Synthesis and Biological Evaluation of a New Furo[2,3-<i>h</i>]quinolin-2(1<i>H</i>)-one

A new furoquinolinone derivative, namely 4-hydroxymethyl-1,6,8-trimethylfuro[2,3-h]quinolin-2(1H)-one (HOFQ), was synthesized and its biological activity studied. By UVA activation, HOFQ induced strong antiproliferative effects in Ehrlich ascite cells, which lost their ability to transmit the tumor by transplantation. HOFQ exhibited poor genotoxicity and absence of skin phototoxicity. Actually, HOFQ sensitization forms DNA-protein cross-linkages but not interstrands cross-links. Therefore, HOFQ appears to be a new promising drug for PUVA photochemotherapy and photopheresis

Gold Dithiocarbamate Derivatives as Potential Antineoplastic Agents: Design, Spectroscopic Properties, and in Vitro Antitumor Activity

At present, cisplatin (cis-diamminodichloroplatinum(II)) is one of the most largely employed anticancer drugs as it is effective in the treatment of 70−90% of testicular and, in combination with other drugs, of ovarian, small cell lung, bladder, brain, and breast tumors. Anyway, despite its high effectiveness, it exhibits some clinical problems related to its use in the curative therapy, such as a severe normal tissue toxicity (in particular, nephrotoxicity) and the frequent occurrence of initial and acquired resistance to the treatment. To obtain compounds with superior chemotherapeutic index in terms of increased bioavailability, higher cytotoxicity, and lower side effects than cisplatin, we report here on some gold(I) and gold(III) complexes with dithiocarbamate ligands (DMDT = N,N-dimethyldithiocarbamate; DMDTM = S-methyl-N,N-dimethyldithiocarbamate; ESDT = ethylsarcosinedithiocarbamate), which have been synthesized, purified, and characterized by means of elemental analyses, conductivity measurements, mono- and bidimensional NMR, FT-IR, and UV−vis spectroscopy, and thermal analyses. Moreover, the electrochemical properties of the designed compounds have been studied through cyclic voltammetry. All the synthesized gold complexes have been tested for their in vitro cytotoxic activity. Remarkably, most of them, in particular gold(III) derivatives of N,N-dimethyldithiocarbamate and ethylsarcosinedithiocarbamate, have been proved to be much more cytotoxic in vitro than cisplatin, with IC50 values about 1- to 4-fold lower than that of the reference drug, even toward human tumor cell lines intrinsically resistant to cisplatin itself. Moreover, they appeared to be much more cytotoxic also on the cisplatin-resistant cell lines, with activity levels comparable to those on the corresponding cisplatin-sensitive cell lines, ruling out the occurrence of cross-resistance phenomena and supporting the hypothesis of a different antitumor activity mechanism of action

Gold(III) Dithiocarbamate Derivatives for the Treatment of Cancer: Solution Chemistry, DNA Binding, and Hemolytic Properties

Gold(III) compounds are emerging as a new class of metal complexes with outstanding cytotoxic properties and are presently being evaluated as potential antitumor agents. We report here on the solution and electrochemical properties, and the biological behavior of some gold(III) dithiocarbamate derivatives which have been recently proved to be one to 4 orders of magnitude more cytotoxic in vitro than the reference drug (cisplatin) and to be able to overcome to a large extent both intrinsic and acquired resistance to cisplatin itself. Their solution properties have been monitored in order to study their stability under physiological conditions; remarkably, they have shown to undergo complete hydrolysis within 1 h, the metal center remaining in the +3 oxidation state. Their DNA binding properties and ability in hemolyzing red blood cells have been also evaluated. These gold(III) complexes show high reactivity toward some biologically important isolated macromolecules, resulting in a dramatic inhibition of both DNA and RNA synthesis and inducing DNA lesions with a faster kinetics than cisplatin. Nevertheless, they also induce a strong and fast hemolytic effect (compared to cisplatin), suggesting that intracellular DNA might not represent their primary or exclusive biological target

Cisplatinum and Transplatinum Complexes with Benzyliminoether Ligands; Synthesis, Characterization, Structure−Activity Relationships, and In Vitro and In Vivo Antitumor Efficacy

New benzyliminoether derivatives [PtCl2{N(H)C(OMe)CH2Ph}2] of cis (1a, 1b) and trans (2a, 2b) geometry were prepared and characterized by means of elemental analysis, multinuclear NMR and FT-IR techniques, and X-ray crystallography; this latter was carried out for 1b. The cytotoxic properties of these new platinum(II) complexes were evaluated in terms of cell growth inhibition against a panel of different types of human cancer cell lines. cis-[PtCl2{E-N(H)C(OMe)CH2Ph}2] (1a) was significantly more potent than cisplatin against all tumor cell lines tested, showing IC50 values from about 2- to 17-fold lower than the reference compound. Chemosensitivity tests performed on cisplatin-sensitive and -resistant cell lines have demonstrated that complex 1a is able to overcome cisplatin resistance. Analyzing the mechanism by which complex 1a led to cell death, we have found that it induced apoptosis in a dose-dependent manner, accompanied by the activation of caspase-3. The in vivo studies carried out using two transplantable tumor models (L1210 leukemia and Lewis lung carcinoma) showed that derivative 1a induced a remarkable antitumor activity in both tumor models, as measured by prolonged survival and reduced tumor mass compared to control groups