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O'Callaghan K.,Trinity College Dublin | Palagano E.,Trinity College Dublin | Butini S.,University of Siena | Campiani G.,University of Siena | And 4 more authors.
Molecular Medicine Reports

Oral cancer (OC) is a largely asymptomatic disease, resulting in one of the highest mortality rates of any cancer. OC is currently ranked as the sixth most common cancer in the world, according to a recent World Health Organization analysis, and its prevalence is increasing, both in western and developing regions. Depending on the stage of OC, treatment strategies include surgery, radiation therapy and chemotherapy, or a combination thereof. As with numerous other types of cancer, resistance to conventional chemotherapeutic drugs is increasing in oral squamous cell carcinoma (OSCC). The present study aimed to investigate the use of a novel group of compounds, the pyrrolo-1,5-benzoxazepines (PBOXs), as a therapeutic alternative for the treatment of OC. PBOXs are microtubule-targeting agents that are able to induce apoptosis in numerous cancer cell types, thereby preventing tumour cell proliferation. Ca9.22 gingival and TR146 buccal cell lines were used as models for OSSC. Cell viability and proliferation in the presence of two PBOXs: PBOX-6 and PBOX-15, was monitored using an AlamarBlue™ assay. Flow cytometric analysis of propidium iodide-stained cells was used to determine the DNA content, and therefore the percentage of cells in each phase of the cell cycle. Microtubule disruption was determined by indirect immunofluorescence staining. Changes in protein expression and degradation were determined by western blotting. The results of the present study indicated that both PBOX-6 and -15 were able to induce apoptotic cell death by disrupting the microtubule network in both cell lines. The EC50 values were subsequently calculated for both PBOX-6 and -15, and PBOX-15 was shown to possess a higher potency. Both compounds displayed anti-proliferative effects mediated through sustained G2/M arrest accompanied by tubulin disruption, and a decrease in DNA repair protein poly (ADP ribose) polymerase expression. These findings suggest that PBOXs may prove useful, either alone or in combination with other agents, in the treatment of chemotherapeutic resistant OSCC. Source

Brogi S.,University of Siena | Brogi S.,European Research Center for Drug Discovery and Development NatSynDrugs | Papazafiri P.,National and Kapodistrian University of Athens | Roussis V.,National and Kapodistrian University of Athens | Tafi A.,University of Siena
European Journal of Medicinal Chemistry

The development of a novel approach for the prediction of antiestrogenic activity is described, bringing up to date a previous pharmacophore study. Software Phase has been used to derive a 3D-QSAR model based, as alignment rule, on a pharmacophore built on three compounds highly active against MCF-7 cell line. Five features comprised the pharmacophore: two hydrogen-bond acceptors, one hydrogen-bond donor, and two aromatic rings. The sequential 3D-QSAR yielded a test set q2 equal to 0.73 and proved to be predictive with respect to an external test set of 21 compounds (r2 = 0.69). The model was used to detect new MCF-7 inhibitors through 3D-database searching and identified fourteen compounds that were subsequently tested in vitro against the MCF-7 human breast adenocarcinoma cell line. Eleven out of the fourteen compounds exhibited inhibitory activity with IC50 values ranging between 30 and 186 μM. The results of the study confirmed the fundamental validity of the chosen approach as a hit discovery tool. © 2013 Elsevier Masson SAS. All rights reserved. Source

Gemma S.,European Research Center for Drug Discovery and Development NatSynDrugs | Gemma S.,University of Siena | Gemma S.,University of Turin | Kunjir S.,European Research Center for Drug Discovery and Development NatSynDrugs | And 31 more authors.
Journal of Medicinal Chemistry

Here we report the synthesis and evaluation of antiplasmodial activity of a novel series of bicyclic peroxides inspired by the marine natural compound dihydroplakortin. We developed a synthetic strategy leading to the dihydroplakortin-related peroxides in only a few steps. The in vitro antiplasmodial potency of the peroxides was similar to, or greater than, that of the reference natural compound, and structure-activity relationship studies revealed several key structural requirements for activity and potency. © 2011 American Chemical Society. Source

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