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

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

Evolution of strategies to prepare synthetic mimics of carboxylate-bridged diiron protein active sites

We present a comprehensive review of research conducted in our laboratory in pursuit of the long-term goal of reproducing the structures and reactivity of carboxylate-bridged diiron centers used in biology to activate dioxygen for the conversion of hydrocarbons to alcohols and related products. This article describes the evolution of strategies devised to achieve these goals and illustrates the challenges in getting there. Particular emphasis is placed on controlling the geometry and coordination environment of the diiron core, preventing formation of polynuclear iron clusters, maintaining the structural integrity of model complexes during reactions with dioxygen, and tuning the ligand framework to stabilize desired oxygenated diiron species. Studies of the various model systems have improved our understanding of the electronic and physical characteristics of carboxylate-bridged diiron units and their reactivity toward molecular oxygen and organic moieties. The principles and lessons that have emerged from these investigations will guide future efforts to develop more sophisticated diiron protein model complexes.National Institute of General Medical Sciences (U.S.

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

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

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

Peptide-based targeting of fluorescent zinc sensors to the plasma membrane of live cells

Combining fluorescent zinc sensors with the facile syntheses and biological targeting capabilities of peptides, we created green- and blue-emitting probes that (i) are readily prepared on the solid-phase, (ii) retain the photophysical and zinc-binding properties of the parent sensor, and (iii) can be directed to the extracellular side of plasma membranes in live cells for detection of mobile zinc.National Institute of General Medical Sciences (U.S.) (Grant GM065519

Understanding and Improving Platinum Anticancer Drugs - Phenanthriplatin

Approximately half of all patients who receive anticancer chemotherapy are treated with a platinum drug. Despite the widespread use of these drugs, the only cure that can be claimed is that of testicular cancer following cisplatin treatment. This article reviews some of our recent work on phenanthriplatin, a cisplatin derivative in which a chloride ion is replaced by phenanthridine, and on one of its analogues, the previously reported pyriplatin. These cationic complexes form monofunctional adducts on DNA that do not significantly distort the duplex, yet efficiently block transcription. Cell-based assays reveal altered cellular uptake properties and a cancer cell-killing profile different from those of established platinum drugs. Mechanistic work, including a crystal structure analysis of platinum-modified DNA in the active site of RNA polymerase II, is discussed herein.National Cancer Institute (U.S.) (Grant CA034992)Misrock Foundation (Postdoctoral Fellowship

Photoluminescent DNA binding and cytotoxic activity of a platinum(ii) complex bearing a tetradentate β-diketiminate ligand

A platinum(II) complex of a monoanionic, tetradentate β-diketiminate (BDI) ligand with pendant quinoline arms, BDIQQH, is reported. The complex, [Pt(BDI[superscript QQ])]Cl, is emissive in DMSO, but non-emissive in aqueous buffer. Upon binding DNA in buffer, however, a 150-fold turn-on in emission intensity occurs. Dynamic light scattering and [superscript 1]H NMR spectroscopy indicate that [Pt(BDI[superscript QQ])]Cl forms non-emissive aggregates in aqueous solution; DNA-binding disperses the aggregates leading to the large emission turn-on response. The cytotoxic activity of the complex, measured in two cancer cell lines, is comparable to or better than that of the established anticancer drug cisplatin.National Cancer Institute (U.S.) (Grant CA034992)David H. Koch Graduate FellowshipNational Institutes of Health (U.S.) (Grant 1S10RR13886