Buccinasco, Italy
Buccinasco, Italy

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La Regina G.,University of Rome La Sapienza | Bai R.,Frederick National Laboratory for Cancer Research | Coluccia A.,University of Rome La Sapienza | Famiglini V.,University of Rome La Sapienza | And 22 more authors.
Journal of Medicinal Chemistry | Year: 2014

We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light II cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway. © 2014 American Chemical Society.


Fancelli D.,Genextra | Fancelli D.,Italian National Cancer Institute | Abate A.,Genextra | Abate A.,Temple University | And 35 more authors.
Journal of Medicinal Chemistry | Year: 2014

In this account, we report the development of a series of substituted cinnamic anilides that represents a novel class of mitochondrial permeability transition pore (mPTP) inhibitors. Initial class expansion led to the establishment of the basic structural requirements for activity and to the identification of derivatives with inhibitory potency higher than that of the standard inhibitor cyclosporine-A (CsA). These compounds can inhibit mPTP opening in response to several stimuli including calcium overload, oxidative stress, and thiol cross-linkers. The activity of the cinnamic anilide mPTP inhibitors turned out to be additive with that of CsA, suggesting for these inhibitors a molecular target different from cyclophylin-D. In vitro and in vivo data are presented for (E)-3-(4-fluoro-3-hydroxy-phenyl)-N-naphthalen-1-yl- acrylamide 22, one of the most interesting compounds in this series, able to attenuate opening of the mPTP and limit reperfusion injury in a rabbit model of acute myocardial infarction. © 2014 American Chemical Society.


La Regina G.,University of Rome La Sapienza | Bai R.,U.S. National Cancer Institute | Coluccia A.,University of Rome La Sapienza | Famiglini V.,University of Rome La Sapienza | And 30 more authors.
Journal of Medicinal Chemistry | Year: 2015

We designed 39 new 2-phenylindole derivatives as potential anticancer agents bearing the 3,4,5-trimethoxyphenyl moiety with a sulfur, ketone, or methylene bridging group at position 3 of the indole and with halogen or methoxy substituent(s) at positions 4-7. Compounds 33 and 44 strongly inhibited the growth of the P-glycoprotein-overexpressing multi-drug-resistant cell lines NCI/ADR-RES and Messa/Dx5. At 10 nM, 33 and 44 stimulated the cytotoxic activity of NK cells. At 20-50 nM, 33 and 44 arrested >80% of HeLa cells in the G2/M phase of the cell cycle, with stable arrest of mitotic progression. Cell cycle arrest was followed by cell death. Indoles 33, 44, and 81 showed strong inhibition of the SAG-induced Hedgehog signaling activation in NIH3T3 Shh-Light II cells with IC50 values of 19, 72, and 38 nM, respectively. Compounds of this class potently inhibited tubulin polymerization and cancer cell growth, including stimulation of natural killer cell cytotoxic activity and repression of Hedgehog-dependent cancer. © 2015 American Chemical Society.


Thaler F.,Genextra | Thaler F.,Italian National Cancer Institute | Moretti L.,Italian National Cancer Institute | Amici R.,Genextra | And 23 more authors.
European Journal of Medicinal Chemistry | Year: 2016

In the last decades, inhibitors of histone deacetylases (HDAC) have become an important class of anti-cancer agents. In a previous study we described the synthesis of spiro[chromane-2,4′-piperidine]hydroxamic acid derivatives able to inhibit histone deacetylase enzymes. Herein, we present our exploration for new derivatives by replacing the piperidine moiety with various cycloamines. The goal was to obtain highly potent compounds with a good in vitro ADME profile. In addition, molecular modeling studies unravelled the binding mode of these inhibitors. © 2015 Elsevier Masson SAS.


Amici R.,Genextra | Amici R.,IEO European Institute of Oncology | Bigogno C.,NiKem Research S.r.l. | Bigogno C.,Aphad S.r.l. | And 24 more authors.
ChemMedChem | Year: 2014

Heat-shock protein 90 (Hsp90) is a molecular chaperone involved in the stabilization of key oncogenic signaling proteins, and therefore, inhibition of Hsp90 represents a new strategy in cancer therapy. 2-Amino-7-[4-fluoro-2-(3- pyridyl)phenyl]-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime is a racemic Hsp90 inhibitor that targets the N-terminal adenosine triphosphatase site. We developed a method to resolve the enantiomers and evaluated their inhibitory activity on Hsp90 and the consequent antitumor effects. The (S) stereoisomer emerged as a potent Hsp90 inhibitor in biochemical and cellular assays. In addition, this enantiomer exhibited high oral bioavailability in mice and excellent antitumor activity in two different human cancer xenograft models. Problem resolved: A chemical method to resolve the enantiomers of 2-amino-7-[4-fluoro-2-(3-pyridyl)phenyl]-4-methyl-7,8-dihydro-6H-quinazolin-5- one oxime, a Hsp90 inhibitor targeting the N-terminal adenosine triphosphatase site, and the characterization of their inhibitor activity on Hsp90, along with the consequent antiproliferative effect on cancer cells is explored. Pharmacokinetic properties and antitumor activity are also evaluated. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Marra A.,University of Pavia | Rossi D.,University of Pavia | Pignataro L.,University of Milan | Bigogno C.,Aphad S.r.l. | And 9 more authors.
Future Medicinal Chemistry | Year: 2016

Aim: Nowadays, there is a great interest in the therapeutic potential of sigma1 receptor ligands for treating different CNS pathologies. Our previous investigations led to identify (R)-RC-33 as a potent and selective S1R agonist. Results: Herein, we report the gram-scale synthesis, pharmacokinetic profile and CNS distribution of (R)-RC-33 in the mouse to determine the most suitable dosage schedule for in vivo administration. For comparative purposes, the same experiments were also performed with PRE-084, the most widely used S1R agonist commonly in pharmacological experiments. Discussion: (R)-RC-33 shows a similar pharmacokinetic profile and a better CNS distribution when compared with PRE-084. Conclusion: (R)-RC-33 may be a promising candidate for in vivo studies in animal models of neurodegenerative diseases. © 2016 Future Science Ltd.


PubMed | Aphad S.r.l., University of Pavia, University of Milan Bicocca, Casa Cura Policlinico CCP and University of Milan
Type: Journal Article | Journal: Future medicinal chemistry | Year: 2016

Nowadays, there is a great interest in the therapeutic potential of sigma1 receptor ligands for treating different CNS pathologies. Our previous investigations led to identify (R)-RC-33 as a potent and selective S1R agonist.Herein, we report the gram-scale synthesis, pharmacokinetic profile and CNS distribution of (R)-RC-33 in the mouse to determine the most suitable dosage schedule for in vivo administration. For comparative purposes, the same experiments were also performed with PRE-084, the most widely used S1R agonist commonly in pharmacological experiments.(R)-RC-33 shows a similar pharmacokinetic profile and a better CNS distribution when compared with PRE-084.(R)-RC-33 may be a promising candidate for in vivo studies in animal models of neurodegenerative diseases.


Valente S.,University of Rome La Sapienza | Trisciuoglio D.,Regina Elena Cancer Institute | De Luca T.,Regina Elena Cancer Institute | Nebbioso A.,The Second University of Naples | And 10 more authors.
Journal of Medicinal Chemistry | Year: 2014

We describe 1,3,4-oxadiazole-containing hydroxamates (2) and 2-aminoanilides (3) as histone deacetylase inhibitors. Among them, 2t, 2x, and 3i were the most potent and selective against HDAC1. In U937 leukemia cells, 2t was more potent than SAHA in inducing apoptosis, and 3i displayed cell differentiation with a potency similar to MS-275. In several acute myeloid leukemia (AML) cell lines, as well as in U937 cells in combination with doxorubicin, 3i showed higher antiproliferative effects than SAHA. © 2014 American Chemical Society.

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