http://www.healthcare.uiowa.edu/corefacilities/esr/publications/buettnerpubs/pdf/FRBM-2001-30-1191-FQS-Redox.pdf

Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple.

Structure, Recognition, and Processing of Cisplatin-DNA Adducts.

The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing nonclassical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown, and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this Review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore nonclassical platinum(II) complexes with trans geometry or with a monofunctional coordination mode, polynuclea...

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

Hydrogenation is a core technology in chemical synthesis. High rates and selectivities are attainable only by the coordination of structurally well-designed catalysts and suitable reaction conditions. The newly devised [RuCl(2)(phosphane)(2)(1,2-diamine)] complexes are excellent precatalysts for homogeneous hydrogenation of simple ketones which lack any functionality capable of interacting with the metal center. This catalyst system allows for the preferential reduction of a C=O function over a coexisting C=C linkage in a 2-propanol solution containing an alkaline base. The hydrogenation tolerates many substituents including F, Cl, Br, I, CF(3), OCH(3), OCH(2)C(6)H(5), COOCH(CH(3))(2), NO(2), NH(2), and NRCOR as well as various electron-rich and -deficient heterocycles. Furthermore, stereoselectivity is easily controlled by the electronic and steric properties (bulkiness and chirality) of the ligands as well as the reaction conditions. Diastereoselectivities observed in the catalytic hydrogenation of cyclic and acyclic ketones with the standard triphenylphosphane/ethylenediamine combination compare well with the best conventional hydride reductions. The use of appropriate chiral diphosphanes, particularly BINAP compounds, and chiral diamines results in rapid and productive asymmetric hydrogenation of a range of aromatic and heteroaromatic ketones and gives a consistently high enantioselectivity. Certain amino and alkoxy ketones can be used as substrates. Cyclic and acyclic alpha,beta-unsaturated ketones can be converted into chiral allyl alcohols of high enantiomeric purity. Hydrogenation of configurationally labile ketones allows for the dynamic kinetic discrimination of diastereomers, epimers, and enantiomers. This new method shows promise in the practical synthesis of a wide variety of chiral alcohols from achiral and chiral ketone substrates. Its versatility is manifested by the asymmetric synthesis of some biologically significant chiral compounds. The high rate and carbonyl selectivity are based on nonclassical metal-ligand bifunctional catalysis involving an 18-electron amino ruthenium hydride complex and a 16-electron amido ruthenium species.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1521-3773%2820010105%2940%3A1%3C40%3A%3AAID-ANIE40%3E3.0.CO%3B2-5

Asymmetric Catalysis by Architectural and Functional Molecular Engineering: Practical Chemo‐ and Stereoselective Hydrogenation of Ketones

The quest for alternative drugs to the well-known cisplatin and its derivatives, which are still used in more than 50% of the treatment regimes for patients suffering from cancer, is highly needed.1,2 Despite their tremendous success, these platinum compounds suffer from two main disadvantages: they are inefficient against platinum-resistant tumors, and they have severe side effects such as nephrotoxicity. The latter drawback is the consequence of the fact that the ultimate target of these drugs is ubiquitous: It is generally accepted that Pt anticancer drugs target DNA, which is present in all cells.3,4 Furthermore, as a consequence of its particular chemical structure, cisplatin in particular offers little possibility for rational improvements to increase its tumor specificity and thereby reduce undesired side effects.

In this context, organometallic compounds, which are defined as metal complexes containing at least one direct, covalent metal−carbon bond, have recently been found to be promising anticancer drug candidates. Organometallics have a great structural variety (ranging from linear to octahedral and even beyond), have far more diverse stereochemistry than organic compounds (for an octahedral complex with six different ligands, 30 stereoisomers exist!), and by rational ligand design, provide control over key kinetic properties (such as hydrolysis rate of ligands). Furthermore, they are kinetically stable, usually uncharged, and relatively lipophilic and their metal atom is in a low oxidation state. Because of these fundamental differences compared to “classical coordination metal complexes”, organometallics offer ample opportunities in the design of novel classes of medicinal compounds, potentially with new metal-specific modes of action. Interestingly, all the typical classes of organometallics such as metallocenes, half-sandwich, carbene-, CO-, or π-ligands, which have been widely used for catalysis or biosensing purposes, have now also found application in medicinal chemistry (see Figure ​Figure11 for an overview of these typical classes of organometallics).



Figure 1

Summary of the typical classes of organometallic compounds used in medicinal chemistry.



In this Perspective, we report on the recent advances in the discovery of organometallics with proven antiproliferative activity. We are emphasizing those compounds where efforts have been made to identify their molecular target and mode of action by biochemical or cell biology studies. This Perspective covers more classes of compounds and in more detail than a recent tutorial review by Hartinger and Dyson.(5) Furthermore, whereas recent reviews and book contributions attest to the rapid development of bioorganometallic chemistry in general,6,7 this Perspective focuses on their potential application as anticancer chemotherapeutics. Another very recent review article categorizes inorganic anticancer drug candidates by their modes of action.(8) It should be mentioned that a full description of all currently investigated types of compounds is hardly possible anymore in a concise review. For example, a particularly promising class of organometallic anticancer compounds, namely, radiolabeled organometallics, has been omitted for space limitations. Recent developments of such compounds have been reviewed in detail by Alberto.(9)

http://pubs.acs.org/doi/pdf/10.1021/jm100020w

Organometallic Anticancer Compounds

Part I The start: platinum complexes for the treatment of cancer - why the search goes on Part II Cisplatin - how good is it?: clinical status of cisplatin and other PT antitumor drugs Part III How does it possibly work? - biochemistry: the response of cellular proteins to cisplatin - damaged DNA the mechanism of action of cisplatin - from adducts to apoptosis replication of platinated DNA and its mutagenic consequences interstand cross-links in cisplatin- or transplatin-modified DNA Part IV Chemistry relevant to PT-biomolecule interactions: platinum complexes - hydrolysis and binding to N7 and N1 of purines reactivity and inertness of PT-nucleobase complexes kinetics and selectivity of DNA platination structure and dynamics of PT anticancer drug adducts from nucleotides to oligonucleotides as revealed by NMR methods 195Pt and 15N NMR spectroscopic studies of cisplatin reactions with biomolecules structural aspects of PT-purine interactions - from models to DNA platinum-sulfur interactions involved in antitumor drugs, rescue agents and biomolecules diammine- and diamineplatinum complexes with non-sulfur-containing amino acids and peptides Part V Inorganic chemistry revived or initiated by cisplatin: platinum blues - on the way toward unraveling a mystery heteronuclear PT(II) complexes with pyrimidine nucleobases displatinum(III) complexes - chemical species more widely spread than suspected inorganic and organometallic chemistry of cisplatin-derived PT(III) complexes Part VI New developments: structure-activity relationships within di- and trinuclear platinum phase I clinical anticancer agents the development of orally-active platinum drugs methods for screening the potential antitumor activity of platinum compounds in combinatorial libraries computational studies on platinum antitumor complexes and their adducts with nucleid acids constituents

Bernhard Lippert

Papers

Cisplatin : chemistry and biochemistry of a leading anticancer drug