Advances in Bioorganometallic Chemistry

Toshikazu Hirao, Toshiyuki Moriuchi

• Publisher: Elsevier
• Year: 2018
• Print ISBN: 9780128141977
• eBook ISBN: 9780128141984
• Topic: Physical Sciences
• Subtopic: Inorganic Chemistry

Advances in Bioorganometallic Chemistry examines the synthesis, structure and reactivity of bioorganometallics, their pharmaceutical applications, hydrogenase, vitamin B12-like systems, and metalloproteins. It is written by the top researchers in the field and compiled by editors Toshikazu Hirao and Toshiyuki Moriuchi. Developments in this new field of bioorganometallic chemistry, a hybrid between biology and organometallic chemistry, happen very quickly and this comprehensive reference offers the latest research and findings in the field. The book features a discussion of the synthesis, structure, and reactivity of bioorganometallics, and an examination of hydrogenase-like systems, which were designed to demonstrate catalytic activities and functional properties.Advances in Bioorganometallic Chemistry also includes a discussion of bioorganometallics as they relate to medicinal chemistry, specifically applications of metalloproteins, metalloenzymes, and applications in bioimaging. The book concludes with coverage of vitamin B12-like systems, including the latest developments in derivatives designed to perform bio-inspired catalytic reactions.This work is a valuable resource for chemists working in organometallic chemistry and biology, including biochemists, bioorganic chemists, bioinorganic chemists, as well as pharmaceutical scientists, medicinal chemists, and students studying in these areas.Representative authors: R. H. Fish, T. Moriuchi, T. Hirao, H.-B. Kraatz, H. Takaya, T. P. Curran, G. van Koten. E. Rosenberg, J. M. Lynam, C. G. Hartinger, U. Schatzschneider, G. S. Smith, R. Alberto, S. Takenaka, T. Ihara, T. Hayashi, T. Ueno, P. Schollhammer, Y. Shomura, Y. Hisaeda, H. Shimakoshi, B. Kräutler- Provides a balanced overview of the latest research in the field of bioorganometallic chemistry, drawing together the top researchers from around the world- Covers topics in the areas of synthesis, reactivity, hydrogenase-like systems, medicinal chemistry, applications of metalloproteins, metalloenzymes, and applications in bioimaging

Part I

Synthesis, Structure, and Reactivity of Bioorganometallic Compounds

Outline

• Chapter 1 Organometallic Chemistry at the Interface with Biology
• Chapter 2 Design of Bioorganometallic Conjugates Composed of Dipeptides or Nucleobases to Induce Chirality-Organized Structures
• Chapter 3 Ferrocene Peptide-based Supramolecular Gels
• Chapter 4 Metalated Amino Acids and Peptides
• Chapter 5 Controlling Peptide Conformation Using Tungsten Alkyne Coordination
• Chapter 6 NCN-Pincer Organometallics in Bioorganometallic Chemistry
• Chapter 7 Carbon Monoxide-Releasing Molecules

Chapter 1

Organometallic Chemistry at the Interface with Biology

Richard H. Fish, Lawrence Berkeley National Laboratory, University of California, Berkeley, CA, United States

Abstract

We will review various perspectives of our bioorganometallic chemistry studies that included reactions of organotin compounds with cytochrome P450 enzymes, and their Mn/Fe porphyrin biomimics to provide regioselective C-OH compounds; reactions of a Cp*Rh tris aqua dicationic complex, [Cp*Rh(H₂O)₃](OTf)₂, with nucleobases/NAD⁺, as a function of pH; supramolecular Cp*Rh-nucleobase complexes in host-guest chemistry in water; chemoselective reduction of NAD⁺ biomimetics with an in situ formed [Cp*Rh(bpy)H](OTf) to provide 1,4-NADH biomimetic co-factors, in tandem with HLADH enzymatic catalysis for stereoselective reductions of achiral ketones to chiral S-alcohols, as well as oxidation reactions with mutant cytochrome P450 enzymes; synthesis, DFT mechanism, and bioassays of organorhodium-hydroxytamoxifen complexes as potential breast cancer pharmaceuticals; and synthesis and bioactivity of Cp*Rh-tyrosine selective G-Protein-Coupled Receptor Peptide complexes, including molecular docking studies of the [(η⁶-Cp*Rh-Tyr¹)-Leu-Enkephalin]²⁺ complex to the X-ray crystallographic defined, µ-, ∂-, and κ−Opioid receptors.

Keywords

Aqueous Synthesis; biocatalysis; host-guest non-covalent interactions; anticancer drugs; [(η⁶-Cp*Rh-tyrosine] GPCR peptide complexes; molecular docking at the µ−, ∂−, and κ−οpioid receptors; mechanistic aspects; the biological implications; tandem enzyme biocatalysis; DNA base reactions

1.1 Introduction

In 1975, we published one of the first papers on bioorganometallic chemistry at the interface with biocatalysis, that focused on the oxidative metabolism of tributyltin acetate utilizing cytochrome P450 enzymes from rat liver microsomes, since these organotin compounds were being sprayed on food products for pest control, and therefore, the metabolic tributyltin compounds formed, and their toxicity, was important to determine for health related reasons.¹ In this overview of our bioorganometallic chemistry studies, we will start from 1975, and peruse the bioorganometallic chemistry projects we have conducted up to the present at LBNL/UC Berkeley, and with colleagues around the globe, that focus on aqueous synthesis, mechanisms, and the biological implications.

Thus, the following topics will be discussed that represents the important findings of our bioorganometallic chemistry studies: Tributyltin acetate and cyclohexyltriphenyltin metabolism studies with cytochrome P450 enzymes to provide predominately (α and β-hydroxybutyl)dibutyltin acetate, and the trans-4-hydroxycyclohexyltriphenyltin metabolites; respectively, as the major oxidation products; [Cp*Rh(H₂O)₃](OTf)₂ reactions with nucleobases; for example, 1-methylthymine (1-MT), providing, at pH 10, a unique complex of anion and cation components, which was further stabilized by π–π interactions of the Cp*Rh moiety of [(Cp*Rh)₂(µ-OH)₃]⁺ with the 1-MT linear complex, [Rh(η¹(N³)-1-MT)₂]⁻; synthesis and bioassay of [cis-Cp*Rh-hydroxytamoxifen](OTf)₂, as a breast cancer antagonist drug, formed via a novel N-π rearrangement; 2D NMR and DFT structures of [(η⁶-Cp*Rh-Tyr^#)-GPCR peptides]²⁺ formed in the chemoselective reactions of the G-protein-coupled receptor peptides, [Tyr^#]-GPCR, with [Cp*Rh(H₂O)₃](OTf)₂, at pH 5.5, the synthon for many of our aqueous reactions; molecular docking studies of the [(η⁶-Cp*Rh-Tyr¹)-Leu-Enkephalin]²⁺ complex to the X-ray crystallographic defined, µ-, ∂-, and κ−opioid receptors; biomimetic co-factors, N-substituted-1,4-dihydronicotinamide derivatives, formed by a chemoselective reaction of [Cp*Rh(bpy)H](OTf) with NAD⁺ biomimics, in tandem with enzymes, horse liver alcohol dehydrogenase (HLADH) for achiral ketone reductions to chiral alcohols, and a cytochrome P450 BM3 Double Mutant enzyme, for biological oxidation reactions; Host, cyclic trimer, [Cp*Rh(2′-deoxyadenosine)]₃(OTf)₃, molecular recognition of Guests, such as, L-Tryptophan. Finally, our chapter, and others in this book, will demonstrate that the burgeoning bioorganometallic chemistry discipline represents exciting new vistas at the interface with biology.

1.2 Bioorganotin Metabolism Chemistry: Tributyltin Acetate, and Cyclohexyltriphenytin in reactions with the enzyme, Cytochrome P450, for Regio- and Stereoselectivity Hydroxylation, and the Possibilities of a Free Radical Mechanism

Our studies in the field of bioorganometallic chemistry began in 1973. We were interested in the metabolism of organotin compounds, which were being utilized as pesticides in agricultural applications. The focus was on the metabolism of tributyltin compounds in reactions with rat liver microsomes, cytochrome P450 enzymes for biological oxidation studies, for obvious environmental and health reasons. Thus, we discovered the first metabolites of tributyltin acetate with cytochrome P450 enzymes, and also studied their toxicology. Therefore, a new area of organometallic chemistry research, which we coined at the time, bioorganotin chemistry, was initiated with tributyltin acetate (Eq. 1.1), while the primary sites of hydroxylation were the α and β positions to the Sn atom.^1a–c Thus, we surmised that the Sn–C bond controlled the regiochemistry. This pattern of hydroxylation suggested a free radical mechanism, where the Sn-C sigma bond electrons stabilized the developing carbon 2p orbital radicals, on predominately, both α and β carbon positions, and to a lesser extent, the γ and ∂ positions.

(1.1)

It was also important to study the chemo and stereoselectivity of these biological P450 enzyme reactions, and to understand more about a possible free radical mechanism; therefore, we conducted studies with cyclohexyltriphenyltin, and were able to define both aspects, with cytochrome P450 rat liver microsomes,² and their biomimetic models, Mn, and Fe porphyrin derivatives (Fig. 1.1).³

Figure 1.1 Biomimetic oxidation of cyclohexyltriphenyltin, 1, with a cytochrome P450 model, [Mn(III)T...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of Contributors
• Preface
• Part I: Synthesis, Structure, and Reactivity of Bioorganometallic Compounds
• Part II: Medicinal Chemistry and Imaging Probe
• Part III: Metalloprotein, Hydrogenase, and Vitamin B12
• Index