][PF6] (POP = bis(2-(diphenylphosphanyl)phenyl)ether and xantphos = 4,5-bis(diphenylphosphanyl)-9,9-dimethyl-9H-xanthene) are described. The single crystal structures of both complexes were determined; the copper(I) ion is in a distorted tetrahedral environment and in [Cu(xantphos)(6-Cl-6′-Mebpy)][PF6], the disorder of the 6-Cl-6′-Mebpy ligand indicates there is no preference of the ‘bowl’-like cavity of the xanthene unit to host either the methyl or chloro-substituent, consistent with comparable steric effects of the two groups. The electrochemical and photophysical properties of [Cu(POP)(6-Cl-6′-Mebpy)][PF6] and [Cu(xantphos)(6-Cl-6′-Mebpy)][PF6] were investigated and are compared with those of the related compounds containing 6,6′-dichloro-2,2′-bipyridine or 6,6′-dimethyl-2,2′-bipyridine ligands. Trends in properties of the [Cu(P^P)(N^N)]+ complexes were consistent with 6-Cl-6′-Mebpy behaving as a combination of the two parent ligands.

Marco Meyer, Fabian Brunner, Alessandro Prescimone, Edwin C. Constable, Catherine E. Housecroft. Inorganics, 8 (5), 33, 2020.

Two different raltitrexed gold and silver nanoparticles for the delivery of an antitumoral drug into cancer cells were synthesized and characterized. A cysteine linker was used for the covalent bonding of raltitrexed to the surface of nanoparticles. To evaluate the efficacy of the antifolate-derivative nanoparticles, their cytotoxicity was assayed in vitro with A549 human lung adenocarcinoma and HCT-116 colorectal carcinoma human cells. Modified nanoparticles are a biocompatible material, and administration of silver raltitrexed nanoparticles strongly inhibited the viability of the cancer cells; gold raltitrexed nanoparticles do not show any type of cytotoxic effect. The results suggest that silver raltitrexed nanoparticles could be a potential delivery system for certain cancer cells.

Jeroni Morey, Pere Llinás, Alberto Bueno-Costa, Alberto J. León, M. Nieves Piña. Materials, 14 (3), 534, 2021.

Tumor suppressor p53-directed apoptosis triggers loss of normal cells, which contributes to the side-effects from anticancer therapies. Thus, small molecules with potential to downregulate the activation of p53 could minimize pathology emerging from anticancer therapies. Acetylation of p53 by the histone acetyltransferase (HAT) domain is the hallmark of coactivator CREB-binding protein (CBP) epigenetic function. During genotoxic stress, CBP HAT-mediated acetylation is essential for the activation of p53 to transcriptionally govern target genes, which control cellular responses. Here, we present a small molecule, NiCur, which blocks CBP HAT activity and downregulates p53 activation upon genotoxic stress. Computational modeling reveals that NiCur docks into the active site of CBP HAT. On CDKN1A promoter, the recruitment of p53 as well as RNA Polymerase II and levels of acetylation on histone H3 were diminished by NiCur. Specifically, NiCur reduces the levels of acetylation at lysine 27 on histone H3, which concomitantly increases the levels of trimethylation at lysine 27. Finally, NiCur attenuates p53-directed apoptosis by inhibiting the Caspase 3 activity and cleavage of Poly (ADP-ribose) polymerase (PARP) in normal gastrointestinal epithelial cells. Collectively, NiCur demonstrates the potential to reprogram the chromatin landscape and modulate biological outcomes of CBP-mediated acetylation under normal and disease conditions.

Adam Vincek, Jigneshkumar Patel, Anbalagan Jaganathan, Antonia Green, Valerie Pierre-Louis, Vimal Arora, Jill Rehmann, Mihaly Mezei, Ming-Ming Zhou, Michael Ohlmeyer, Shiraz Mujtaba. Molecules, 23 (8), 1930, 2018.

Although mollugin, the main ingredient of the oriental medicinal herb Rubia cordifolia, has considerable anti-inflammatory effects, it has poor aqueous solubility as well as poor metabolic and plasma stability. To overcome these shortfalls, various mollugin derivatives have been synthesized and evaluated for their ability to inhibit U937 monocyte cell adhesion to HT-29 colonic epithelial cells in TNF-α- or IL-6-induced models of colon inflammation. The 2-(4-morpholinyl)-ethyl ester of CF3-substituted mollugin (compound 15c) showed good water solubility, improved metabolic and plasma stability, and greater inhibitory activity than mesalazine in both the TNF-α- and IL-6-induced colonic epithelial cell adhesion assays, suggesting that 15c is a potential anti-inflammatory agent.

Ki Hong, Darong Kim, Bo-Kyung Kim, Seo Woo, Ji Lee, Seung-Hee Han, Gyu-Un Bae, Soosung Kang. Molecules, 23 (8), 2030, 2018.