Antiproliferative Ruthenium Complexes

Due to the severe toxicity of anticancer platinum complexes and acquired drug resistance, research has focused on cymene ruthenium complexes as viable alternatives. Specifically, [(η6-p-cymene)Ru(ethylene-diamine)Cl]PF6 (RAED-C) is cytotoxic against primary tumors while [(η6-p-cymene)Ru(1,3,5-triaza-7-phosphaadamantane)Cl2 (RAPTA-C) is effective against cancer metastasis, but both exhibit low uptake in cells. Our hypothesis is that glucose ligands will improve cellular uptake of cymene ruthenium complexes and therefore cytotoxicity. Reaction of the sodium salt β-D-thioglucose with [cymeneCl2Ru]2 dimer forms either a dinuclear, dithiolate bridged complex or a dinuclear, trithiolate bridged complex depending on reaction conditions. We are working towards building a library of related compounds focused on variations to the cymene backbone and placement of the thioglucose. Collaboration with Luke Wisniewski and Dr. Maria Burnatowska-Hledin has allowed us to determine some of the properties of these compounds in vitro

Synthesis and Characterization of Mono- and Diruthenium Compounds

This thesis will focus on two broad topics: the synthesis and characterization of various diruthenium aryl compounds and of mono- and bis-alkynyl unsymmetric compounds based on Ru(II)(dppm)2 and Ru(II)(dppe)2bridges (dppm = 1,2-bis(diphenylphosphino)methane; dppe = 1,2-bis(diphenylphophino)ethane). Chapters 1–3 focus on multiply bonded metal–metal compounds, utilizing four different ‘paddlewheel’ motifs (dinuclear ruthenium units that are supported by four bidentate ligands). These highly stable mono- and bis-aryl diruthenium compounds are readily prepared using lithium-halogen exchange reactions. Two different oxidation states have been accessed, Ru2(II,III) and Ru2(III,III), through modification of the paddlewheel ligands or coordination of a small, π-accepting ligand at the vacant ruthenium site in Ru2(ap)4(Ar) compounds (ap = 2-anilinopyridinate; Ar = aryl). Chapter 1 discusses the modification of the bidentate ligand to yield two unique Ru2(ap\u27)4(Ar) series, which both exhibit improved solubility over the previously reported un-modified Ru2(ap)4(Ar) series, and the structural, electronic, and optical characterizations of the compounds within these two new Ru2(II,III) series. Chapter 2 builds upon our lab’s previous studies on electron transfer between the two ruthenium centers in [Ru2(ap)4]2(μ-C≡C)x compounds and applies this towards synthesizing and characterizing mixed-valency within a Ru2(III,III) phenylene bridged compound [(NC)Ru2(ap)4]2(μ-1,4-C6H4). Chapter 3 highlights the synthesis and characterization of bis-aryl and bis-alkynyl Ru2(III,III) compounds, Ru2(amtfmp)4(Y)2(Y = -C≡CPh, -Ph), supported with the electron-withdrawing paddlewheel ligand amtfmp (amtfmp = 2-amino-3-(trifluoromethyl)pyridinate). Chapters 4 and 5 are focused on the synthesis and characterization of both mono- and bis-alkynyl unsymmetric compounds to study photo-induced electron transfer (PET) processes. Chapter 4 features as an introduction to the synthesis of these Ru(II)(dppm)2 and Ru(II)(dppe)2 alkynyl compounds along with some material applications. Chapter 5 discusses the mono- and bis-alkynyl compounds based on Ru(II)(dppm)2 and Ru(II)(dppe)2 bridges that utilized a highly electron-withdrawing chromophore ‘acceptor’ ligand, NAPR (R = isopropyl, mesityl), to generate the B-A (mono-alkynyl) and D-B-A(unsymmetric bis-alkynyl) compounds

Emerging Ruthenium-Glucose Complexes with Chemotherapeutic Potential and Inquiry into the Biochemical Mechanism of Action

Due to the severe toxicity of anticancer platinum complexes and acquired drug resistance, research has focused on arene ruthenium complexes as viable alternatives. Arene complexes of the formula [areneRu(µ2-L)Cl]2 and (areneRu)2(µ2-L)3+ (L = alkyl thiolate) are known to be cytotoxic with IC50 values in the micromolar and submicromolar ranges, respectively. Our goals are to investigate whether glucose ligands or hydrophobic ligands on cymene ruthenium complexes improve specificity for cancerous cells over normal cells. Reaction of the sodium salt of β-D-thioglucose with [cymeneCl2Ru]2 forms [(cymeneRu(µ2­-thioglucose)Cl]2 (1) and (cymeneRu)2(µ2-thioglucose)3+ (2). These compounds were successfully purified by HPLC and characterized by NMR spectroscopy. Toxicity of 1 has been investigated in vitro. Half-sandwich arene ruthenium complexes with hydrophobic N-heterocyclic ligands of the formula (arene)Ru(L)Cl2 have been synthesized where L= 4-phenyl pyridine, isoquinoline, benzimidazole, and CF3, and have been investigated and characterized spectroscopically

Assigning and Testing Function from Structure of Uncharacterized Proteins

In 2000, the National Institutes of Health initiated the Protein Structure Initiative as a multi-center structural biology program with “an initial goal to make the three-dimensional, atomic-level structures of most proteins easily obtainable from knowledge of their corresponding DNA sequences.” (NIGMS website). The third and final phase of this program concluded in 2015 with the publication and distribution of more than 5000 previously uncharacterized proteins. The work described here leverages the availability of high-quality structures and pre-cloned expression plasmids to combine forces of undergraduate biochemistry teaching lab courses across a diverse range of participating institutions. This consortium of undergraduate biochemistry faculty and students seeks to identify functional properties of a subset of these uncharacterized proteins, seeking to unify structure-and-function relationships. The current biochemistry laboratory class at Hope College has expressed and purified seven of these proteins, finding that structural information can guide, although not predict entirely, functional predictions regarding substrate specificity