Foto del docente

Mirella Rambaldi

Adjunct professor

Department of Pharmacy and Biotechnology

Research

Keywords: Imidazothiazoles Indoles apoptosis Synthesis of new molecules Evaluation of the antitumor activity G-quadruplex

Synthesis and cytotoxic activity of new molecules

Synthesis of new compounds interfering with mitochondrial respiratory chain

Synthesis and specificity evaluation of new antiinflammatory

Synthesis of tubulin ligands

Synthesis of G-quadruplex ligands

 



The main research line is devoted to the development of antitumor agents belonging to the following classes: imidazothiazole guanylhydrazones, indolylmethylene-2-indolinones and imidazothiazolylmethylene-2-indolinones; moreover substituted indolinones have been condensed, through a methine bridge, with a trimethoxyphenyl group which is present in well known antitumor drugs such as combretastatin, podophyllotoxin and colchicine. Even the synthesis of bis-indole derivatives has been considered which led to file a patent.

The great majority of the published compounds showed an interesting activity with 50% growth inhibition values of 10-7 and 10-8 M and low toxicity.

The antitumor activity was evaluated in agreement with the protocols available at the National Cancer Institute (NCI, Bethesda, MD) on a panel of 60 human cell lines. The most interesting derivatives were selected by the Biological Evaluation Commitee of NCI for an in deep evaluation and some of them were tested in vivo. Many derivatives were studied with COMPARE (an NCI algorithm) showing strong cellular response correlation.

Since it is clear now that numerous indole derivatives may induce arrest of the cell cycle in the G2/M phase and/or apoptosis in different cell lines, the most interesting compounds were studied by means of flow cytometry on cell growth and cell cycle progression in colon adenocarcinoma HT29 cell lines and on ovarian carcinoma IGROV-1 cells. These tests demonstrated that compounds showing low toxicity may interfere with cell cycle progression with a block in G2/M without a significant effect on tubulin polymerization whereas other derivatives seem to trigger a different and not yet identified biochemical pathway. Several compounds led to apoptosis as shown by caspase activation at least in ovarian carcinoma cells. These observations suggest that the test compounds could interfere with cell proliferation by means of multiple mechanisms.

Recently, the synthesis of new ligands of G-quadruplex has been developed as another theme of research. The study is mainly aimed to hydrazone derivatives with core diimidazopyrimidine. They could significantly stabilize G-quadruplex structures, selectively with respect to duplex DNA, highlighting preferential interactions for G-quadruplex structures in parallel.

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