That’s a scary picture what is it?




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COLCHICINE

That’s a scary picture – what is it?

It’s an image of gout, drawn by the famous English satirical artist, James Gillray (1757-1815).

Ouch, it really looks painful – what causes it?

Gout is caused by crystallisation of uric acid in the joints; gout is a type of inflammatory arthritis. Uric acid is naturally formed in the body by breakdown of purine bases (adenine, guanine) via xanthine; it is mainly removed via the kidneys, but sometimes there is more than a body can cope with.



And there’s a good treatment?

Traditionally colchicine is used.

And it works?

Perhaps the best testimony is due to the Rev. Sydney Smith (1771-1845), the famous writer and wit (who once said “I never read a book before reviewing it; it prejudices a man so.”) In a letter dated December 1838 he wrote: - “On Sunday I was on crutches utterly unable to put foot on the ground, on Tuesday I walked 4 miles such is the power of Colchicum.” It was Smith who commented that gout was “the only enemy that I do not wish to have at my feet”. On another occasion, observing some of his autumn crocuses in flower, he remarked “There, who would guess the virtue of that little plant? But I find the power of Colchicum so great that if I feel a little gout coming on, I go into the garden and hold out my little toe to that plant, and it gets well immediately”.

What does colchicine look like?



That’s an unusual looking molecule.

How do you mean?

Well it has seven-membered rings.

That is right, and it was years before the structure of colchicine was sorted out. It was first isolated in 1820 by two French chemists Pierre Joseph Pelletier and Jean Bienaimé Caventou. They are better known for their isolation of quinine (as well as strychnine).

Originally a structure based on six-membered rings (above) was suggested by Windaus, and it was not until 1945 that M. J. S. Dewar (correctly) suggested the presence of seven-membered rings, confirmed subsequently by X-ray diffraction.

And it is an alkaloid?
If you define alkaloids as “nitrogenous organic compounds of plant origin” (made from breakdown of amino acids), the answer is yes. Some people expect all alkaloids to be basic. Colchinine’s nitrogen atom is part of an amide group, which means that it can’t be protonated, so colchicine is not a base, and by this count not an alkaloid.

Where does the name come from?



It comes from the autumn crocus, or meadow saffron (Colchicum autumnale), which in turn originates in Colchis (Greek  ) on the Black Sea coast of what is now Georgia. A few other plants contain it, such as Gloriosa superba (glory lily). Colchis is famous in classical literature. Colchicum autumnale, the yellow crocus of Colchis, is associated in legend with Medea, the sorceress daughter of Aeëtes, King of Colchis; she used the poison from its roots – which included colchicine – among her potions. The goddess Aphrodite made Medea fall in love with Jason, leader of the Argonauts, who relied on her assistance in his quest for the Golden Fleece, in overcoming the tasks set for him by the king. Some have identified Colchicum autumnale with the Golden Fleece itself. Jason and Medea sailed off together into the sunset, but the story does not have a happy ending, as subsequently Jason dumps Medea for a younger woman, Glauce (daughter of the King of Corinth). In revenge, Medea killed Glauce with a poisoned dress and also in some accounts killed her children with colchicine.



Jason on the Douris cup (5th century BC) being regurgitated by the snake guarding the Golden Fleece.



So colchicine is a poison?

Indeed. Several people have died through mistaking the autumn crocus for wild garlic. According to some accounts, the symptoms are similar to cholera. The lethal dose varies, with some people killed by as little as 7 mg, others surviving doses of 60 mg. It has also been used as a poison and as an instrument of suicide. Arkady Vaksberg has alleged that the influential Russian businessman Roman Tsepov died in 2004 of colchicine poisoning, and Catherine Wilson, the last woman to be hanged publicly in the UK (1862) used colchicine as her preferred weapon of death; she is believed to have carried out at least seven murders. A few other cases are known of homicide by colchicine.

How long back does its use go?

Colchicine has been around for some 3000 years – it was described by ancient Greek writers. It is said that it was introduced into the USA by Benjamin Franklin, who had taken it while in Paris. Mind you, it took the American Food and Drug Administration (FDA) until 2009 to “confirm” that it was an effective treatment for gout.

How does it work as a medicine?

Colchicine binds to -tubulin, a protein that joins with -tubulin forming a dimer. When colchicine is bound, the dimer is curved, not linear as usual, and this inhibits the process of assembly of tubulin into microtubules, the key components of the cytoskeleton. In turn, this affects the formation of the spindle in the nucleus of eukaryotic cells, stopping from mitosis from occurring and leading to cell death. One consequence of this which has attracted attention is the fact that cancer cells undergo mitosis significantly faster than normal cells so that cancer cells are more liable to be poisoned by colchicine than normal cells. Its high toxicity is one factor mitigating against the potential of colchicine as an anticancer drug.

Bibliography

Chapman and Hall Combined Chemical Dictionary compound code number: CFR10-M (props, bibliography)

History of colchicine

P. J. Pelletier and J. B. Caventou, Ann. Chim. Phys., 1820, 14, 69-81 (isolation)

A. Windaus and H. Schiele, J. Liebigs Ann. Chem., 1924, 439, 54-68 (incorrect structure)

M. Delépine, J. Chem. Ed., 1951, 28, 454-461 (biographies of Pelletier and Caventou)

M. J. S. Dewar, Nature, 1945, 155, 141-142 (structure)

M. V. King, J. L. De Vries and R. Pepinsky, Acta Cryst., 1952, 5, 437-440 (crystal structure)


O. J. Eigsti and P. Dustin, Colchicine in Agriculture, Medicine, Biology, and Chemistry, The Iowa State College Press, Ames, Iowa, 1955.

T. Graening and H.-G. Schmalz, Angew. Chem. Int. Ed., 2004, 43, 3230 – 3256 (review of syntheses)


Colchicine poisoning

B. Weakley-Jones, J. Gerber and G. Biggs, Am. J. Forensic Med. Pathol., 2001, 22, 203-206 (two homicides with colchicine)

M. J. Maxwell, P. Muthu and P. E. Pritty, Emerg. Med. J., 2002, 19, 265–267 (accidental fatal overdose)

M. Brvar, T. Ploj, G. Kozelj, M. Mozina, M. Noc and M. Bunc, Critical Care, 2004, 8, R56-R59; Z. Sundov, Z. Nincevic, M. Definis-Gojanovic, M. Glavina-Durdov, I. Jukic, N. Hulina and A. Tonkic, Forensic Science International, 2005, 149, 253–256; F. Wehner, F. Mußhoff, M. M. Schulz, D. D. Martin and H.-D. Wehner, Forensic Science, Medicine, and Pathology, 2006, 2, 193-197; M. Amrollahi-Sharifabadi, A. Seghatoleslami, M. Amrollahi-Sharifabadi, F. Bayani and M. Mirjalili, Am. J. Forensic Med. Pathol., 2013, 34, 295-298 (accidental fatal poisoning from autumn crocus)

L. Gussow, Emergency Medicine News, Sept 2009, 14 (fatal dose of 7.2 mg)

Y. Finkelstein, S. E. Aks, J. R. Hutson et al., Clin. Toxicol. 2010, 48, 407-414 (“Colchicine poisoning: the dark side of an ancient drug”)

K.R. Nagesh, R. G. Menezes, P. Rastogi, N.R. Naik, J. M. Rasquinha, S. Senthilkumaran and A. Fazil, J. Forensic Leg. Med., 2011, 18, 285-287 (suicide)

A. Vaksberg, Toxic Politics: The Secret History of the Kremlin's Poison Laboratory - From the Special Cabinet to the Death of Litvinenko, Santa Barbara, Praeger Publishers, 2011, pp 184-186.


Best Practice Journal New Zealand, 2014, 63, 58-60 (toxicity of colchicine)

Colchicine in medicine

E. F. Hartung, Ann. Rheum. Dis., 1954, 13, 190-200 (gout treatment)

M. Levy, M. Spino and S. E. Read, Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 1991, 11, 196–211 (review)

R. Porter and G. S. Rousseau, Gout: The Patrician Malady, Yale University Press, 1998, pp. 2, 135 and 166 (Smith quotations)

B. Bhattacharyya, D. Panda, S. Gupta and M. Banerjee, Medicinal Research Reviews, 2008, 28, 155-183. (colchicine as anti-cancer drug)

R. A. Terkeltaub, New Engl. J. Med., 2003, 349, 1647-1655 (treatment of gout)

G. Weissmann, FASEB J., 2009, 23, 2791-2794 (review of colchicine in medicine)

R. A. Terkeltaub, D. E. Furst, K. Bennett, K. A. Kook, R. S. Crockett and M. W. Davis, Arthritis & Rheumatism, 2010, 62, 1060–1068.

S. M. Nidorf, J. W. Eikelboom, C. A. Budgeon and P.L. Thompson, J. Am. Coll. Cardiol., 2013, 61, 404-410. (colchicine for secondary prevention of cardiovascular disease)

S. Deftereos, G. Giannopoulos, N. Papoutsidakis, V. Panagopoulou, C. Kossyvakis, K. Raisakis, M. W. Cleman and C. Stefanadis, J. Am. Coll. Cardiol., 2013, 62, 1817-1825. (colchicine in cardiovascular medicine)

F. Roubille, E. Kritikou, D. Busseuil, S. Barrere-Lemaire and J-C. Tardif, Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2014, 12, 14-23
How colchicine works

S. B. Hastie, Pharmac. Ther., 1991, 51, 377-401. (review of binding to tubulin)

R. B. G. Ravelli, B. Gigant, P. A. Curmi, I. Jourdain, S. Lachkar, A. Sobel and M. Knossow, Nature, 2004, 428, 194-198; A. Dorléans, B. Gigant, R. B. G. Ravelli, P. Mailliet, V. Mikol, and M. Knossow, Proc. Natl. Acad. Sci. U.S.A, 2009, 106, 13775–13779 (structure of colchicine-tubulin complex)

B. Bhattacharyya, D. Panda, S. Gupta and M. Banerjee, Medicinal Research Reviews, 2008, 28, 155-183. (colchicine and its binding to tubulin)

Y. Lu, J. Chen, M. Xiao, W. Li and D. D. Miller, Pharm Res., 2012, 29, 2943–2971 (tubulin inhibitors)

Illustrations

Plants


Colchicum autumnale

http://upload.wikimedia.org/wikipedia/commons/9/97/Colchicum_autumnale.jpg or

http://upload.wikimedia.org/wikipedia/commons/a/a5/Herbstzeitlose_(Colchicum_autumnale)_IMG_7799.JPG

Gloriosa superba

http://upload.wikimedia.org/wikipedia/commons/b/bc/Gloriosa_superba_1.jpg

Picture of Sydney Smith



http://en.wikipedia.org/wiki/Sydney_Smith#mediaviewer/File:Sydney_smith.jpg

James Gillray's 1799 engraving The gout,



http://upload.wikimedia.org/wikipedia/commons/b/b8/The_gout_james_gillray.jpg

Roman Tsepov



http://usimages.detik.com/content/2012/07/19/10/130624_romantsepovrosprescom.jpg

Medea (3 different ones)



http://en.wikipedia.org/wiki/Medea#mediaviewer/File:De_Morgan_Medea.jpg

http://en.wikipedia.org/wiki/Medea#mediaviewer/File:Jason_and_Medea_-_John_William_Waterhouse.jpg (with Jason)

(by Waterhouse 1907)



http://en.wikipedia.org/wiki/Medea#mediaviewer/File:Medea-Sandys.jpg

Jason on the Douris cup



http://commons.wikimedia.org/wiki/File:Douris_cup_Jason_Vatican_16545.jpg


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