The main reasearch topic is the synthesis of new compounds
endowed with antitumor 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
antichlolinesterase, antiinflammatory, antimuscarinic 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 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.
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.
