Ívina Paula de Souza*
Received: August 02, 2019; Published: August 09, 2019
Corresponding author:Ívina Paula de Souza, Department of Chemistry, Centro Federal de Educação Tecnológica de Minas Gerais, Brazil
The accidental discovery of cisplatin, cis-diaminodichloroplatinum (II), by Rosenberg and Van Camp in 1969, as a chemotherapeutic agent opened a new perspective by including metal complexes as possible antitumor agents [1,2]. Cisplatin was approved in the medical clinic, by Food and Drug Administration of the United States in 1978, and its importance in the treatment of various types of cancer, such as testicular, ovarian and pulmonary carcinoma is unequivocal [3,4]. However, the use of cisplatin has shown some limitations, such as the appearance of side effects, low solubility in water, and, especially, the development of cellular resistance [5,6]. The limitations in the treatment of neoplasic diseases with cisplatin have encouraged diverse research groups in the pursuit of other metal complexes, which should be more active and less toxic. An alternative would be replacing the metal center. In this context, copper complexes have shown to be an interesting alternative. Copper is an essential metallic ion that is involved in numerous biological process, playing an important role in diverse cellular function. In addition, copper may be less toxic for normal cells rather than to cancer cells [7,8]. The anoxic characteristic of cancer cells promotes the reduction of Cu(II) to Cu(I), which is not possible in normal cells. Cu(I) can catalyze the formation of reactive oxygen species (ROS) and induce lipidic peroxidation [9-11].
Keywords: Casiopeinas; Metallodrugs; Chemotherapy; Lipidic peroxidation; Phenathroline
Many studies have been reported about the antitumor activity of copper complexes and there seems to be more than one mechanism. Highest importance has been given for mechanisms involved in DNA damages, since they play an essential role in cell division processes. Copper complexes interact with DNA in different ways combining the generation of ROS [12,13] or phosphate hydrolysis  with either grove binding  or intercalative interactions [16,17].
Pioneer research developed by Sigman, has led to substantial interest in complexes with copper and phenathroline and their derivatives as anticancer . Bis(1,10-phenanthroline)copper(II) complex, [Cu(phen)2]2+, cleaves DNA, which is reduced in situ, rising to [Cu(phen)2]+, which binds to the minor DNA groove, combines with molecular oxygen, leading to the formation of ROS, that induces DNA degradation through free-radical oxidation of desoxyribose [19-22]. Another copper(II) complex, [Cu(N9-ABS) (phen)2] (where N9-ABS = N-(9Hpurin-6-yl)benzenesulfonamine), intercalates with DNA, and cleaves it in the presence of ascorbate, and this compound was more active than [Cu(phen)2]2+ in Caco- 2 cells and Jurkat T lymphocytes . Kellett et al. reported complexes of bis-chelate Cu(II) and phenanthroline-phenazine that exhibit high DNA binding constant, are capable of intercalating DNA and minor-groove binding, forwarding the complete degradation of pUC19, and these compounds also show activity against SKOV3 human cancer cells [24,25]. Our research group has shown that other copper(II) ternary complexes containing N,N-heterocyclic ligands and an antibiotic are also capable of inhibiting the growth of tumor cells at low concentrations and are among the most potent agents capable of fragmenting DNA molecule through oxidative mechanism [12,26-28]. Some these compounds also demonstrated enhancement cytotoxicity effects when irradiated with UV-light making them potential agents for photodynamic therapy .
Antitumor activity of wide variety of copper complexes has been studied. Mono and binuclear copper(II) complexes with thiosemicarbazones with different coordination number have been reported and their nuclease and antitumor activities have been demonstrated [30-33]. Copper complexes with O,O-donor ligands in aromatic systems have also been described. They have ability to noncovalently bound, by intercalating to DNA base pairs, and to inhibit topoisomerase-I activity .
Special attention has been given to one promising class of copper compounds which has been examined in clinical trial-casiopeinas. Casiopeinas have been synthesized and patented [35,36]. They are ternary copper complexes with a general formula [Cu(N-N) (A-A)]NO3, where N-N represents diimine donors, and A-A stands for N-O or O-O donors, and it was demonstrated that casiopeinas show activities in vitro and in vivo which are dependent of organic moieties [37-39]. It was observed that casiopeinas lead to cell death via apoptosis in several human tumor cells lines. This process is promoted by increment in ROS, which damages the mitochondria [37,39-41]. In addition, casiopeinas-like complexes have also demonstrated antitumor activity, and the mechanism seems to be by DNA intercalation and electrostatic force, beside inhibiting topoisomerase-I activity . One of such complex, known as Casiopeina III-ia, is in clinical trial as a potential antitumoral agent . Casiopeinas, however, exhibit very low solubility in aqueous medio, which may present a pharmaceutical barrier.
There are numerous barriers for a new compound be approved and used in medical clinic as chemotherapy, which include high cytotoxic effect in cancer cells, low cytotoxicity in normal cells, aqueous solubility, low side effect, among others. An attempt to design new complexes involve enhancing the effect of ligands that exhibit antitumor activity by combining with metallic ion that also exhibit antitumor activity. This seem to promise derivatives that should deserve further investigation in vivo experiments followed eventually by clinical trials.
Moreover, in agree with Santini et al. , “integration of empirical screening approaches with novel knowledge emerging from genome and proteome research as well as bioinformation technologies might be the most efficient way forward in order to identify other promising targets and gain molecular insights into the mechanism of action of copper species. This information may hopefully allow a move away from the mere synthesis of cytotoxic agents, with unknown mechanisms of actions, to rational design of copper-based anticancer therapeutics”.
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Gastroenterology and HepatologyUniversity of Alabama, UK
Department of MedicineUniversities of Bradford, UK
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Radiation ChemistryNational University of Mexico, USA
Analytical ChemistryWentworth Institute of Technology, USA
Minimally Invasive SurgeryMercer University school of Medicine, USA
Pediatric DentistryUniversity of Athens , Greece
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