Organoselenium Compounds in Biology and Medicine: Synthesis, Biological and Therapeutic Treatments - Hardcover

Hardcover

ISBN 10: 1788010299 ISBN 13: 9781788010290

Publisher: Royal Society of Chemistry, 2017

Synopsis

This book discusses organoselenium chemistry and biology in the context of its therapeutic potential, taking the reader through synthetic techniques, bioactivity and therapeutic applications

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Bhabha Atomic Research Centre, Mumbai

Bhabha Atomic Research Centre, Mumbai

From the Back Cover

Organoselenium shows incredible promise in medicine, particularly cancer therapy. This book discusses organoselenium chemistry and biology in the context of its therapeutic potential, taking the reader through synthetic techniques, bioactivity and therapeutic applications.
Divided into three sections, the first section describes synthetic advances in bioactive selenium compounds, revealing how organoselenium compound toxicity, redox properties and specificity can be further tuned. The second section explains the biophysics and biochemistry of organoselenium compounds, as well as selenoproteins. The final section closes with several chapters devoted to therapeutic and medicinal applications of organoselenium compounds, covering radioprotectors, anticancer agents and antioxidant behaviour.
With contributions from leading global experts, this book covers recent advances in the field and is an ideal reference for those researching organoselenium compounds.

Excerpt. © Reprinted by permission. All rights reserved.

Organoselenium Compounds in Biology and Medicine

Synthesis, Biological and Therapeutic Treatments

By Vimal Kumar Jain, K. Indira Priyadarsini

The Royal Society of Chemistry

Copyright © 2018 The Royal Society of Chemistry
All rights reserved.

ISBN: 978-1-78801-029-0

Contents

Chapter 1 An Overview of Organoselenium Chemistry: From Fundamentals to Synthesis Vimal K. Jain, 1, 
Chapter 2 Looking Beyond the Traditional Idea of Glutathione Peroxidase Mimics as Antioxidants C. Santi, F. Marini and E. J. Lenardao, 37, 
Chapter 3 Synthesis of Organoselenium Compounds with Potential Biological Activities Fateh V. Singh and Thomas Wirth, 77, 
Chapter 4 The Relevant Chemistry of Imidazoline-2-selone Donors with Potential Biological Applications V. Lippolis, 122, 
Chapter 5 Organoselenium Cations: Structures, Reactivity and Applications Sangit Kumar and Harkesh B. Singh, 150, 
Chapter 6 Organoselenide Fluorophores for Probing Reactive Oxygen Species and Heavy Metals Sandip V. Mulay, Youngsam Kim, Woo Hyun Lee, Shubhangi Singh and David G. Churchill, 178, 
Chapter 7 Non-bonded Selenium Heteroatom Interactions in Selenoenzyme Glutathione Peroxidase and Mimics M. Iwaoka and K. Arai, 199, 
Chapter 8 Carbohydrate-derived Organoselenium Compounds: Synthesis and Application in the Structural Analysis of Biomolecules Chandrababunaidu Kona, Junpei Shimabukuro, Makoto Kiso and Hiromune Ando, 223, 
Chapter 9 Reaction of Selenium Compounds with Reactive Oxygen Species and the Control of Oxidative Stress Luke D. Carroll and Michael J. Davies, 254, 
Chapter 10 Reactive Selenium Species: Redox Modulation, Antioxidant, Antimicrobial and Anticancer Activities Muhammad Jawad Nasim, Wesam Ali, Enrique Dominguez-Alvarez, Eufranio N. da Silva Junior, Rahman Shah Zaib Saleem and Claus Jacob, 277, 
Chapter 11 Ebselen and Thioredoxin Systems in Human Health, Disease and Therapeutic Potential Jun Lu, Xiaoyuan Ren, Lili Zou and Arne Holmgren, 303, 
Therapeutic Applications of Organoselenium Compounds, 
Chapter 12 History and Development of Selenium-based Radioprotectors: Distinctions between the Inorganic and Organic Forms A. Kunwar and K. I. Priyadarsini, 319, 
Chapter 13 Toxicology and Anticancer Activity of Synthetic Organoselenium Compounds João B. T. Rocha, Claudia S. Oliveira and Pablo A. Nogara, 342, 
Chapter 14 Metabolism of Selenium/Selenocystine and Their Roles in the Prevention and Treatment of Human Cancer Sougat Misra and Mikael Bjornstedt, 377, 
Chapter 15 Organoselenium Compounds as Cancer Therapeutic Agents Valentina Gandin and Aristi P. Fernandes, 401, 
Chapter 16 Cancer Prevention by Different Forms of Selenium A. M. Diamond, 436, 
Subject Index, 452, 

CHAPTER 1

An Overview of Organoselenium Chemistry: From Fundamentals to Synthesis

VIMAL K. JAIN

Chemistry Division, Bhabha Atomic Research Centre, Mumbai-400 085, India

Email: jainvk@barc.gov.in

1.1. Introduction

Selenium is a member of the group 16 elements (O, S, Se, Te and radioactive Po), collectively known as chalcogens. It was discovered in 1817 by J. J. Berzelius in the reddish deposits that formed in the lead chambers at his sulfuric acid plant at Gripsholm in Sweden. He named the element selenium in the honour of Greek goddess 'Selene' meaning moon.

The chemistry of selenium compounds was neglected for more than a century; the entire literature comprised only ~200 papers until 1920 and it remained an arcane field of investigation until 1970. This slow development can be attributed to the malodorous reputation of its compounds, toxicity, the instability of certain derivatives as well as the general belief that the chemistry of selenium, due to its proximity to sulfur, would be more or less similar to that of sulfur compounds. However, such beliefs and perceptions for organoselenium compounds were defied by an exponential growth of organoselenium chemistry during past three decades or so. The following three major, interdependent factors have contributed to this rapid development of the field.

(i) Role in organic chemistry: since its discovery in the early 1930s as an oxidizing agent for organic compounds, selenium dioxide (SeO) was used predominantly in organic synthesis until the early 1970s. However, around this time several useful reactions and processes were discovered and the interest in organoselenium compounds was further catalysed with the publication of a monograph by Klayman and Gunther. Since then, the number of reactions as well as the variety of selenium compounds have grown dramatically. Selenium can be introduced to a myriad organic substrates as an electrophile, nucleophile or even as a radical in a chemo-, regio- and stereo-selective manner.

(ii) Organometallic chemistry and materials science: although metal complexes of seleno ligands (e.g. [PtCl2(R2Se)2]; R = Me, Et, Prn, Ph) were first synthesized more than a century ago, reports on organo-selenium complexes appeared only sporadically until the early 1990s, possibly due to poorly developed synthetic processes for the desired organoselenium compounds. Selenium ligands quite often show unusual reactivity that differs from their sulfur counterparts. Platinum group metal complexes with seleno ligands were developed as catalysts for various reactions since the 1990s, and in some cases exhibit even better catalytic activity than the corresponding thio derivatives. Further impetus to selenium chemistry comes from recent interest in semiconductor metal selenide nano-materials. Metal selenolates have emerged as versatile single-source molecular precursors for the synthesis of nano-particles and deposition of thin films of metal selenides.

(iii) Selenium in biology: selenium was long considered a poison until 1957 when Schwarz and Foltz identified it as an essential micronutrient. Fifteen years later selenocysteine, the 21st amino acid, was discovered at the active site of glutathione peroxidase (GPx), establishing the role of selenium in mammals. Since then, approximately 40 seleno enzymes, exhibiting a range of functions have been identified. GPx has been extensively investigated due to its diversity of biological roles. To mimic the functions of GPx and related enzymes, several organoselenium compounds have been designed and developed. Ebselen is a promising candidate as an oxidant. The mechanistic aspects of the antioxidant activity of GPx have been worked out and the formation of several selenium species has been proposed during the catalytic cycle.

In the light of the above, an overview of organoselenium chemistry is presented in this chapter.

1.2 General Considerations

Selenium is a trace element occurring at an average level of 9x10-5% (0.09 ppm) in the earth's crust. There is substantial geographical variations in agricultural soils, giving selenium-deficient, -adequate and -excess (toxic) regions. In general, selenium-deficient and -adequate regions are much more widespread than the selenium-excess regions. Selenium exists in various chemical forms in soil, which influences the availability of the element to plants. Selenium in food grains, legumes and vegetables occurs primarily in organic form (such as MetSe, cysSeMe, cysSeSecys, etc.) and is often referred as dietary selenium. Keshan disease, Kashin-Beck disease and several dangerous viral infections (H1N1 influenza, SARS, HIV/AIDS, Ebola, etc.) are associated with selenium deficiency and outbreaks of them have originated either in bio-geo-chemically selenium-poor regions of China or selenium nutrient-depleted sub-Saharan Africa. Acute toxicities in grazing animals were first reported in South Dakota in the 1930s, which was locally known as 'alkali disease'. More recently, high selenium content (750–5000 µg day-1 per person) has been reported in food grown in the Punjab province of India. Selenium intake varies worldwide, ranging from 7 µg day-1 to 4990 µg day-1. In fact, there is a very narrow window between dietary deficiency (<40 µg day-1) and toxic levels (>400 µg day-1) in humans, and the recommended dietary intake of selenium is 50–70 µg day-1. For this reason, selenium is referred as an 'essential poison'.

Selenium occurs in sulfide ores of heavy non-ferrous metals — copper, Copper–nickel and multi-metallic sulfides. There is a wide variation in the selenium content of these ores. As there is no primary mineral/ore that contains an economically significant amount of selenium, it is recovered as a by-product, mostly from the anode slimes generated from the electrolytic refining of copper. The selenium content of the slimes vary from 2% to 55%, the average being ~10%. Although selenium was discovered in 1817, its commercial production in appreciable quantities began only about a century later. Global production of selenium is hard to estimate, because it is a by-product of copper refineries. Nevertheless, it is estimated that in 2013 the global production (excluding USA and China) was >2170 metric tonnes (Figure 1.1a). The first practical application of selenium was realized in 1873 when photo-conducting properties were reported, which were exploited for the development of photo-cells. Since then a wide range of applications have been developed which include (i) electronics and photocopier machines (~30%); (ii) the glass industry (~35%); (iii) pigments (~10%); (iv) metallurgy (~10%); (v) agriculture and biology (~10%); and (vi) others (~5%) (Figure 1.1b).

Selenium has several allotropic forms in both the amorphous and crystalline states at room temperature and adopts either helical polymeric chain or Se8 ring structures with Se-Se distances varying between 2.32 and 2.37 [Amstrong]. The density of selenium varies between 4.20 and 4.81 g cm-3. The following modifications of selenium are now well recognized: (i) amorphous or a-selenium (red and black forms); (ii) vitreous or glassy selenium (ordinary commercial form); (iii) crystalline monoclinic or ß-selenium (red a-form and deep-red ß-form); and (iv) trigonal grey or ?-selenium. The latter form (grey selenium), comprising of helical polymeric chains, is a p-type semiconductor and shows appreciable photoconductivity, whereas other modifications are insulators.

Selenium can adopt a range of integral and fractional formal oxidation states. The main integral oxidation states are — 2 (e.g. sodium selenide, Na2Se), — 1 (e.g. disodium diselenide, Na2Se2), 0 (e.g. Se8), +1 (e.g. diselenium dichloride, Se2Cl2), +2 (e.g. selenium dichloride, SeCl2), +4 (e.g. sodium selenite, Na2SeO3) and +6 (e.g. sodium selenate, Na2SeO4); the latter oxidation state being less stable than the corresponding known sulfur compounds. The fractional oxidation states are reported in polyselenium-cations (Sen2+; n = 4 (oxidation state +1/2) and n = 8 (oxidation state +1/4)) and -anions (Sen2-n = 3-11,16). The hypervalent nature of selenium based on 3c–4e interactions is also encountered in its compounds. In the divalent state, selenium can either weakly donate its electron pair (a Lewis base) to a metal centre (M) or partially accept a lone pair (a Lewis acid) from another atom (Y, such as H, N, O, S, Cl, I, etc.) (Scheme 1.1). The latter interaction results in a linear C–Se-Y bond, which is thought to be responsible for the bioactivity of these compounds. Redox cycling of selenium between various oxidation states occurs readily (Scheme 1.2). Accordingly, selenium can act as an oxidant as well as reductant in many reactions. Various single-bond energies involving selenium, such as Se–H (66 kcal mol-1), Se–C (56 kcal mol-1), Se–Se (46 kcal mol-1), are intermediate between corresponding sulfur and tellurium compounds.

NMR Spectroscopy

Out of six naturally occurring isotopes of selenium, only the 77Se isotope has spin quantum number 1/2 with natural abundance of 7.58%. It has favorable nuclear magnetic resonance (NMR) properties that include a positive magnetogyric ratio (5.101) and 5.26x10-4 relative receptivity with respect to proton. The nuclear Overhauser effects are absent, while longitudinal relaxation times (T1) are usually a few seconds (1–30 s), are influenced by spin-rotation (small molecules) and chemical shift anisotropy (larger molecules) mechanisms. Accordingly, 77Se NMR spectroscopy has emerged as a powerful diagnostic tool in organoselenium chemistry and its popularity is growing, although initial progress was sluggish — only ~300 articles were published before 198 5. Different materials have been used as a reference; dimethylselenide (Me2Se) is now universally accepted, but being malodorous and volatile, a secondary reference, diphenyldiselenide (Ph2Se2; d 77Se = 463 ppm) in C6D6 is commonly used.

Like any other heavy nuclei, the 77Se NMR chemical shifts cover a large spectral window of ~3300 ppm, bridging selenides being most shielded (e.g. [|CpW(CO)2}2 (µ-Se)] d 77Se = -900 ppm), while selenoaldehydes are most deshielded (e.g. 2,4,6-But3C6H2 –C(H)=Se; d 77Se = 2398 ppm). The large chemical shift range is advantageous in the dispersion of resonances of closely related species; even a small chemical shift difference of diastereomeric diselenides can be resolved. For instance, for a mixture of regio-isomeric diselenides (Scheme 1.3), closely spaced (~1 ppm) resonances for two distinct selenium centers for each isomeric diselenide have been reported. The Se NMR chemical shifts are highly sensitive to oxidation state, the stereochemistry of selenium and its local environment. Larger d values (deshielding) are usually associated with a decrease in electron density of selenium. A wide variation in 77Se NMR chemical shifts with respect to the chemical state of selenium can be noted in biologically important compounds: H3N+CH2CHSeH (d 77Se = -81.6 ppm), H3N+CH2CH2Se- (d 77Se = -245.6 ppm), (H3N+CH2CH2Se) 2 (d 77Se = 251.3 ppm), H2N+ CH2CH2SeSCH2CH2NH3+ (d 77Se = 322.7 ppm) and H2 NCH2CH2 SeO2H (d 77Se = 1226 ppm). The effect of the local environment on 77Se NMR chemical shifts, as an example, is evident in o-carbonyl benzeneselenenyl compounds, 2-RC6H4SeX. With a given R the shifts are spread over >800 ppm on changing X (X = Cl, Br, SCN, CN, Me) (R = Ac, X = Cl (d, 1087 ppm); X = Me (d, 282 ppm)), while this variation is ~100 ppm upon varying R and keeping the X group reserved. The intramolecular non-bonding Se···X interaction, resulting from a nx-s*Se orbital interaction leads to a downfield shift of the 77Se NMR resonance. Approximate linear correlation between the 77Se NMR shifts and the strength of non-bonding 77Se···X interaction has been found using theoretical calculations. 77Se NMR spectroscopy is gaining momentum for understanding various process, like conformational mobility, molecular interactions of selenocysteine (sec) in biological macromolecules etc., involving selenoproteins in biological samples. Site-specific pKa values of multiple sec-incorporated peptides have been determined using 77Se NMR spectroscopy, which differ (3.3 and 4.3) depending on its position in the polypeptide, and are significantly lower than the values for free sec (5.2–5.6). Peroxidase activity of selenosubtilisin and selenonicotinamide has been investigated using Se NMR spectroscopy and the involvement of selenol (RSeH), selenenic acid (RSeOH), selenenyl sulfide (RseSR') and seleninic acid (RSe(O)OH), have been identified in the catalytic

The presence of other nuclear spin 1/2 nuclei results in spin–spin couplings which appear as satellite peaks and provide invaluable information about the structure and stereochemistry of the molecule. Almost all coupling constants nJ(77Se-X) are now reported. The 1J(77Se–1H) coupling constants for selenol range between 44 and 65 Hz. The 1J(77Se–13C) couplings in organoselenium compounds vary in the range 45–90 Hz, whereas these values are much larger (127-250 Hz) in fluorinated selenium compounds and selenocynates. The 2J(77Se–13C) couplings in alkylseleno-ethers and dialkyldiselenides are 4–15 Hz. Selenium-phosphorus couplings have been extensively investigated. The magnitude of 1J(77Se–31P) couplings falls in the range 200–500 Hz and 500–~1000 Hz for formal selenium-phosphorus single and double bonds, respectively. The 2J(77Se –31P) values vary from few hertz to a few tens of hertz and have great diagnostic importance in determining the stereochemistry of the molecule (e.g.2J(77Se–31P) values for cis and trans isomers of [Pt(SePh)2 (PPh3)2] are 45 Hz and 7 Hz, respectively). The 1J77–77Se) couplings in diselenides and inorganic seleno-cations fall in the range of 11–400 Hz; cations and cyclic diselenides showing larger coupling constants. Single bond coupling with heavier nuclei can run in several hundreds of hertz. The 1J(119Sn–77Se) in diorganotin selenolates (e.g. [Me2Sn{SeC4H(Me-4,6) 2N2}2], 1J(119Sn –77Se) = 725 Hz) varies in the range 595–1000 Hz. Similarly, the 1J(195Pt–77Se) coupling constants range from ~100 Hz to several hundred hertz (e.g.1J(195Pt–77Se) for trans-[Pt (SeC5H4N-4)2(PEt3)2] is 81 Hz and for [Pt2Cl2(µp-SeBz)2 (PPr3)2] is 134 229 Hz).

Mass Spectrometry

Naturally occurring selenium is a mixture of six isotopes: 74Se (0.87%), 76Se (9.02%), 77Se (7.58%), 78Se (23.52%), 80Se (49.82%) and 82Se (9.19%). This distribution gives rise to characteristic isotopic patterns in mass spectra of selenium compounds. Mass spectrometry has therefore emerged as one of the principal techniques for characterization of selenium-containing molecules. Besides its routine use in synthetic organic chemistry of selenium, its use for the characterization of selenium-containing metabolites in Se-rich yeast, as well as in biological samples is growing.

X-ray Crystallography

In addition to the 77Se NMR and mass spectral investigations on selenium compounds, a rapid progress can also be attributed to X-ray crystallography. A search of the Cambridge Structural Database (2015) revealed that there were ~300 structural data on selenium compounds before 1980, which increased rapidly after 2000. The database now covers >11 000 structures (Figure 1.2). The structures of selenium compounds in all covalencies from one to six, as well as cyclic ring compounds are reported. Structures, in general, are consistent with the valence shell electron pair repulsion model where a stereochemically active lone pair of electrons is involved. The C–Se distances fall in the region 1.89–1.98 [Angstrom] with Calkyl–Se being longer than the Caryl–Se distances. Compounds containing hydroxyl, carboxyl and amino groups are associated in the solid state through intra- and/or inter-molecular hydrogen bonding, resulting in dimeric to infinite chains. The stereochemistry of selenium compounds is quite diverse (Table 1.1).

(Continues...)

Excerpted from Organoselenium Compounds in Biology and Medicine by Vimal Kumar Jain, K. Indira Priyadarsini. Copyright © 2018 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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Edition details

• Publisher: Royal Society of Chemistry
• Publication date: 2017
• Language: English
• ISBN 10: 1788010299
• ISBN 13: 9781788010290
• Binding: Hardcover
• Number of pages: 480
• Editor: Vimal Kumar Jain