Synthesis, Characterization, and Oxygenation Studies of Carboxylate-Bridged Diiron(II) Complexes with Aromatic Substrates Tethered to Pyridine Ligands and the Formation of a Unique Trinuclear Complex

In this study, diiron(II) complexes were synthesized as small molecule mimics of the reduced active sites in the hydroxylase components of bacterial multicomponent monooxygenases (BMMs). Tethered aromatic substrates were introduced in the form of 2-phenoxypyridines, incorporating hydroxy and methoxy functionalities into windmill-type diiron(II) compounds [Fe[subscript 2](μ-O[subscript 2]CAr[superscript R])[subscript 2](O[subscript 2]CAr[superscript R])[subscript 2](L)[subscript 2]] (1–4), where[superscript –]O[subscript 2]CAr[superscript R] is a sterically encumbering carboxylate, 2,6-bis(4-fluorophenyl)-, or 2,6-bis(p-tolyl)benzoate (R = 4-FPh or Tol, respectively). The inability of 1–4 to hydroxylate the aromatic substrates was ascertained. Upon reaction with dioxygen, compounds 2 and 3 (L = 2-(m-MeOPhO)Py, 2-(p-MeOPhO)Py, respectively) decompose by a known bimolecular pathway to form mixed-valent diiron(II,III) species at low temperature. Use of 2-(pyridin-2-yloxy)phenol as the ligand L resulted in a doubly bridged diiron complex 4 and an unprecedented phenoxide-bridged triiron(II) complex 5 under slightly modified reaction conditions.National Institute of General Medical Sciences (U.S.) (Grant GM032134

Redox activation of metal-based prodrugs as a strategy for drug delivery

This review provides an overview of metal-based anticancer drugs and drug candidates. In particular, we focus on metal complexes that can be activated in the reducing environment of cancer cells, thus serving as prodrugs. There are many reports of Pt and Ru complexes as redox-activatable drug candidates, but other d-block elements with variable oxidation states have a similar potential to serve as prodrugs in this manner. In this context are compounds based on Fe, Co, or Cu chemistry, which are also covered. A trend in the field of medicinal inorganic chemistry has been toward molecularly targeted, metal-based drugs obtained by functionalizing complexes with biologically active ligands. Another recent activity is the use of nanomaterials for drug delivery, exploiting passive targeting of tumors with nano-sized constructs made from Au, Fe, carbon, or organic polymers. Although complexes of all of the above mentioned metals will be described, this review focuses primarily on Pt compounds, including constructs containing nanomaterials.German Academic Exchange Service (DAAD fellowship)German Academic Exchange Service (DAAD reintegration grant)National Cancer Institute (U.S.) (grant CA034992

Imaging mobile zinc in biology

Trafficking and regulation of mobile zinc pools influence cellular functions and pathological conditions in multiple organs, including brain, pancreas, and prostate. The quest for a dynamic description of zinc distribution and mobilization in live cells fuels the development of increasingly sophisticated probes. Detection systems that respond to zinc binding with changes of their fluorescence emission properties have provided sensitive tools for mobile zinc imaging, and fluorescence microscopy experiments have afforded depictions of zinc distribution within live cells and tissues. Both small-molecule and protein-based fluorescent probes can address complex imaging challenges, such as analyte quantification, site-specific sensor localization, and real-time detection.National Institute of General Medical Sciences (U.S.) (grant GM065519

Synthetic Methods for the Preparation of Platinum Anticancer Complexes

The demonstration in the 1960s that cis-diammine-dichloroplatinum(II), or cisplatin, inhibits cellular division of Escherichia coli led to the subsequent discovery that this simple coordination compound is also an effective antitumor agent in mouse models. Subsequent studies validated cisplatin as an effective anticancer agent in humans as well, and FDA approval of cisplatin for the treatment of metastatic ovarian and testicular cancers was granted in 1978. Its introduction as a chemotherapeutic agent significantly improved the survival outlook for many cancer patients; the cure rate for testicular cancer before the approval of cisplatin was less than 10%, significantly lower than the 90% cure rate attained with modern platinum chemotherapy.National Cancer Institute (U.S.) (Grant CA034992)David H. Koch Institute for Integrative Cancer Research at MIT (Graduate Fellowship

Bioinorganic Chemistry

This book covers material that could be included in a one-quarter or one-semester course in bioinorganic chemistry for graduate students and advanced undergraduate students in chemistry or biochemistry. We believe that such a course should provide students with the background required to follow the research literature in the field. The topics were chosen to represent those areas of bioinorganic chemistry that are mature enough for textbook presentation. Although each chapter presents material at a more advanced level than that of bioinorganic textbooks published previously, the chapters are not specialized review articles. What we have attempted to do in each chapter is to teach the underlying principles of bioinorganic chemistry as well as outlining the state of knowledge in selected areas. We have chosen not to include abbreviated summaries of the inorganic chemistry, biochemistry, and spectroscopy that students may need as background in order to master the material presented. We instead assume that the instructor using this book will assign reading from relevant sources that is appropriate to the background of the students taking the course. For the convenience of the instructors, students, and other readers of this book, we have included an appendix that lists references to reviews of the research literature that we have found to be particularly useful in our courses on bioinorganic chemistry

19F NMR study of ligand dynamics in carboxylate-bridged diiron(II) complexes supported by a macrocyclic ligand

A series of asymmetrically carboxylate-bridged diiron(II) complexes featuring fluorine atoms as NMR spectroscopic probes, [Fe[subscript 2](PIM)(Ar[superscript 4F-Ph]CO[subscript 2])[subscript 2]] (10), [Fe[subscript 2](F[subscript 2]PIM)(Ar[superscript Tol]CO[subscript 2])[subscript 2]] (11), and [Fe[subscript 2](F[subscript 2]PIM)(Ar[superscript 4F-Ph]CO[subscript 2])[superscript 2]] (12), were prepared and characterized by X-ray crystallography, Mössbauer spectroscopy, and VT [superscript19]F NMR spectroscopy. These complexes are part of a rare family of syn-N diiron(II) complexes, [Fe[subscript 2](X[subscript 2]PIM)(RCO[subscript 2])[superscript 2]], that are structurally very similar to the active site of the hydroxylase enzyme component of reduced methane monooxygenase (MMOH[subscript red]). Solution characterization of these complexes demonstrates that they undergo intramolecular carboxylate rearrangements, or carboxylate shifts, a dynamic feature relevant to the reactivity of the diiron centers in bacterial multicomponent monooxygenasesNational Institute of General Medical Sciences (U.S.) (Grant GM 32114)National Science Foundation (U.S.). Graduate Research Fellowship Program (Grant 1122374

Single Turnover Reveals Oxygenated Intermediates in Toluene/o-Xylene Monooxygenase in the Presence of the Native Redox Partners

Toluene/o-xylene monooxygenase (ToMO) is a non-heme diiron protein that activates O₂ for subsequent arene oxidation. ToMO utilizes four protein components, a catalytic hydroxylase, a regulatory protein, a Rieske protein, and a reductase. O₂ activation and substrate hydroxylation in the presence of all four protein components is examined. These studies demonstrate the importance of native reductants by revealing reactivity unobserved when dithionite and mediators are used as the reductant. This reactivity is compared with that of other O₂-activating diiron enzymes.United States. National Institutes of Health (GM032134)United States. National Institutes of Health (T32GM008334

Cell-Trappable Quinoline-Derivatized Fluoresceins for Selective and Reversible Biological Zn(II) Detection

The synthesis and spectroscopic characterization of two new, cell-trappable fluorescent probes for Zn(II) are presented. These probes, 2-(4,5-bis(((6-(2-ethoxy-2-oxoethoxy)quinolin-8-yl)amino)methyl)-6-hydroxy-3-oxo-3H-8 xanthen-9-yl)benzoic acid (QZ2E) and 2,2′-((8,8′-(((9-(2-carboxyphenyl)-6-hydroxy-3-oxo-3H-xanthene-4,5-diyl)bis(methylene))bis(azanediyl))bis(quinoline-8,6-diyl))bis(oxy))diacetic acid (QZ2A), are poorly emissive in the off-state but exhibit dramatic increases in fluorescence upon Zn(II) binding (120 ± 10-fold for QZ2E, 30 ± 7-fold for QZ2A). This binding is selective for Zn(II) over other biologically relevant metal cations, toxic heavy metals, and most first-row transition metals and is of appropriate affinity (K[subscript d1](QZ2E) = 150 ± 100 μM, K[subscript d2](QZ2E) = 3.5 ± 0.1 mM, K[subscript d1](QZ2A) = 220 ± 30 μM, K[subscript d2](QZ2A) = 160 ± 80 μM, K[subscript d3](QZ2A) = 9 ± 6 μM) to reversibly bind Zn(II) at physiological levels. In live cells, QZ2E localizes to the Gogli apparatus where it can detect Zn(II). It is cell-membrane-permeable until cleavage of its ester groups by intracellular esterases produces QZ2A, a negatively charged acid form that cannot cross the cell membrane.National Science Foundation (U.S.) (CHE-0907905

Generation, Translocation, and Action of Nitric Oxide in Living Systems

Nitric oxide (NO) is a gaseous diatomic radical that is involved in a wide range of physiological and pathological functions in biology. Conceptually, the biochemistry of NO can be separated into three stages: generation (stage 1), translocation (stage 2), and action (stage 3). In stage 1 the oxygenase domain of NO synthase converts L-arginine to L-citrulline and NO (g). Owing to its short-lived nature, this molecule is converted into a different nitrogen oxide such as NO[subscript 2], an organonitrosyl such as a nitrosothiol, or a metal nitrosyl such as a heme-nitrosyl, for transportation in stage 2. Each of these derivatives features unique physical characteristics, chemical reactivity, and biological activity. Upon delivery in stage 3, NO exerts its physiological or pathological function by reaction with biomolecules containing redox-active metals or other residues.National Science Foundation (U.S.) (Grant CHE-0907905

Consequences of Cisplatin Binding on Nucleosome Structure and Dynamics

The effects of cisplatin binding to DNA were explored at the nucleosome level to incorporate key features of the eukaryotic nuclear environment. An X-ray crystal structure of a site-specifically platinated nucleosome carrying a 1,3-cis-{Pt(NH[subscript 3])[subscript 2]}[superscript 2+]-d(GpTpG) intrastrand cross-link reveals the details of how this adduct dictates the rotational positioning of DNA in the nucleosome. Results from in vitro nucleosome mobility assays indicate that a single platinum adduct interferes with ATP-independent sliding of DNA around the octamer core. Data from in vitro transcription experiments suggest that RNA polymerases can successfully navigate along cisplatin-damaged DNA templates that contain nucleosomes, but stall when the transcription elongation complex physically contacts a platinum cross-link located on the template strand. These results provide information about the effects of cisplatin binding to nuclear DNA and enhance our understanding of the mechanism of transcription inhibition by platinum anticancer compounds.National Cancer Institute (U.S.) (Grant CA034992)David H. Koch Cancer Research FundNational Center for Research Resources (U.S.) (Award RR-15301)United States. Dept. of Energy. Office of Basic Energy Sciences (DE-AC02-06CH11357