Update of the Preclinical Situation of Anticancer Platinum Complexes: Novel Design Strategies and Innovative Analytical Approaches

Abstract

Research in the field of bioinorganic chemistry has been stimulated by the worldwide success of the anticancer drug cisplatin. 40 years after the first report about its biological activity, carboplatin and oxaliplatin are in routine clinical use today, whereas nedaplatin, lobaplatin, and heptaplatin (SKI2053R) are only approved in Japan, China, and South Korea, respectively. Up to now, about 35 platinum complexes entered clinical trials in order to circumvent the side-effects and the problem of tumor resistance to cisplatin. Additionally, improvement of tumor selectivity as well as the need for a broader spectrum of indications are the motivations for tremendous efforts in the development of novel anticancer platinum-based drugs. New synthetic strategies and innovative analytical approaches provide a basis for a deeper understanding of the pharmacological profile of cisplatin and analogues (biodistribution, clearance, detoxification, side-effects, tumor specificity, cellular uptake, acquired or intrinsic resistance, platinum-DNA adduct removal by the cellular machinery) and give rise to a rational design of promising anticancer platinum coordination compounds. This article reviews the recent development of preclinical platinum complexes with interesting in vitro and in vivo tumor inhibiting properties. It focuses also on innovative synthetic strategies leading to novel classes of platinum complexes. A small part of the review is dedicated to new analytical approaches which have been supplied to or emerged in this field of research.

A novel anti-cancer bifunctional platinum drug candidate with dual DNA binding and histone deacetylase inhibitory activity

“…Nearly 50% of all cancer therapies are platinum (Pt)-based, 1 yet surprisingly to date only three Pt drugs have been approved for world-wide clinical use, namely cisplatin, carboplatin and oxaliplatin. 1,2 The cytotoxicity of Pt drugs is attributed to their ability to bind DNA nucleobases and induce apoptosis.…”

“…1,2 The cytotoxicity of Pt drugs is attributed to their ability to bind DNA nucleobases and induce apoptosis. 2 Despite their enormous success, their widespread application and efficacy are hindered by toxic side effects, their limited activity against many human cancers and their susceptibility to acquired drug resistance.…”

Novel trans-platinum complexes of the histone deacetylase inhibitor valproic acid; synthesis, in vitro cytotoxicity and mutagenicity

“…Currently nearly 50% of all anti-cancer therapies are platinum (Pt)-based [1,2]. Surprisingly only three Pt-based drugs have been approved for worldwide clinical use, namely cisplatin, carboplatin and oxaliplatin ( Fig.…”

“…Surprisingly only three Pt-based drugs have been approved for worldwide clinical use, namely cisplatin, carboplatin and oxaliplatin ( Fig. 1) while three others; nedaplatin, heptaplatin and lobaplatin, have been approved only in Japan, South Korea and China, respectively [1,3]. The cytotoxicity of Pt drugs is attributed to their ability to bind DNA and thereby induce DNA damage and ultimately apoptosis [3,4].…”

Metal-Based Compounds as Proteasome-Inhibitory Anti Cancer Drugs

“…The mechanism by which cisplatin triggers apoptosis is well-understood: cisplatin interacts with DNA and forms adducts which interfere with replication and transcription [24]. While cisplatin has contributed to the cure or treatment of many cancers since its inception, toxicities and resistance associated with cisplatin treatment have hindered its clinical use and spurred the search for new, less toxic metal-based treatments [25,26], using biologically active metals like copper, as well as other metals like gold which have been used successfully in the treatment of other ailments, with different mechanisms of action, such as inhibition of the UPP.…”