Novel Approaches Towards Development of Non-Classical Platinum-Based Antineoplastic Agents: Design of Platinum Complexes Characterized by an Alternative DNA-Binding Pattern and/or Tumor-Targeted Cytotoxicity

Abstract

Cisplatin is an essential antineoplastic agent whose introduction in clinical use revolutionized the treatment of several solid malignancies, especially those of germinative origin. The unfavorable toxicological profile of this drug, however as well as the resistance of some common malignancies solicited the search of platinum complexes, characterized by lower toxicity and/or broader antitumor spectrum. Thus during the last three decades a plethora of several thousand platinum coordination compounds have been synthesized and evaluated as potential antineoplastic agents. Despite of the numerous compounds investigated however only few of the proved to be of clinical significance and actually none of them could be considered as an ideal substitute for cisplatin regarding both lower toxicity and broader spectrum of anticancer activity. To a great extent the platinum-based drug discovery was confined at structural modification of the parent compound in line with the classic structure-activity relationship concept. Conversely, since the majority of platinum complexes developed so far are closely related structural analogues of cisplatin, it is not surprising that they produce similar cellular effects and any altered pattern of antitumor activity and/or toxicity is likely to be due to pharmacokinetic, rather than truly mechanistic, factors. Studies over the last few years have shown that the structural resemblance to cisplatin is not an absolute requirement for cytotoxicity, which broadens the search for cisplatin analogues towards non-classical compounds with prominent structural/pharmacodynamic dissimilarity to the prototype. This review covers the major approaches to elaboration of non-classical platinum complexes with emphasis on complexes interacting with DNA in a cisplatin-dissimilar fashion and complexes with tumor-targeted cytotoxicity.

PLGA-encapsulated tea polyphenols enhance the chemotherapeutic efficacy of cisplatin against human cancer cells and mice bearing Ehrlich ascites carcinoma

“…CDDP needs to be administered at high doses to obtain the required therapeutic response, thereby leading to severe adverse effects. 1 Low aqueous solubility, high protein binding that reduces drug potency, systemic toxicity, and inherent/or acquired resistance have been reported as major disadvantages of CDDP in cancer therapy. 2,3 Therefore, finding novel ways of lowering the dosage needed without loss of efficacy is very important.…”

Synthesis and analysis of the anticancer activity of platinum(ii) complexes incorporating dipyridoquinoxaline variants

“…This is thought to be due to the larger aromatic surface of the dpq I L , as it contains a higher density of π-electrons that can stack with the basepairs in the binding site. However, the same trend was not observed in complexes that incorporated the methylated intercalating ligands; the 56Me 2 phen complexes (11,12,15,16) bound to CT-DNA with greater affinity than those incorporating both dpq and 23Me 2 dpq (1)(2)(3)(4)(5)(6)(7)(8). This suggests that the structure of the 56Me 2 phen I L is the optimum size when it comes to DNA binding affinity.…”

“…These compounds have great potential as chemotherapeutic agents as they are able to both bypass traditional cell resistance mechanisms and exert higher cytotoxicity than cisplatin and its analogues. [6][7][8][9] To this end, our group has developed a large family of platinum(II) complexes (PCs), many of which are more biologically active than cisplatin in many cell lines. 10 The general structure of these complexes is [Pt(I L )(A L )] 2+ , where I L is an aromatic intercalating ligand and A L is a bidentate ancillary ligand.…”

“…Here we present the synthesis of eight PCs, including [Pt- (6), [Pt-(23Me 2 dpq)(SS-dacp)]Cl 2 (7), and [Pt(23Me 2 dpq)(RR-dacp)]Cl 2 (8). The L1210 murine leukaemia cell line cytotoxicity and calfthymus DNA (CT-DNA) binding affinity of these complexes were determined and compared to similar complexes incorporating the I L s 1,10-phenanthroline ( phen) and 5,6-dimethyl-1,10-phenanthroline (56Me 2 phen) (Fig.…”

Coordination Chemistry of Palladium(II) Ternary Complexes with Relevant Biomolecules

“…Replacement of the chloro ligands by carboxylate groups in carboplatin, cis-diamine(1,1cyclobutanedicarboxylate)platinum (II), is a widely used second-generation platinum anticancer drug showing less side effects than cis-platin. The development of several new anticancer platinum drugs including Carboplatin, Nedaplatin, Lobaplatin and Oxaliplatin (Scheme 1) still have draw-backs and offer no more clinical advantages over the existing cisplatin (Gill, 1984;Galanski et al, 2005;Momekov et al, 2005). Furthermore, the development of acquired resistance to cis-platin is frequently observed during chemotherapy (Heim, 1993).…”