Chemical connections: dexamethasone, hydroxychloroquine and rheumatoid arthritis

The chemical structure of dexamethasone (image from Wikimedia Commons)

It’s been widely reported today that a “cheap and widely-available” steroid treatment has been shown to be effective in patients suffering the most severe COVID-19 symptoms, significantly reducing the risk of death for both patients on ventilators and those on oxygen treatment.

Most of the reports have understandably focused on the medical aspects, but this is a chemistry blog (mostly) so *cracks chemistry knuckles* what is dexamethasone, exactly?

Its story starts a little over 60 years ago when, in 1958, a paper was published on “clinical observations with 16a-methyl corticosteroid compounds”. Bear with me, I shall explain. Firstly, corticosteroids are hormones which are naturally produced in our bodies. They do all sorts of nifty, useful things like regulate our immune response, reduce inflammation and help us to get energy from carbohydrates. Two of the most familiar names are probably cortisol and cortisone—both of which are released in response to stress.

The discovery of corticosteroids was an important one. So important, in fact, that a few years earlier, in 1950, Tadeusz ReichsteinEdward Calvin Kendall and Philip Showalter Hench had been awarded a Nobel Prize in Physiology and Medicine for “discoveries relating to the hormones of the adrenal cortex”.

The adrenal glands are two small glands found above the kidneys. The outermost part of these glands is called the adrenal cortex (“cortex” from the Latin for (tree) bark and meaning, literally, an outer layer). In the mid-1930s Kendall and Reichstein managed to isolate several hormones produced by these glands. They then made preparations which, with input from Hench, were used in the 1940s to treat a number of conditions, including rheumatoid arthritis.

This was hugely significant at the time, because until this point the treatments for this painful, debilitating condition were pretty limited. Aspirin was known, of course, but wasn’t particularly effective and long-term use had potentially dangerous side effects. Injectable gold compounds (literally chemical compounds containing Au atoms/ions) had also been tried, but those treatments were slow to work, if they worked at all, and were expensive. The anti-malarial drug, hydroxychloroquine (which has also been in the news quite a lot), had been tried as a “remittive agent”—meaning it could occasionally produce remission—but it wasn’t guaranteed.

Rheumatoid arthritis causes warm, swollen, and painful joints (image from Wikimedia Commons)

Corticosteroids were a game-changer. When Hench and Kendall treated patients with what they called, at the time, “compound E” (cortisone) there was a rapid reduction in joint inflammation. It still caused side effects, and it didn’t prevent joint damage, but it did consistently provide relief from painful symptoms.

Fast-forward to the 1958 paper I mentioned earlier, and scientists had discovered that a little bit of fiddling with the molecular structure of steroid molecules caused them to have different effects in the body. The particular chemical path we’re following here started with prednisolone, which had turned out to be a useful treatment for a number of inflammatory conditions. However, placing a methyl group (—CH3) on the 16th carbon—which is, if you have a look at the diagram below, the one on the pentagon-shaped ring, roughly in the middle—changed things.

The steroid “nucleus”: each number represents a carbon atom (image from Wikimedia Commons)

In 1957, four different molecules with methyl groups on that 16th carbon were made available for clinical trial. One of them was 16a-methyl 9a-fluoroprednisolone, more handily known as dexamethasone.

(Quick aside to explain that on the diagram of dexamethasone at the start of this post, the methyl group on the 16th carbon is represented by a dashed wedge-shape. It’s a 2D diagram of a 3D molecule, and the dashed wedge tells us that the methyl group is pointing away from us, through the paper, or rather, screen. This matters because molecules like this have mirror image forms which usually have very different effects in the body—so it’s important to get the right one.)

Dexamethasone is on the WHO Model List of Essential Medicines

It turned out that dexamethasone had a much stronger anti-inflammatory action than plain prednisolone, and it was also more effective the other molecules being tested. It caused a bigger reduction in symptoms, at lower doses. A win all round. It did still have side effects—weight gain, skin problems and digestive issues—but these were no worse than other steroids, and better than some. In fact, salt and water retention were less with dexamethasone, which meant less bloating. It also seemed to have less of an effect on carbohydrate metabolism, making it potentially safer for patients with diabetes.

Skipping forward to 2020, and dexamethasone is routinely used to treat rheumatoid arthritis, as well as skin diseases, asthma, COPD and various other conditions. It is on the WHO Model List of Essential Medicines—a list of drugs thought to be the most important for taking care of the health needs of the population, based on their effectiveness, safety and relative cost.

In the wake of more and more evidence that COVID-19 disease was leading to autoimmune and autoinflammatory diseases, scientists have been looking at anti-inflammatory drugs to see if any of them might help. The Recovery Trial at the University of Oxford was set up to investigate a few different drugs, including hydroxychloroquine (there it is again) and dexamethasone.

It’s not a miracle cure but, in the most severe cases, dexamethasone—a cheap, 60+ year old drug—might just make all the difference.

And that brings us back to today’s news: in the trial, 2104 patients were given dexamethasone once per day for ten days and compared to 4321 patients who were given standard care. The study, led by Professor Peter Horby and Professor Martin Landray, showed that dexamethasone reduced the risk of dying by one-third in ventilated patients and by one fifth in other patients receiving only oxygen.

It’s not a miracle cure by any means: it doesn’t help patients who don’t (yet) need respiratory support, and it doesn’t work for everyone, but, if you find yourself on a ventilator, there’s a chance this 60+ year-old molecule that was first developed to cure rheumatoid arthritis might, just, save your life. And that’s pretty good news.

EDIT 17th June 2020: Chemistry World published an article pointing out that “the trial results have yet to be released leading some to urge caution when interpreting them” and quoting Ayfer Ali, a specialist in drug repurposing, as saying “we have to wait for the full results to be peer reviewed and remember that it is not a cure for all, just one more tool.


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How many scientists does it take to discover five elements? More than you might think…

My last post chronicled (see what I did there?) a meandering stroll through all 118 elements in the periodic table. As I read through all the pieces of that thread, I kept wanting to find out more about some of the stories. This is the international year of the periodic table, after all — what better time to go exploring?

But, here’s the thing: 118 is a lot. It took ages even just to collect all the (mostly less than) 280-character tweets together. Elemental stories span the whole of human existence and are endlessly fascinating, but telling all of them in any kind of detail would take whole book (not a small one, either) and would be a project years in the making. So, how about instead having a look at some notable landmarks? A sort of time-lapse version of elemental history and discovery, if you will…

Carbon

The word “carbon” comes from the Latin “carbo”, meaning coal and charcoal.

Let’s begin the story with carbon: fourth most abundant element in the universe and tenth most abundant in the Earth’s crust (give or take). When the Earth first formed, about 4.54 billion years ago, volcanic activity resulted in an atmosphere that was mostly carbon dioxide. The very earliest forms of life evolved to use carbon dioxide through photosynthesis. Carbon-based compounds make up the bulk of all life on this planet today, and carbon is the second most abundant element in the human body (after oxygen).

When we talk about discovering elements, our minds often leap to “who”. But, as we’ll see throughout this journey, that’s never an entirely straightforward question. The word “carbon” comes from the Latin carbo, meaning coal and charcoal. Humans have known about charcoal for many thousands of years — after all, if you can make a fire, it’s not long before you start to wonder if you can do something with this leftover black stuff. We’ll never know who first “discovered” carbon. But we can be sure of one thing: it definitely wasn’t an 18th century European scientist.

Diamond is a form of carbon used by humans for over 6000 years.

Then there are diamonds, although of course it took people a bit longer to understand how diamonds and other forms of carbon were connected. Human use of diamonds may go back further than we imagine, too. There’s evidence that the Chinese used diamonds to grind and polish ceremonia tools as long as 6,000 years ago.

Even the question of who first identified carbon as an element isn’t entirely straightforward. In 1722, René Antoine Ferchault de Réaumur demonstrated that iron was turned into steel by absorbing some substance. In 1772, Lavoisier showed for the first time that diamonds could burn (contrary to a key plot point in a 1998 episode of Columbo).

In 1779, Scheele demonstrated that graphite wasn’t lead, but rather was a form of charcoal that formed aerial acid (today known as carbonic acid) when it was burned and the products dissolved in water. In 1786 Claude Louis Berthollet, Gaspard Monge and C. A. Vandermonde again confirmed that graphite was mostly carbon, and in 1796, Smithson Tennant showed that burning diamond turned limewater milky — the established test for carbon dioxide gas — and argued that diamond and charcoal were  chemically identical.

Even that isn’t quite the end of the story: fullerenes were discovered 1985, and Harry Kroto, Robert Curl, and Richard Smalley were awarded a Nobel Prize for: “The discovery of carbon atoms bound in the form of a ball” in 1996.

Type “who discovered carbon” into a search engine and Lavoisier generally appears, but really? He was just one of many, most of whose names we’ll never know.

Zinc

Brass, an alloy of zinc, has been used for thousands of years.

Now for the other end of the alphabet: zinc. It’s another old one, although not quite as old as carbon. Zinc’s history is inextricably linked with copper, because zinc ores have been used to make brass alloys for thousands of years. Bowls made of alloyed tin, copper and zinc have been discovered which date back to at least 9th Century BCE, and many ornaments have been discovered which are around 2,500 years old.

It’s also been used in medicine for a very long time. Zinc carbonate pills, thought to have been used to treat eye conditions, have been found on a cargo ship wrecked off the Italian coast around 140 BCE, and zinc is mentioned in Indian and Greek medical texts as early as the 1st century CE. Alchemists burned zinc in air in 13th century India and collected the white, woolly tufts that formed. They called it philosopher’s wool, or nix alba (“white snow”). Today, we know the same thing as zinc oxide.

The name zinc, or something like it, was first documented by Paracelsus in the 16th century — who called it “zincum” or “zinken” in his book, Liber Mineralium II. The name might be derived from the German zinke, meaning “tooth-like” — because crystals of tin have a jagged, tooth-like appearance. But it could also suggest “tin-like”, since the German word zinn means tin. It might even be from the Persian word سنگ, “seng”, meaning stone.

These days, zinc is often used as a coating on other metals, to prevent corrosion.

P. M. de Respour formally reported that he had extracted metallic zinc from zinc oxide in 1668, although as I mentioned above, in truth it had been extracted centuries before then. In 1738, William Champion patented a process to extract zinc from calamine (a mixture of zinc oxide and iron oxide) in a vertical retort smelter, and Anton von Swab also distilled zinc from calamine in 1742.

Despite all that, credit for discovery of zinc usually goes to Andreas Marggraf, who’s generally considered the first to recognise zinc as a metal in its own right, in 1746.

Helium

Evidence of helium was first discovered during a solar eclipse.

Ironically for an element which is (controversially) used to fill balloons, helium’s discovery is easier to pin down. In fact, we can name a specific day: August 18, 1868. The astronomer Jules Janssen was studying the chromosphere of the sun during a total solar eclipse in Guntur, India, and found a bright, yellow line with a wavelength of 587.49 nm.

In case you thought this was going to be simple, though, he didn’t recognise the significance of the line immediately, thinking it was caused by sodium. But then, later the same year, Norman Lockyer also observed a yellow line in the solar spectrum — which he concluded was caused by an element in the Sun unknown on Earth. Lockyer and Edward Frankland named the element from the Greek word for the Sun, ἥλιος (helios).

Janssen and Lockyer may have identified helium, but they didn’t find it on Earth. That discovery was first made by Luigi Palmieri, analysing volcanic material from Mount Vesuvius in 1881. And it wasn’t until 1895 that William Ramsay first isolated helium by treating the mineral cleveite (formula UO2) with acid whilst looking for argon.

Mendeleev’s early versions of the periodic table, such as this one from 1871, did not include any of the noble gases (click for image source).

Interestingly, Mendeleev’s 1869 periodic table had no noble gases as there was very little evidence for them at the time. When Ramsay discovered argon, Mendeleev assumed it wasn’t an element because of its unreactivity, and it was several years before he was convinced that any of what we now call the noble gases should be included. As a result, helium didn’t appear in the periodic table until 1902.

Who shall we say discovered helium? The astronomers, who first identified it in our sun? Or the chemists, who managed to collect actual samples on Earth? Is an element truly “discovered” if you can’t prove you had actual atoms of it — even for a brief moment?

Francium

So far you may have noticed that all of these discoveries have been male dominated. This is almost certainly not because women were never involved in science, as there are plenty of records suggesting that women often worked in laboratories in various capacities — it’s just that their male counterparts usually reported the work. As a result the men got the fame, while the women’s stories were, a lot of the time, lost.

Marguerite Perey discovered francium (click for image source).

Of course, the name that jumps to mind at this point is Marie Curie, who famously discovered polonium and radium and had a third element, curium, named in honour of her and her husband’s work. But she’s famous enough. Let’s instead head over to the far left of the periodic table and have a look at francium.

Mendeleev predicted there ought to be an element here, following the trend of the alkali metals. He gave it the placeholder name of eka-caesium, but its existence wasn’t to be confirmed for some seventy years. A number of scientists claimed to have found it, but its discovery is formally recorded as having been made in January 1939 by Marguerite Perey. After all the previous failures, Perey was incredibly meticulous and thorough, carefully eliminating all possibility that the unknown element might be thorium, radium, lead, bismuth, or thallium.

Perey temporarily named the new alkali metal actinium-K (since it’s the result of alpha decay of 227Ac), and proposed the official name of catium (with the symbol Cm), since she believed it to be the most electropositive cation of the elements.

But the symbol Cm was assigned to curium, and Irène Joliot-Curie, one of Perey’s supervisors, argued against the name “catium”, feeling it suggested the element was something to do with cats. Perey then suggested francium, after her home country of France, and this was officially adopted in 1949.

A sample of uraninite containing perhaps 100,000 atoms of francium-223 (click for image source).

Francium was the last element to be discovered in nature. Trace amounts occur in uranium minerals, but it’s incredibly scarce. Its most stable isotope has a half life of just 22 minutes, and bulk francium has never been observed. Famously, there’s at most 30 g of francium in the Earth’s crust at any one time.

Of all the elements I’ve mentioned, this is perhaps the most clear-cut case. Perey deservedly takes the credit for discovering francium. But even then, she wouldn’t have been able to prove so conclusively that the element she found wasn’t something else had it not been for all the false starts that came before. And then there are all the other isotopes of francium, isolated by a myriad of scientists in the subsequent years…

Tennessine

All of which brings us to one of the last elements to be discovered: tennessine (which I jokingly suggested ought to be named octarine back in 2016). As I mentioned above, francium was the last element to be discovered in nature: tessessine doesn’t exist on Earth. It has only ever been created in a laboratory, by firing a calcium beam into a target made of berkelium (Bk) and smashing the two elements together in a process called nuclear fusion.

Element 117, tennessine, was named after Tennessee in the USA.

Like tennessine, berkelium isn’t available on Earth and had to be made in a nuclear reactor at Oak Ridge National Laboratory (ORNL) in Tennessee — the reason for the new element’s name. One of the scientists involved, Clarice E. Phelps, is believed to be the first African American to discover a chemical element in recent history, having worked on the purification of the 249Bk before it was shipped to Russia and used to help discover element 117.

Tennessine’s discovery was officially announced in Dubna in 2010 — the result of a Russian-American collaboration — and the name tennessine was officially adopted in November 2016.

Who discovered it? Well, the lead name on the paper published in Physical Review Letters is Yuri Oganessian (for whom element 118 was named), but have a look at that paper and you’ll see there’s a list of over 30 names, and that doesn’t even include all the other people who worked in the laboratories, making contributions as part of their daily work.

From five to many…

There’s a story behind every element, and it’s almost always one with a varied cast of characters.

As I said at the start, when we talk about discovering elements, our minds often leap to “who” — but they probably shouldn’t. Scientists really can’t work entirely alone: collaboration and communication are vital aspects of science, because without them everyone would have to start from scratch all the time, and humans would never have got beyond “fire, hot”. As Isaac Newton famously said in a letter in 1675: “If I have seen further it is by standing on the shoulders of giants.”

There’s a story behind every element, and it’s almost always one with a varied cast of characters.


This post was written by with the help of Kit Chapman (so, yes: it’s by Kit and Kat!). Kit’s new book, ‘Superheavy: Making and Breaking the Periodic Table‘, will be published by Bloomsbury Sigma on 13th June.


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Women who ignored the limits: five famous female chemists

Browsing a popular newspaper site the other day I came across this very funny article by Dean Burnett, inspired by the brilliant Harry Enfield ‘Women, know your limits!’ sketch of a few years ago in which a woman dares to offer a dangerous opinion of her own.  In the sketch, filmed in the style of a 40’s black and white public information film, Mr Enfield claims that over-education leads to ugliness, premature ageing and beard growth, and beseeches women to stick to what they know best, namely, fluffy kittens.  know your limits

All very funny and yet… ask anyone to name some famous scientists and I bet you anything that at least the first five names they come up with are men.  Perhaps this is to be expected, after all the scientific method has been kicking around for ooh, well, it’s debatable, but at least 1000 years if not more.  Whereas the ludicrous idea that most women might be capable of learning about tricky things like numbers and and stuff has only been widely accepted, in this country in any case, for a few decades or so.

So to balance the books a bit, here’s my list of five famous(ish) women chemists, none of whom had beards (as far as I can tell).  Absorb and learn.  If nothing else, should the topic of scientists ever come up on the TV quiz show Pointless I can guarantee most of these will be down there in single figures, if not actually pointless.

Cleopatra the Alchemist (dates unknown)
Not the same person as Cleopatra VII, this one lived (probably) in the 3rd or 4th century.  The title Cleopatra the Alchemist is a pseudonym and her real name has been lost.  She was thought to be one of only four women who knew how to make the mythical philosopher’s stone (yes, just like in Harry Potter.  Well sort of) and, perhaps more scientifically, her work also contained several descriptions and drawings of the technical process of furnaces.  She’s also sometimes credited with the invention of an early type of distillation apparatus.  Without this useful chemical technique, we wouldn’t have petrol, plastics or, indeed, vodka.  Cheers!

Marie Curie (1867-1934)
The Polish Madame Marie Curie is most famous for her work on radioactivity and is often thought of as more of a physicist.   However she definitely earned her chemical chops for discovering two (count ’em, two) whole new elements: polonium (Po) and radium (Ra).  She painstakingly managed to isolate about 0.1 g of radium chloride from 1 ton (907185 g) of the mineral pitchblende.  Now that’s patience.  In 1948 the element curium (Cm) was named in her, and her husband Pierre’s, honour.

Elizabeth Arden (1884-1966)
A famous name, if not one we necessarily associate with science, she was born Florence Nightingale Graham and changed her name in 1909.  Although not formally educated as such, she counts as a chemist for formulating, as well as manufacturing and marketing, her cosmetic products.  She pioneered the idea that cosmetics could and should be scientifically formulated, a concept that many other companies subsequently copied.  She did wear an awful lot of pink, but nobody’s perfect.

Rosalind Franklin (1920-1958)
Who discovered the structure of DNA? Wasn’t that Watson and Crick? Actually it was x-ray crystallographer Rosalind Franklin who produced the first images of deoxyribonucleic acid, and Watson and Crick even publicly admitted to using her data to develop their hypothesis.  Sadly Franklin was a cautious scientist and her work, based on experimental results, was published after their theoretical paper.  Subsequently she’s often forgotten about, particularly because, as she died in 1958 and the rules forbid posthumous nominations, she was never included included in the Nobel Prize awarded to Crick, Watson and Wilkins in 1962.  Don’t hide your light girls.

Anna Jane Harrison (1912-1998)
Harrison, who unlike many historical chemists (when you spend your days messing about with substances that so often turn out to be toxic, you’re invariably in danger of shuffling off this mortal coil earlier than most) managed to live until the ripe old age of 86, was an American organic chemist and the first female president of the American Chemical Society.  She was also the recipient of twenty honorary degrees, none of which were bought from dodgy internet sites.  She worked on toxic smoke during the second world war, and also contributed to research on ultraviolet light.

Sadly, none of these ladies are alive today.  Can you think of any other female chemists who’ve made important discoveries?  Tell me about her…