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 the Department of Biochemistry (University of
Bologna).
Additional research topics are the synthesis of
antichlolinesterase, antiinflammatory, antimuscarinic,
antitubercular and cardiovascular 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.
Since the COX2 selective antiinflammatory agents used in therapy
show undesired side effects limiting their use, the search of safer
molecules is still active. In this context we synthesized and
evaluated the inhibitory activity of a series of
N-benzyl-2-chloroindol-3-carboxylic acids. Some derivatives showed
inhibitory activity similar to that of rofecoxib.
A class of drugs used for the therapy of Alzheimer's disease act
as acetylcholinesterase inhibitors. The presence of a peripheral
site of the enzyme, besides the catalytic site, and the binding to
both the sites given by bisquaternary compounds, led us to design
and prepare compounds containing two imidazothiazole systems,
separated by different spacers. From some of them even the
bisammonium salts were prepared. The inhibitory activity was
studied with a chemiluminescent method.
Due to their important functions, voltage-gated Ca2+ channels
have been extensively studied and different drugs are available
that are known to interact with them. L-type calcium channel
blockers have gained a critical role in the treatment of different
cardiovascular pathologies. The 1,4-DHP nucleus appears to be an
interesting structure interacting with a wide variety of channel
and receptors and is an example of a "privileged structure": a core
structure that by appropriate molecular decoration can be directed
to diverse pharmacological tissues. We reported the synthesis,
characterization, and functional in vitro assays in cardiac
tissues and smooth muscle (vascular and nonvascular) of a number of
4-heteroaryl-1,4-dihydropyridines.
