1,721,206 research outputs found
From cisplatin to the design of original promising gold-based antineoplastic agents
No full textAmong the non-platinum anticancer agents, gold complexes have recently gained
increasing attention due to their strong tumor cell growth inhibitory effects generally
achieved by exploiting non-cisplatin-like pharmacodynamic and pharmacokinetic
properties and mechanisms of action [1]. In this context, during the last decade,
a number of gold(III)-dithiocarbamato derivatives have been designed and tested by
our research group as potential anticancer agents, and up-to-date results have been
recently reviewed [2,3]. The choice of dithiocarbamato ligands is not accidental; in fact,
dithiocarbamates are still being evaluated for their efficacy as inhibitors of cisplatininduced
nephrotoxicity without decreasing its antitumor activity. In particular, some
compounds showed promising and outstanding properties in terms of greater in vitro
and in vivo antitumor activity, reduced nephrotoxicity and acute toxicity compared to
cisplatin [4]. The capability to overcome both acquired and intrinsic resistance showed
by some types of tumors toward cisplatin confirms that they exert their antitumor
activity by activating different apoptotic and non-apoptotic pathways compared to the
clinically-established platinum-based drugs.
Although their mechanism of action has not been completely elucidated yet, some
potential biological targets have been identified, and proteasome has been recognized
as a major in vitro and in vivo target [5], as well as the selenoenzyme thioredoxin
reductase, both cytosolic and mitochondrial [6,7]. Thus, the idea of combining the
antitumoral properties of metal ion with the presence of a dithiocarbamato moiety as
intrinsic chemoprotectant, appears to be an original and innovative strategy in order to
develop novel and more selective metal-based chemotherapeutic agents
Beyond platinums: gold complexes as anticancer agents
No full textThe accidental discovery of the anticancer properties of cisplatin in the mid 1960s has triggered
the development of alternative platinum-based drugs. However, the platinum-based treatment of
tumor diseases is massively hampered by severe side-effects and resistance development. Sulfurcontaining
biomolecules play a significant role in platinum anticancer chemotherapy because of
their high affinity to platinum(II) ion. Sulfur is involved in the entire metabolic process of platinum
drugs. Strong and irreversible binding of cisplatin to intracellular thiolato ligands is considered as a
major inactivation step, and reactions with sulfur donors in proteins are believed to affect
enzymatic processes. Consequently, the development of novel metal-based compounds with a
pharmacological profile different from that of the clinically-established platinum drugs is a major
goal of modern medicinal chemistry and drug design. Among the non-platinum antitumor agents,
gold(III) complexes have recently gained increasing attention due to their strong tumor cell growth
inhibiting effects generally achieved by exploiting non-cisplatin-like mechanisms of action. The real
breakthrough is not simply the use of gold compounds to treat cancer, but the rational design of
gold-based drugs which may be very effective, non-toxic and potentially selective towards cancer
cells, their potential impact relying on the possible site-specific delivery in localized cancers, thus
strongly improving the cellular uptake and minimizing unwanted side-effects. Cancer cells are
known to overexpress specific biomarkers and receptors needed for tumor growth. Among them,
two integral plasma membrane proteins mediate the cellular uptake of di- and tripeptides and
peptide-like drugs. They are present predominantly in epithelial cells of the small intestine, bile
duct, mammary glands, lung, choroid plexus, and kidney but are also localized in other tissues and
are upregulated in some types of tumors. Accordingly, we have been designing gold(III)-
peptidedithiocarbamato derivatives which could combine both the antitumor properties and
reduced side-effects of the previously reported gold(III) analogues1 with an enhanced
bioavailability and tumor selectivity achieved by exploiting peptide transporters. Our compounds
showed interesting in vitro cytotoxic properties towards a number of cancer cell lines and in vivo
on xenograft models together with negligible organ and acute toxicity. With respect to their
mechanism of action, we identified mitochondria and proteasome as major in vitro and in vivo
targets. These results allowing the filing of an international patent2 for the use of gold(III)
peptidomimetics in cancer chemotherapy as well as providing a solid starting point for them to enter Phase I clinical trials in a few month
Groundbreaking gold(III)-based anticancer agents
No full textAmong the large number of new molecules reported as anticancer agents, gold(III)-dithiocarbamato complexes were found to be potentially better than other chemotherapeutics. Our compounds, has been designed to combine the ‘bullet’ character of the metal center with the stabilizing effect of the sulfur chelating ligands. Moreover, the targeting properties of the peptide moiety recognized by PEPTs peptide transporters, grant a marked cell penetrating properties which results in good antitumor activity together with negligible toxicity. Two compounds in particular, dubbed AuD8 and AuD6, have been selected as potential candidates for the development
“Composti di coordinazione, sintesi, nanoformulazione ed uso degli stessi come antinfiammatori”
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“Composti di coordinazione, sintesi, nanoformulazione ed uso degli stessi come antinfiammatori”
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