Volume 10, Nº 5 (2010)

Historically, DNA has been the target for many metal-based anti-cancer drugs, but drawbacks of prevailing therapies have stimulated the search for new molecular targets which may present unique opportunities for therapeutic exploitation. Enzyme inhibition has recently been identified as an alternative and significant target. The pursuit of novel metallodrug candidates that selectively target enzymes is now the subject of intense investigation in medicinal bioinorganic chemistry and chemical biology. In the field of drug design, it is recognised by many that exploiting the structural and chemical diversity of metal ions for the identification of potential hit and lead candidates can dramatically increase the number of possible drug candidates that may be added to the already abundant armoury of chemotherapeutic agents. This review will focus on recent key advancements in enzyme inhibition as a key target for the development of novel metal-based anti-cancer therapeutics. The enormous clinical success of classical platinum drugs, amongst others, coupled with the wealth of knowledge accumulated in recent years on enzyme structure and function, has undoubtedly been the impetus behind the development of new metallodrug candidates with enzyme inhibitory properties. Recent trends in this field will be reviewed with a particular emphasis on metal complexes that inhibit protein and lipid kinases, matrix metalloproteases, telomerases, topoisomerases, glutathione-Stransferases, and histone deacetylases.

Platinum-based anticancer chemotherapy constitutes a cornerstone for the treatment of various solid tumors. However, existing platinum drugs like cisplatin encounter many obstacles such as drug resistance and systemic toxicity in clinical applications. Extensive attempts have been made to minimize the side effects of platinum drugs. This review concentrates on the major development of novel platinum complexes in the last five years, and highlights the complexes with DNA damage mode fundamentally different from that of cisplatin. Diverse platinum complexes are discussed in the text, including analogues of cisplatin or oxaliplatin, monofunctional platinum( II) complexes, polynuclear platinum(II) complexes, trans-platinum(II) complexes, and platinum(IV) complexes. All of these complexes display impressive antitumor activity and some of them show remarkable potentiality to circumvent the resistance to cisplatin. On the basis of these new facts, it can be concluded that structural modifications could substantially modulate the DNA binding mode and DNA damage process, and as a result largely improve the antitumor efficacy of platinum complexes.

For thousands of years medicine and natural products have been closely linked through the use of traditional medicines and natural poisons. Mushrooms have an established history of use in traditional oriental medicine, where most medicinal mushroom preparations are regarded as a tonic, that is, they have beneficial health effects without known negative side-effects and can be moderately used on a regular basis without harm. Mushrooms comprise a vast and yet largely untapped source of powerful new pharmaceutical products. In particular, and most importantly for modern medicine, they represent an unlimited source of compounds which are modulators of tumour cell growth. Furthermore, they may have potential as functional foods and sources of novel molecules. We will review the compounds with antitumor potential identified so far in mushrooms, including low-molecular-weight (LMW, e.g. quinones, cerebrosides, isoflavones, catechols, amines, triacylglycerols, sesquiterpenes, steroids, organic germanium and selenium) and high-molecular-weight compounds (HMW, e.g. homo and heteroglucans, glycans, glycoproteins, glycopeptides, proteoglycans, proteins and RNA-protein complexes).