The main research topic is the synthesis of new compounds endowed with antiproliferative activity. Different classes of compounds have been studied such as 3,4,5-trimethoxybenzylidene-2-indolinones, imidazothiazolylmethylene-2-indolinones, indolylmethylene-2-indolinones, bis-indoles and imidazothiazole guanylhydrazones. The antitumor activity was tested at the National Cancer Institute (USA): several compounds showed significant in vitro antitumor activity and some of them were tested in vivo. The possible mechanisms of action has been studied with the collaboration of several research groups of the Department of Pharmacy and Biotechnology of the University of Bologna and of other Universities. Additional research topics are the synthesis of antiviral, antibacterial, antimycotic and antitubercular agents.
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 well known 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.
In this context, novel benzoimidazothiazole derivatives have recently been investigated, among which the compound MBT3T has shown potent antitumor activity against imatinib-resistant GISTs. The compound exerts its activity by binding to tubulin and inhibiting microtubule polymerization, thereby inducing G2/M cell cycle arrest and apoptosis. MBT3T demonstrated high efficacy in 3D cellular models and in vivo in zebrafish xenografts, significantly reducing tumor growth without inducing systemic toxicity.
Another research line recently developed concerns G-quadruplex-binding compound, currently perceived as possible anticancer therapeutics. Starting from a promising lead, novel hydrazone-based compounds were synthesized and evaluated as G-quadruplex binders. The in vitro G-quadruplex-binding properties of the derivatives were investigated employing both human telomeric and oncogene promoter G-quadruplexes with different folding topologies as targets. This study led to the identification of potent G-quadruplex stabilizers with high selectivity over duplex DNA and preference for one G-quadruplex topology over others. Among them, selected derivatives have been shown to trap G-quadruplex structures in the nucleus of cancer cells. Interestingly, this behavior correlates with efficient cytotoxic activity in human osteosarcoma and colon carcinoma cells.
Research activities have also focused on the design and synthesis of new heterocyclic compounds endowed with antimicrobial activity. In this context, isatin derivatives showing efficacy against Staphylococcus aureus, including antibiotic-resistant strains and bacterial biofilms, have been investigated. These compounds, characterized by low toxicity toward human cells, are able to bind the FtsZ protein, a key target in the bacterial cell division process.
