Lucilla Varoli

Publications (20)63.21 Total impact

• Article: Substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones and analogues: synthesis, cytotoxic activity, and study of the mechanism of action.

  Aldo Andreani, Massimiliano Granaiola, Alessandra Locatelli, Rita Morigi, Mirella Rambaldi, Lucilla Varoli, Natalia Calonghi, Concettina Cappadone, Giovanna Farruggia, Claudio Stefanelli, Lanfranco Masotti, Tam L Nguyen, Ernest Hamel, Robert H Shoemaker
  [show abstract] [hide abstract]
  ABSTRACT: The synthesis of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones and analogues is reported. Their cytotoxic activity was evaluated according to protocols available at the National Cancer Institute (NCI), Bethesda, MD. The action of selected compounds was examined for potential inhibition of tubulin assembly in comparison with the potent colchicine site agent combretastatin A-4. The most potent compounds also strongly and selectively inhibited the phosphorylation of the oncoprotein kinase Akt in cancer cells. The effect of the most interesting compounds was examined on the growth of HT-29 colon cancer cells. These compounds caused the cells to arrest in the G2/M phase of the cell cycle, as would be expected for inhibitors of tubulin assembly.
  Journal of Medicinal Chemistry 03/2012; 55(5):2078-88. · 4.80 Impact Factor
• Article: Imidazo[2,1-b]thiazole guanylhydrazones as RSK2 inhibitors.

  Aldo Andreani, Massimiliano Granaiola, Alberto Leoni, Alessandra Locatelli, Rita Morigi, Mirella Rambaldi, Lucilla Varoli, Deborah Lannigan, Jeff Smith, Dominic Scudiero, Sudhir Kondapaka, Robert H Shoemaker
  [show abstract] [hide abstract]
  ABSTRACT: The activity of a series of imidazo[2,1-b]thiazole guanylhydrazones as inhibitors of p90 ribosomal S6 kinase 2 (RSK2) is described. It was found that a small subset of compounds show both potent inhibition of RSK2 kinase activity and tumor cell growth in vitro. Detailed study of one of the most active compounds indicates a high degree of selectivity for inhibition of RSK2 compared to a spectrum of other related kinases. Selective inhibition of the MCF-7 breast tumor cell line compared to MCF-10A non-transformed cells, as well as selective inhibition of the biomarker GSK3 provides evidence that the compounds can affect the RSK2 target in cells.
  European journal of medicinal chemistry 07/2011; 46(9):4311-23. · 3.27 Impact Factor
• Article: Bis-guanylhydrazone diimidazo[1,2-a:1,2-c]pyrimidine as a novel and specific G-quadruplex binding motif.

  Silvia Sparapani, Stefania Bellini, Mekala Gunaratnam, Shozeb M Haider, Aldo Andreani, Mirella Rambaldi, Alessandra Locatelli, Rita Morigi, Massimiliano Granaiola, Lucilla Varoli, Silvia Burnelli, Alberto Leoni, Stephen Neidle
  [show abstract] [hide abstract]
  ABSTRACT: A bis-guanylhydrazone derivative of diimidazo[1,2-a:1,2-c]pyrimidine has unexpectedly been found to be a potent stabiliser of several quadruplex DNAs, whereas there is no significant interaction with duplex DNA. Molecular modeling suggests that the guanylhydrazone groups play an active role in quadruplex binding.
  Chemical Communications 08/2010; 46(31):5680-2. · 6.17 Impact Factor
• Article: Substituted E-3-(3-indolylmethylene)-1,3-dihydroindol-2-ones with antitumor activity. In depth study of the effect on growth of breast cancer cells.

  Aldo Andreani, Stefania Bellini, Silvia Burnelli, Massimiliano Granaiola, Alberto Leoni, Alessandra Locatelli, Rita Morigi, Mirella Rambaldi, Lucilla Varoli, Natalia Calonghi, Concettina Cappadone, Maddalena Zini, Claudio Stefanelli, Lanfranco Masotti, Robert H Shoemaker
  [show abstract] [hide abstract]
  ABSTRACT: The synthesis of new substituted E-3-(3-indolylmethylene)-1,3-dihydroindol-2-ones is reported. The antitumor activity was evaluated according to protocols available at the National Cancer Institute (NCI), Bethesda, MD. Structure-activity relationships are discussed. The action of selected compounds was investigated in MCF-7 breast cancer cells. The ability of these derivatives to inhibit cellular proliferation was accompanied by increased level of p53 and its transcriptional targets p21 and Bax, interference in the cell cycle progression with cell accumulation in the G2/M phase, and activation of apoptosis.
  Journal of Medicinal Chemistry 08/2010; 53(15):5567-75. · 4.80 Impact Factor
• Article: Antitumor activity and COMPARE analysis of bis-indole derivatives.

  Aldo Andreani, Silvia Burnelli, Massimiliano Granaiola, Alberto Leoni, Alessandra Locatelli, Rita Morigi, Mirella Rambaldi, Lucilla Varoli, Laura Landi, Cecilia Prata, Francesco Vieceli Dalla Sega, Cristiana Caliceti, Robert H Shoemaker
  [show abstract] [hide abstract]
  ABSTRACT: This paper reports the synthesis of new derivatives (formed by two indole systems separated by a central moiety) analogous of potent antitumor agents previously described. The activity of the bis-indoles bearing a pyridine core confirms the good result described in the previous paper and compound 4c was chosen for the first in vivo experiment (Hollow Fiber Assay). COMPARE analysis and structure-activity relationships were also considered. Contrary to data reported by other Authors, no correlations were found between antitumor activity and NQO1 induction.
  Bioorganic & medicinal chemistry 05/2010; 18(9):3004-11. · 2.82 Impact Factor
• Source

  Available from: Emanuela Greco

  Article: New isatin derivatives with antioxidant activity.

  Aldo Andreani, Silvia Burnelli, Massimiliano Granaiola, Alberto Leoni, Alessandra Locatelli, Rita Morigi, Mirella Rambaldi, Lucilla Varoli, Mauro Andrea Cremonini, Giuseppe Placucci, Rinaldo Cervellati, Emanuela Greco
  [show abstract] [hide abstract]
  ABSTRACT: The reaction between isatin and 2,5-dimethoxyaniline is described. The main product was identified as 3,3-bis(4-amino-2,5-dimethoxyphenyl)-1,3-dihydroindol-2-one. The antioxidant activity of the compounds isolated was evaluated with two methods. Three published antitumor E-3-(2-chloro-3-indolylmethylene)1,3-dihydroindol-2-ones entered the same tests to search whether they are endowed with antioxidant activity too. 3,3-Bis(4-amino-2,5-dimethoxyphenyl)-1,3-dihydroindol-2-one and the three antitumor agents showed a good chemical antioxidant activity.
  European journal of medicinal chemistry 04/2010; 45(4):1374-8. · 3.27 Impact Factor
• Article: Antitumor activity of new substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones and 3-(5-imidazo[2,1-b]thiadiazolylmethylene)-2-indolinones: selectivity against colon tumor cells and effect on cell cycle-related events.

  Aldo Andreani, Silvia Burnelli, Massimiliano Granaiola, Alberto Leoni, Alessandra Locatelli, Rita Morigi, Mirella Rambaldi, Lucilla Varoli, Natalia Calonghi, Concettina Cappadone, Manuela Voltattorni, Maddalena Zini, Claudio Stefanelli, Lanfranco Masotti, Robert H Shoemaker
  [show abstract] [hide abstract]
  ABSTRACT: The synthesis of new 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones and 3-(5-imidazo[2,1-b]thiadiazolylmethylene)-2-indolinones is reported. The antitumor activity was evaluated according to the protocols available at the National Cancer Institute (NCI), Bethesda, MD. To investigate the mechanism of action of the most potent antitumor agent of this series, its effect on growth of HT-29 colon carcinoma cells was studied. Its ability to inhibit cellular proliferation was mediated by cell cycle arrest at the G2/M phase, accompanied by inhibition of ornithine decarboxylase (ODC), the limiting enzyme of polyamine synthesis, and followed by induction of apoptosis.
  Journal of Medicinal Chemistry 12/2008; 51(23):7508-13. · 4.80 Impact Factor
• Article: Antitumor Activity of New Substituted 3-(5-Imidazo[2,1-b]thiazolylmethylene)-2-indolinones and 3-(5-Imidazo[2,1-b]thiadiazolylmethylene)-2-indolinones: Selectivity against Colon Tumor Cells and Effect on Cell Cycle-Related Events(1)

  Aldo Andreani, Silvia Burnelli, Massimiliano Granaiola, Alberto Leoni, Alessandra Locatelli, Rita Morigi, Mirella Rambaldi, Lucilla Varoli, Natalia Calonghi, Concettina Cappadone, Manuela Voltattorni, Maddalena Zini, Claudio Stefanelli, Lanfranco Masotti, Robert H. Shoemaker
  [show abstract] [hide abstract]
  ABSTRACT: The synthesis of new 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones and 3-(5-imidazo[2,1-b]thiadiazolylmethylene)-2-indolinones is reported. The antitumor activity was evaluated according to the protocols available at the National Cancer Institute (NCI), Bethesda, MD. To investigate the mechanism of action of the most potent antitumor agent of this series, its effect on growth of HT-29 colon carcinoma cells was studied. Its ability to inhibit cellular proliferation was mediated by cell cycle arrest at the G2/M phase, accompanied by inhibition of ornithine decarboxylase (ODC), the limiting enzyme of polyamine synthesis, and followed by induction of apoptosis.
  11/2008;
• Article: Antitumor activity of bis-indole derivatives.

  Aldo Andreani, Silvia Burnelli, Massimiliano Granaiola, Alberto Leoni, Alessandra Locatelli, Rita Morigi, Mirella Rambaldi, Lucilla Varoli, Laura Landi, Cecilia Prata, Michael V Berridge, Carole Grasso, Heinz-Herbert Fiebig, Gerhard Kelter, Angelika M Burger, Mark W Kunkel
  [show abstract] [hide abstract]
  ABSTRACT: This paper reports the synthesis of compounds formed by two indole systems separated by a heterocycle (pyridine or piperazine). As a primary screening, the new compounds were submitted to the National Cancer Institute for evaluation of antitumor activity in the human cell line screen. The pyridine derivatives were far more active than the piperazine derivatives. For the study of the mechanism of action, the most active compounds were subjected to COMPARE analysis and to further biological tests including proteasome inhibition and inhibition of plasma membrane electron transport. The compound bearing the 5-methoxy-2-indolinone moiety was subjected to the first in vivo experiment (hollow fiber assay) and was active. It was therefore selected for the second in vivo experiment (human tumor xenograft in mice). In conclusion we demonstrated that this approach was successful, since some of the compounds described are much more active than the numerous, so far prepared and tested 3-indolylmethylene-2-indolinones.
  Journal of Medicinal Chemistry 08/2008; 51(15):4563-70. · 4.80 Impact Factor
• Article: Diphenidol-related diamines as novel muscarinic M4 receptor antagonists.

  Lucilla Varoli, Aldo Andreani, Silvia Burnelli, Massimiliano Granaiola, Alberto Leoni, Alessandra Locatelli, Rita Morigi, Mirella Rambaldi, Andrea Bedini, Nicola Fazio, Santi Spampinato
  [show abstract] [hide abstract]
  ABSTRACT: A series of hydrochloride derivatives 2a-9a and quaternary ammonium derivatives 3b-9b of diphenidol have been synthesized and characterized in receptor binding and cellular functional assays versus human muscarinic M(1)-M(5) receptors expressed in CHO cells. Compound 8b, a methiodide derivative with a bipiperidinyl moiety and a second diphenidol framework, showed a potent and selective M(4) activity as competitive antagonist. Moreover 8b, acting as an allosteric modulator, was able to retard the dissociation rate of [(3)H]-N-methylscopolamine from CHO-M(4) cell membranes exposed to atropine. Taken together, these data suggest that 8b might open new avenues to the discovery of novel multivalent antagonists for the muscarinic receptors.
  Bioorganic & medicinal chemistry letters 06/2008; 18(9):2972-6. · 2.65 Impact Factor
• Article: Synthesis and pharmacological profile of a series of 1-substituted-2-carbonyl derivatives of Diphenidol: novel M4 muscarinic receptor antagonists.

  Lucilla Varoli, Piero Angeli, Michela Buccioni, Silvia Burnelli, Nicola Fazio, Gabriella Marucci, Maurizio Recanatini, Santi Spampinato
  [show abstract] [hide abstract]
  ABSTRACT: Novel 2-carbonyl analogues of diphenidol (1) - bearing lipophylic 1-substituents (2) - were synthesized starting from previously investigated diphenidol derivatives acting as M(2)-selective muscarinic antagonists. These compounds were tested for receptor binding affinity versus human muscarinic M(1)-M(5) receptors stably expressed in CHO-K1 cells. Their activity in functional assays carried out on CHO-K1 cells expressing human M(4) receptors (CHO-hM(4)) and on classical models of M(1)-M(3) receptors, in guinea pig and rabbit tissue preparations, was also evaluated. Compound 2d showed an affinity of pK(i) = 7.73 at the human M(4)-receptor subtype with selectivity ratios ranging from 31-fold (M(4)/M(5)) to 60-fold (M(4)/M(2)). Interestingly this compound, in CHO-hM(4) cells, blocked the inhibition of forskolin-activated cAMP accumulation produced by carbachol (IC(50)= 61 nM) whereas it was a weak muscarinic antagonist in functional tests carried out in guinea-pig and rabbit tissue expressing M(1) (pK(b) = 5.96), M(2) (pK(b) = 6.43) and M(3) (pK(b) = 6.09) receptors. In conclusion, the modifications performed in this work on reference compounds led us to obtain surprisingly a M(4) selective antagonist. Considering the therapeutic indications for M(4) selective antagonists, compound 2d may serve as a novel lead compound for further optimization.
  Medicinal Chemistry 04/2008; 4(2):121-8. · 1.50 Impact Factor
• Article: Chemiluminescent high-throughput microassay applied to imidazo[2,1-b]thiazole derivatives as potential acetylcholinesterase and butyrylcholinesterase inhibitors.

  Aldo Andreani, Silvia Burnelli, Massimiliano Granaiola, Massimo Guardigli, Alberto Leoni, Alessandra Locatelli, Rita Morigi, Mirella Rambaldi, Manuela Rizzoli, Lucilla Varoli, Aldo Roda
  [show abstract] [hide abstract]
  ABSTRACT: The synthesis of a new series of imidazo[2,1-b]thiazole derivatives is described. They were tested as potential acetylcholinesterase and butyrylcholinesterase inhibitors by means of a chemiluminescent microassay. Although most of the new compounds did not show significant cholinesterase inhibition potency, three of them displayed selective antiacetylcholinesterase activity in the micromolar range.
  European Journal of Medicinal Chemistry 04/2008; 43(3):657-61. · 3.35 Impact Factor
• Article: New antitumor imidazo[2,1-b]thiazole guanylhydrazones and analogues.

  Aldo Andreani, Silvia Burnelli, Massimiliano Granaiola, Alberto Leoni, Alessandra Locatelli, Rita Morigi, Mirella Rambaldi, Lucilla Varoli, Natalia Calonghi, Concettina Cappadone, Giovanna Farruggia, Maddalena Zini, Claudio Stefanelli, Lanfranco Masotti, Norman S Radin, Robert H Shoemaker
  [show abstract] [hide abstract]
  ABSTRACT: The synthesis of new antitumor 6-substituted imidazothiazole guanylhydrazones is described. Moreover, a series of compounds with a different basic chain at the 5 position were prepared. Finally, the replacement of the thiazole ring in the imidazothiazole system was also considered. All the new compounds prepared were submitted to the NCI cell line screen for evaluation of their antitumor activity. A few selected compounds were submitted to additional biological studies concerning effects on the cell cycle, apoptosis, and mitochondria.
  Journal of Medicinal Chemistry 03/2008; 51(4):809-16. · 5.25 Impact Factor
• Article: New Antitumor Imidazo[2,1-b]thiazole Guanylhydrazones and Analogues1

  Aldo Andreani, Silvia Burnelli, Massimiliano Granaiola, Alberto Leoni, Alessandra Locatelli, Rita Morigi, Mirella Rambaldi, Lucilla Varoli, Natalia Calonghi, Concettina Cappadone, Giovanna Farruggia, Maddalena Zini, Claudio Stefanelli, Lanfranco Masotti, Norman S. Radin, Robert H. Shoemaker
  [show abstract] [hide abstract]
  ABSTRACT: The synthesis of new antitumor 6-substituted imidazothiazole guanylhydrazones is described. Moreover, a series of compounds with a different basic chain at the 5 position were prepared. Finally, the replacement of the thiazole ring in the imidazothiazole system was also considered. All the new compounds prepared were submitted to the NCI cell line screen for evaluation of their antitumor activity. A few selected compounds were submitted to additional biological studies concerning effects on the cell cycle, apoptosis, and mitochondria.
  02/2008;
• Article: Substituted E-3-(2-chloro-3-indolylmethylene)1,3-dihydroindol-2-ones with antitumor activity. Effect on the cell cycle and apoptosis.

  Aldo Andreani, Silvia Burnelli, Massimiliano Granaiola, Alberto Leoni, Alessandra Locatelli, Rita Morigi, Mirella Rambaldi, Lucilla Varoli, Natalia Calonghi, Concettina Cappadone, Giovanna Farruggia, Maddalena Zini, Claudio Stefanelli, Lanfranco Masotti
  [show abstract] [hide abstract]
  ABSTRACT: The synthesis and antitumor activity of new E-3-(2-chloro-3-indolylmethylene)1,3-dihydroindol-2-ones is described. They were studied at the National Cancer Institute, taking into consideration the 50% growth inhibitory power (pGI50), the cytostatic effect (pTGI = total growth inhibition), and the cytotoxic effect (pLC50). All the compounds were potent growth inhibitors, with mean pGI50 ranging from 5.26 to 7.72. They were also analyzed with NCI COMPARE algorithm. Further studies were dedicated to the effects on the cell cycle and apoptosis.
  Journal of Medicinal Chemistry 08/2007; 50(14):3167-72. · 5.25 Impact Factor
• Article: Substituted E-3-(2-Chloro-3-indolylmethylene)1,3-dihydroindol-2-ones with Antitumor Activity. Effect on the Cell Cycle and Apoptosis1

  Aldo Andreani, Silvia Burnelli, Massimiliano Granaiola, Alberto Leoni, Alessandra Locatelli, Rita Morigi, Mirella Rambaldi, Lucilla Varoli, Natalia Calonghi, Concettina Cappadone, Giovanna Farruggia, Maddalena Zini, Claudio Stefanelli, Lanfranco Masotti
  [show abstract] [hide abstract]
  ABSTRACT: The synthesis and antitumor activity of new E-3-(2-chloro-3-indolylmethylene)1,3-dihydroindol-2-ones is described. They were studied at the National Cancer Institute, taking into consideration the 50% growth inhibitory power (pGI50), the cytostatic effect (pTGI = total growth inhibition), and the cytotoxic effect (pLC50). All the compounds were potent growth inhibitors, with mean pGI50 ranging from 5.26 to 7.72. They were also analyzed with NCI COMPARE algorithm. Further studies were dedicated to the effects on the cell cycle and apoptosis.
  06/2007;
• Article: Synthesis and antitumor activity of guanylhydrazones from 6-(2,4-dichloro-5-nitrophenyl)imidazo[2,1-b]thiazoles and 6-pyridylimidazo[2,1-b]thiazoles(1).

  Aldo Andreani, Silvia Burnelli, Massimiliano Granaiola, Alberto Leoni, Alessandra Locatelli, Rita Morigi, Mirella Rambaldi, Lucilla Varoli, Giovanna Farruggia, Claudio Stefanelli, Lanfranco Masotti, Mark W Kunkel
  [show abstract] [hide abstract]
  ABSTRACT: The design and synthesis of antitumor imidazothiazole guanylhydrazones are reported. The compounds were submitted to NCI for testing. All but one were more active than methyl-GAG. A few compounds were selected for further studies in search of a possible mechanism of action. The results from these studies and a final search with the NCI COMPARE algorithm suggest that the guanylhydrazones described in this paper are acting through a novel mechanism of action.
  Journal of Medicinal Chemistry 01/2007; 49(26):7897-901. · 5.25 Impact Factor
• Article: Synthesis and Antitumor Activity of Guanylhydrazones from 6-(2,4-Dichloro-5-nitrophenyl)imidazo[2,1-b]thiazoles and 6-Pyridylimidazo[2,1-b]thiazoles1

  Aldo Andreani, Silvia Burnelli, Massimiliano Granaiola, Alberto Leoni, Alessandra Locatelli, Rita Morigi, Mirella Rambaldi, Lucilla Varoli, Giovanna Farruggia, Claudio Stefanelli, Lanfranco Masotti, Mark W. Kunkel
  [show abstract] [hide abstract]
  ABSTRACT: The design and synthesis of antitumor imidazothiazole guanylhydrazones are reported. The compounds were submitted to NCI for testing. All but one were more active than methyl-GAG. A few compounds were selected for further studies in search of a possible mechanism of action. The results from these studies and a final search with the NCI COMPARE algorithm suggest that the guanylhydrazones described in this paper are acting through a novel mechanism of action.
  12/2006;
• Article: Antitumor activity of substituted E-3-(3,4,5-trimethoxybenzylidene)-1,3-dihydroindol-2-ones1.

  Aldo Andreani, Silvia Burnelli, Massimiliano Granaiola, Alberto Leoni, Alessandra Locatelli, Rita Morigi, Mirella Rambaldi, Lucilla Varoli, Mark W Kunkel
  [show abstract] [hide abstract]
  ABSTRACT: The design and synthesis of anticancer E-3-(3,4,5-trimethoxybenzylidene)-1,3-dihydroindol-2-ones is reported. Strong COMPARE correlations among the cell line responses suggest that these compounds may be acting similarly through a combination of different mechanisms of action. The 5-methoxy derivative (2h) was the most active compound with a mean pGI50 of 6.34, and it is now under review by Biological Evaluation Committee of the National Cancer Institute for possible further studies.
  Journal of Medicinal Chemistry 12/2006; 49(23):6922-4. · 5.25 Impact Factor
• Article: Synthesis and antagonistic activity at muscarinic receptor subtypes of some derivatives of diphenidol.

  Lucilla Varoli, Piero Angeli, Michela Buccioni, Silvia Burnelli, Andrea Cavalli, Gabriella Marucci, Maurizio Recanatini
  [show abstract] [hide abstract]
  ABSTRACT: A series of new derivatives, related to diphenidol and to its 2-carbonyl analogue, were designed as antimuscarinic agents. The synthesized compounds were evaluated both as hydrochlorides and as methiodides by functional tests at guinea-pig heart (M(2)), guinea-pig ileum (M(3)) and rabbit vas deferens (putative M(4)). Two derivatives (3a and 5a) showed an M(3)-selective profile similar to that of the reference compounds, though they resulted less potent.
  Il Farmaco 10/2003; 58(9):651-7.