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

Ronconi, Luca; Giovagnini, Lorena; Marzano, Christine; Bettio, Frazia; Graziani, R.; Pilloni, Giuseppe; Fregona, Dolores

doi:10.1021/ic048260v

Cited by 314 publications

(256 citation statements)

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“…1) has been selected for additional in vivo studies because of its overall favorable solubility, stability and in vitro antitumor properties. 23,34 First, we evaluated the anticancer activity in vivo of AUL12 on three transplantable murine tumor models (i.e., solid Ehrlich carcinoma, Ehrlich ascites and Lewis lung carcinoma) to confirm the promising results previously obtained in vitro toward several human tumor cell lines. 23 Chemotherapy with AUL12 at 10 mg kg À1 was proved to be much more effective than cisplatin toward all three tumor types.…”

Section: Discussionmentioning

confidence: 93%

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Gold(III)‐dithiocarbamato anticancer agents: Activity, toxicology and histopathological studies in rodents

Marzano

Ronconi

Chiara

et al. 2010

Intl Journal of Cancer

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Gold(III)-dithiocarbamato complexes have recently gained increasing attention as potential anticancer agents because of their strong tumor cell growth-inhibitory effects, generally achieved by exploiting non-cisplatin-like mechanisms of action. The rationale of our research work is to combine the antitumor properties of the gold(III) metal center with the potential chemoprotective function of coordinated dithiocarbamates in order to reduce toxic side effects (in particular nephrotoxicity) induced by clinically established platinum-based drugs. In this context, [Au III Br 2 (ESDT)] (AUL12) was proved to exert promising and outstanding antitumor activity in vitro and to overcome both acquired and intrinsic resistance showed by some types of tumors toward cisplatin. As a subsequent extension of our previous work, we here report on detailed in vivo studies in rodents, including antitumor activity toward three transplantable murine tumor models, toxicity, nephrotoxicity and histopathological investigations. Remarkably, the gold(III) complex AUL12 stands out for higher anticancer activity than cisplatin toward all the murine tumor models examined, inducing up to 80% inhibition of tumor growth. In addition, it shows low acute toxicity levels (lethal dose, LD 50 5 30 mg kg 21 ) and reduced nephrotoxicity. Altogether, these results confirm the reliability of our drug design strategy and support the validation of this gold(III)-dithiocarbamato derivative as a suitable candidate for clinical trials.The accidental discovery of the anticancer properties of cisplatin (cis-dichlorodiammineplatinum(II), cis-[Pt II Cl 2 (NH 3 ) 2 ]; Fig. 1) in the mid-1960s 1 has triggered the development of both platinum 2 -and other metal-based 3,4 alternative compounds. Although well-established in current cancer chemotherapy, the use of platinum compounds for the treatment of tumor diseases is massively hampered by severe side effects such as nausea, alopecia, ototoxicity, neurotoxicity, myelosuppression, nephrotoxicity and tumor resistance, either intrinsic or acquired during cycles of therapy. 5 Consequently, the development of novel metallodrugs showing a different pharmacological profile is a major goal of modern medicinal chemistry and drug design.Among the non-platinum antitumor agents, gold complexes have recently gained increasing attention because of their strong inhibitory effects on tumor cell growth, generally achieved by exploiting non-cisplatin-like pharmacodynamic and pharmacokinetic properties and mechanisms of action. 6,7 Owing to their traditional use in medicine for the treatment of rheumatoid arthritis, gold derivatives are suitable candidates as potential alternatives to platinum drugs. In fact, the antiarthritic activity arises from their known immunosuppressive and anti-inflammatory actions, thus establishing, at least in principle, a connection between the two therapies. Moreover, gold(III) complexes show chemical features that are very close to those of clinically established platinum(II) derivatives, such as the pre...

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Section: Discussionmentioning

confidence: 93%

“…The investigated gold(III) complex was proved by 1 H NMR studies to be stable in DMSO-d 6 over 48 hr at room temperature. 23 …”

Section: Chemicalsmentioning

confidence: 99%

Gold(III)‐dithiocarbamato anticancer agents: Activity, toxicology and histopathological studies in rodents

Marzano

Ronconi

Chiara

et al. 2010

Intl Journal of Cancer

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“…Because the cellular environment is generally reducing, Au (III) is expected to be reduced to Au (I) and metallic Au, making Au (III) complexes less effective (109). Interest in these complexes increased after Pt (II) complexes showed positive results, because Au (III) and Pt (II) are isoelectronic and tetracoordinate gold (III) complexes share the same square planar geometry as cisplatin (110).…”

Section: Gold Dithiocarbamatesmentioning

confidence: 99%

“…These newer compounds exhibit a superior chemotherapeutic index than cisplatin due to greater bioavailabilty, increased cytotoxicity, and fewer toxic side effects (109). Dithiocarbamates have been evaluated for their efficacy as inhibitors of cisplatin-induced nephrotoxicity (112)(113)) and have since been tested for in vitro cytotoxicity toward a variety of human tumor cell lines.…”

Section: Gold Dithiocarbamatesmentioning

confidence: 99%

New applications of old metal-binding drugs in the treatment of human cancer

Dou¹

2012

Front Biosci

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Significant advances in the use of metal complexes, precipitated by platinum, have fostered a renewed interest in harnessing their rich potential in the treatment of cancer. In addition to platinum-based complexes, the anticancer properties of other metals such as ruthenium have been realized, and ruthenium-based compounds are currently being investigated in clinical trials. Since the process of drug development can be expensive and cumbersome, finding new applications of existing drugs may provide effective means to expedite the regulatory process in bringing new drugs to the clinical setting. Encouraging findings from laboratory studies reveal significant anticancer activity from different classes of metal-chelating compounds, such as disulfiram, clioquinol, and dithiocarbamate derivatives that are currently approved for the treatment of various pathological disorders. Their use as coordination complexes with metals such as copper, zinc, and gold that target the ubiquitin-proteasome pathway have shown significant promise as potential anticancer agents. This review discusses the unique role of several selected metals in relation to their anti-cancer properties as well as the new therapeutic potential of several previously approved metal-chelating drugs. In vitro and in vivo experimental evidence along with mechanisms of action (e.g., via targeting the tumor proteasome) will also be discussed with anticipation of strengthening this exciting new concept. KeywordsDisulfiram; Clioquinol; Dithiocarbamates; Copper; Zinc; Ubiquitin-Proteasome Pathway; Proteasome Inhibitor; Chymotrypsin-Like Activity; Review INTRODUCTION The use of metal complexes for cancer treatmentThe development of metal-based complexes for the treatment of cancer began with the discovery of the anti-cancer properties of cisplatin in the early 1960s (Figure 1). Over 90% of testicular cancer cases have been cured by cisplatin, and it has also been important in the treatment of several other types of cancer, including ovarian, cervical, bladder, head and neck, melanoma, and lymphomas (1). Cisplatin interacts with DNA and forms adducts which interfere with the replication and transcription processes, and ultimately triggers apoptosis (2). These cisplatin-DNA interactions have been extensively studied, and it has been clearly shown that a (Pt)-GG intrastrand cross-link is responsible for the cytotoxicity of Send correspondence to: Qing Ping Dou, The Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA, doup@karmanos.org. NIH Public Access Author ManuscriptFront Biosci (Schol Ed). Author manuscript; available in PMC 2013 May 07. Published in final edited form as:Front Biosci (Schol Ed). ; 4: 375-391. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript cisplatin (3). However, the toxicities associated with cisplatin, coupled with intrinsic and acquired drug resistance, ha...

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“…Many gold(III) compounds are able to overcome to a large extent resistance to cisplatin, suggesting a different mechanism of action with respect to cisplatin [18][19][20][21]. Mechanistic studies indeed did suggest that, in contrast to cisplatin, DNA is not the primary target of gold complexes.…”

Section: Introductionmentioning

confidence: 99%

The synthesis, chemical and biological properties of dichlorido(azpy)gold(III) chloride (azpy= 2-(phenylazo)pyridine) and the gold-induced conversion of the azpy ligand to the chloride of the novel tricyclic pyrido[2,1-c][1,2,4]benzotriazin-11-ium cation

Garza-Ortiz

Dulk

Brouwer

et al. 2007

Journal of Inorganic Biochemistry

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The synthesis, chemical and biological properties of dichlorido(azpy)gold(III) chloride (azpy = 2-(phenylazo)pyridine) and the gold-induced conversion of the azpy ligand to the chloride of the novel tricyclic pyrido [2,1-c] AbstractA new Au(III) coordination compound with the ligand 2-(phenylazo)pyridine has been synthesized and fully characterized by means of elemental analysis, IR, UV-visible, conductivity measurements, NMR, electrospray ionization (ESI-MS) and inductively coupled plasma optical emission spectrometry (ICP-OES). The chemical stability of the cation in this compound, [Au(azpy)Cl 2 ] + (abbreviated: Au-azpy), was analyzed by means of several physicochemical methods. While stable in the solid state, stability studies performed with the gold compound in solution showed an unexpected and unprecedented reactivity. A cationic organic derivative of 2-(phenylazo)pyridine, (abbreviated: pyrium), was produced from the solution and has been isolated as its chloride salt and characterized by crystal structure determination, elemental analysis, NMR, ESI-MS and conductivity studies in solution. This cyclization reaction is reported for the first time in the case of gold coordination compounds.The Au adduct and the pyrium cation were investigated as potential cytotoxic and anticancer agents, and both show moderate to high cytotoxic properties in cisplatin-sensitive and cisplatin-resistant ovarian carcinoma cell lines, A2780; and cisplatin-sensitive and cisplatinresistant murine lymphocytic leukemia cell lines, L1210. Significant anticancer activity against the cisplatin resistant cell lines was found for the pyrium salt, ruling out the occurrence of cross resistance phenomena.

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

Cited by 314 publications

References 73 publications

Gold(III)‐dithiocarbamato anticancer agents: Activity, toxicology and histopathological studies in rodents

Gold(III)‐dithiocarbamato anticancer agents: Activity, toxicology and histopathological studies in rodents

New applications of old metal-binding drugs in the treatment of human cancer

The synthesis, chemical and biological properties of dichlorido(azpy)gold(III) chloride (azpy= 2-(phenylazo)pyridine) and the gold-induced conversion of the azpy ligand to the chloride of the novel tricyclic pyrido[2,1-c][1,2,4]benzotriazin-11-ium cation

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