{"id":84,"date":"2017-03-17T14:49:49","date_gmt":"2017-03-17T18:49:49","guid":{"rendered":"http:\/\/sites.williams.edu\/cec5\/?page_id=84"},"modified":"2017-04-10T17:53:47","modified_gmt":"2017-04-10T21:53:47","slug":"gold-complexes-for-arthritic-therapies","status":"publish","type":"page","link":"https:\/\/sites.williams.edu\/bigchem\/topics\/metals-in-medicine\/gold-complexes-for-arthritic-therapies\/","title":{"rendered":"Gold Complexes for Arthritic Therapies"},"content":{"rendered":"

https:\/\/giphy.com\/gifs\/pPzjpxJXa0pna<\/p>\n

Besides lining our pockets like Team Rocket, how else could gold be important to your life?<\/h3>\n

Executive Summary<\/b><\/h3>\n

Rheumatoid arthritis is an autoimmune disease centered on an immune driven inflammatory response capable of causing pain and deterioration of the small joints of the body, as well as complications in major organs such as the heart and lungs (due to that same inflammation). Chrysotherapy, the use of gold based compounds for therapeutic uses, has long been used for rheumatoid arthritis. It is the unique chemistry of gold that gives these compounds, such as auranofin, their therapeutic effect. Gold complexes are preferential to tertiary and primary cationic states. They are also primarily found in <\/span>linear geometries and in coordination with sulfur atoms. The structural and electronic properties of gold are the result of the relativistic effect. Gold can readily react with many sulfur containing-endogenous compounds in the body, such as cysteine amino acid residues, glutathione, and the albumin carrier protein. Readily exchangeable interactions, gold lability, is amazing chemistry in and of itself, but is also the source of \u00a0observed anti-inflammatory therapeutic effects such as \u00a0cellular toxicity among others. While complete mechanistic detail for chrysotherapy of rheumatoid arthritis has not been outlined in the literature, gold complexes continue to be a source of fascination. Auranofin, among other compounds, also have therapeutic effects against cancer, HIV, and malaria. Gold nanoparticles, much larger than gold complexes, have novel properties useful in other areas of medicine too!<\/span><\/p>\n

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Table of Contents<\/strong><\/p>\n

1. Rheumatoid Arthritis<\/a><\/p>\n

1.1. Background<\/a><\/p>\n

1.2. Autoimmune Mechanism<\/a><\/p>\n

1.3. RA Therapeutics<\/a><\/p>\n

2. Gold Chemistry <\/a><\/p>\n

2.1. General Chemistry and Relativistic Effects<\/a><\/p>\n

2.2 Relativistic Effects Govern Gold Chemistry<\/a><\/p>\n

3.Chrysotherapy & RA<\/a><\/p>\n

Biological Effects of Gold Complexes<\/a><\/p>\n

4. Gold Elsewhere<\/a><\/p>\n

<\/a><\/p>\n

1. Rheumatoid Arthritis <\/b><\/h2>\n

(<\/span>Rheum<\/span><\/i>-troubled flow, –<\/span>oid<\/span><\/i>-resembling, <\/span>Arthr<\/span><\/i>-joint, –<\/span>itis<\/span><\/i>– inflammation)<\/span><\/p>\n

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Depiction of RA in the hand (5).<\/p>\n

<\/a>
\nBackground<\/strong>
\nRheumatoid arthritis (RA) is the most common type of <\/span>autoimmune disease<\/b>, affecting more than 1.3 millions Americans, 75 % of which are women. Symptoms result in severe <\/span>inflammation<\/b>, pain, and stiffness in small joints (including the wrist) and major organs, such as the heart and lung due to inflammation. Disease progression leads to \u00a0the immobilization of joints from the erosion of cartilage between them (<\/span>5,6).<\/span><\/p>\n

<\/a>
\nAutoimmune Mechanism<\/strong><\/p>\n

The immune system comprises the body’s defense against foreign invaders such as bacteria, viruses, parasites, and fungi. The inability of the immune system to distinguish between self cells and foreign invaders results in unnecessary activation of immune mechanism. <\/span>Inflammation<\/b>, the hallmark feature, results in <\/span>recruitment <\/b>and <\/span>activation of immune system <\/b>cells via soluble <\/span>signaling factors<\/b> known as cytokines and chemokines (chemotactic cytokines). Active immune cells (neutrophils, macrophages, cytotoxic T cells, B cells, etc.) These cells release cytotoxic chemical and eat away at their target, in this case, us!<\/span><\/p>\n

<\/p>\n

Inflammation in RA is caused by activation of T cells, B cells and macrophages, which releases cytokines such as IL-1, IL-6 and TNF. These cytokines cause local joint damage through increased production of metalloproteinases and activation of osteoclasts. IL-1, IL-6 and TNF also leak out to the blood stream resulting in systemic inflammation: anaemia, thrombocytosis, fatigue, osteoporosis and the acute-phase response. Abbreviations: IL, interleukin; RA, rheumatoid arthritis (3).<\/p>\n

<\/a>
\nRA Therapeutics<\/strong><\/p>\n

Treatment seeks to relieve symptoms and immune system mediated damage via anti-inflammatories (NSAIDS) such as ibuprofen. In more severe cases, disease-modifying antirheumatic drugs (DMARDs) and immunosuppressants are used. <\/span>Chrysotherapy<\/b> (the use of gold containing compounds as therapeutics) is an older DMARD, two important examples are myochrysine and Auranofin. These can be can be injected or swallowed as a pill, respectively (<\/span>5,7,9).<\/span><\/p>\n

<\/a>
\n2. Gold Chemistry<\/strong><\/h2>\n

<\/a>
\nGeneral Chemistry and Relativistic Effects<\/strong><\/p>\n

Gold is a noble, group 11 element with an electron configuration of [Xe] 4<\/span>f<\/span><\/i>14<\/span> 5<\/span>d<\/span><\/i>10<\/span> 6<\/span>s<\/span><\/i>1 <\/span>.Elemental forms are stable a wide range of conditions, including aqueous environments. It exists in oxidation states -I to +V , where \u00a0Au(I) and Au(III) are the most common. \u00a0In vivo (living organisms), gold exists as Au(I) in primarily linear coordination complexes\u2014trigonal planar and tetrahedral forms exist as well. <\/span>As a soft acid, it prefers ligands such as sulfur over hard bases such as nitrogen and oxygen. \u00a0Au(III) prefers square planar geometries, is a hard acid, and is implicated in toxicity. Gold complexes discussed here are in the gold oxidation state, with properties governed by something called relativistic effects.<\/span>
\n<\/a>
\nRelativistic Effects Govern Gold Chemistry<\/strong><\/p>\n

These have to do with the change in physical and chemical properties of gold due to its high nuclear charge that make its electrons orbit the nucleus at higher mass and speeds. <\/span>According this theory, (<\/span>E = mc<\/span>2<\/span>) <\/span>\u00a0mass interconverts with energy at the speed of light. <\/span><\/p>\n

In a post-lanthanide element such as gold, a very high nuclear charge (+79) creates an electric field that prompts inner <\/span>s<\/span><\/i> electrons to move closer to the nucleus at speeds approaching <\/span>c<\/span><\/i> (3×10<\/span>8<\/span>m\/s).<\/span><\/p>\n

We are used to thinking of mass as a fixed quantity. For elements like gold, that isn\u2019t the case! For electrons in gold, because they are moving at high speeds approaching <\/span>c<\/span><\/i>. As v increases, relative mass increases, which is associated with a proportional amount of energy. <\/span><\/p>\n

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Think like a physicist!<\/b> Einstein\u2019s Theory of special relativity relates to chemical properties.<\/span><\/p>\n

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