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

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.