Strategy on Remedial Use of Colchicine and Its Derivatives: a Review
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Central Journal of Pharmacology & Clinical Toxicology Bringing Excellence in Open Access Review Article *Corresponding author Shyambhavee, Department of Community Medicine, University College of Medical Sciences Strategy on Remedial Use of and GTB Hospital, New Delhi-110095, India, Email: Submitted: 09 October 2017 Colchicine and Its Derivatives: Accepted: 20 October 2017 Published: 23 October 2017 A Review ISSN: 2333-7079 Copyright Shyambhavee1* and Basanta Kumara Behera2 © 2017 Shyambhavee et al. 1Department of Community Medicine, University College of Medical Sciences and GTB Hospital, India OPEN ACCESS 2SANMAR Speciality Chemical Ltd, India Keywords • Colchicine Abstract • Colchicoside Colchicine is one of the oldest medications still in use today and is commonly used for • Colchicine derivative the treatment of gout and familial Mediterranean fever. Its anti-inflammatory properties • Microbial transformation have raised the question of its utility in managing several cardiovascular diseases, including • Anticancer postoperative atrial fibrillation and pericarditis. Colchicine is commonly produced by plants like Colchicum autumnale and Gloriosa superba. It is originally used to treat rheumatic complaints, especially gout, and still finds its uses for these purposes today despite dosing issues concerning its toxicity. It is also prescribed for its cathartic and emetic effects. Initially oral colchicine has not been approved as a drug by U.S. Food and Drug Administration (FDA). But now FDA approved colchicine as a drug for some disorders. The present review is mainly focused on the chemistry of colchicines and its derivatives. Microbial transformation techniques have been highlighted on the production of efficient, direct and green biotransformation of thiocolchicine into thiocolchicoside, performed by a specific strain of Bacillus sp. The same process, with minor modifications, can be used to convert the by- product 3-O-demethyl-thiocolchicine into thiocolchicoside. In addition, it has been described the upcoming demand of colchicines derivatives for curing various cancer and chronic pain. ABBREVIATIONS context of co-morbidities and drug-drug interactions. The plant source of colchicine, the autumn crocus (Colchicum autumnale), FDA: Food and Drug Administration; SAR: Structure-Activity was described for treatment of rheumatism and swelling in Relationship; P-gp: P-glycoprotein; FMF: Familial Mediterranean the Ebers Papyrus (circa 1500 BC), an Egyptian medical papyrus Fever; COPE: Colchicine for Acute Pericarditis; HPLC: High Performance Liquid Chromatography; SFE: Supercritical Fluid times of ancient Greece, initially as a purgative agent and later Extraction; LBP: Low Back Pain [3]. It has been used in medicinal application dating back to the Padanius Dioscorides, a Greek surgeon in the Roman Army in the INTRODUCTION as treatment for gout. Colchicum extract was first described by The colchicine has been on the market since before the existence of Food and Drug Administration (FDA). In 2006, the firstUse century of the BC asbulb-like a treatment corms for goutof Colchicum in De Materia to Medicatreat gout [4]. FDA has given approval as therapeutic herbal drug to prevent probably dates to around 550 AD, as the “hermodactyl” gout attacks in adults. In 2015,URL Pharma, Inc., a pharmaceutical recommended by Alexander of Tralles. Colchicum corms were company owned by Takeda Pharmaceuticals in Japan (but based used by the Persian physician Avicenna, and were recommended th in Philadelphia), seized the opportunity and launched Colcrys®, by Ambroise Pare in the 16 century, and appeared in the London Pharmacopoeia Colchicum plants were brought to Company, Inc. Received letter of approval for manufacturing North America by Benjamin Franklin, United States Ambassador of 1618 [5]. fromthe first FDA. branded colchicines [1]. In 2009, Mutual Pharmaceutical Although colchicine’s medicinal properties have been to France who suffered from gout himself [6]. Colchicine alkaloid was first isolated in 1820 by the two French chemists P.S. under the United States Food and Drug Administration (FDA) Pelletier and J. Caventou [7], and they regarded it as veratrine. In recognized for centuries, the drug was first approved in 2009, 1833, P.L. Geiger purified an active ingredient, which he named colchicine dosing regimens, and a greater emphasis on safety in the importantcolchicines contribution[8]. The determination when he suggested of colchicine’s that, among structure the unapproved drugs initiative [2]. FDA approval brought changes in required decades, although in 1945, Michael Dewar made an Cite this article: Shyambhavee, Behera BK (2017) Strategy on Remedial Use of Colchicine and Its Derivatives: A Review. J Pharmacol Clin Toxicol 5(7):1098. Shyambhavee et al. (2017) Email: Central Bringing Excellence in Open Access molecule’s three rings, two were seven-member rings [9]. Its pain-relieving and anti-inflammatory effects for gout were linked to its ability to bind with tubulin. However, Dewar did not prove the structure of colchicine; he merely suggested that it contained two seven-membered rings. [11].Colchicine’s structure was determined by X-ray crystallography in 1952 [10]. Its total synthesis was first accomplished in 1959 CHEMISTRY OF COLCHICINE The exact mechanism of action by which colchicine exerts Figure 1 its effect has not been clearly understood. However, it has been established that Colchicine binds to tubulin, thereby (1). Methyl group at C-1, C-2 and C-10 position are essential for tubulin binding. (2). Demethylation at C-3 position has no role in interfering with the polymerization of tubulin, interrupting tubulin binding as ‘A’ (3). 3-demethylation proved less toxic and more microtubule dynamics, and disrupting mitosis. This leads to an potent molecule used for anti-cancer. inhibition of migration of leukocytes and other inflammatory cells, thereby reducing the inflammatory response to deposited uratecrystal. Colchicine may also interrupt the It has been used as an antiparasitic agent in ethnoveterinaryC. cycle of monosodium urate crystal deposition in joint tissues, luteumuse [21]. Colchicine is also used in the treatment of Behcet’s thereby also preventing the resultant inflammatory response. syndrome and some forms of psoriasis [22-24]. The corms of Overall, colchicine decreases leukocyte chemotaxis/migration have aphrodisiac, carminative and laxative property. They and phagocytosis to inflamed areas, and inhibits the formation are used in India to treat gout, rheumatismC. luteum and also diseases of and release of a chemotactic glycoprotein that is produced during bulb,the liver are andpoisonous spleen. causingWhen grown vomiting, from violent seed its purging, plant can serious take phagocytosis of urate crystals. 4 - 5 years to flower. All parts of , but especially the The chemical name for colchicine is (S)-N-(5,6,7,9- tetrahydro- 1,2,3,10-tetramethoxy-9 oxobenzol [a] heptalen-7-yl) acetamide, inflammation of the stomach and bowels, and death. is a pale yellow powder soluble in water in 1:25 dilution. The The corm contains an alkaloid demecolcine (colchamine) in structural formula is represented below: addition to colchicine that is best known as an orally-administered Structurally, colchicine consists of a trimethoxyphenyl drug in the treatment of chronic myeloid leukaemia. Colchicine is ring (A-ring), a saturated seven-membered ring containing an also used to treat familial Mediterranean fever (FMF; an inborn acetamido group (B-ring), and a tropolone ring (C-ring) (Figure agecondition and older. that Colchicinecauses episodes is not aof pain fever, reliever pain, and cannotswelling be of used the 1) .The A- and C-rings of colchicine are key structural features stomach area, lungs, and joints) in adults and children 4 years of required for its high binding to tubulin and biological activity [12- 16]. Any modification in the C-1, C-2 and C10 of A-ring of colchicine to treat pain that is not caused by gout or FMF. Colchicine is in a causes a complete loss of binding, whereas demethylation of C-3 class of medications called anti-gout agents. It works by stopping position has no role in tubulin binding. Modifications to both the the natural processes that cause swelling and other symptoms of B- and C-rings are possible. In addition, both a minimal size and a gout and FMF. nitrogen atom at C-7 of the B-ring are required for P-glycoprotein Colchicine has been used for centuries to treat and prevent (P-gp) recognition and transport [22] (Figure 1). Therefore, many studies have focused on structural modifications of C-7 of the gouty attacks [25], and more recently has been recommended to B-ring to discover colchicine analogues with improved potency treat and prevent serositis in patients with familial Mediterranean and less toxicity or analogues that overcome drug resistance. fever and recurrent pericarditis [26,27]. Preliminary data from Colchicine consists of pale yellow scales or powder; it darkens on nonrandomized trials have also supported the use of colchicine exposure to light due to photoisomerization and formation of α-, for the treatment and prevention of acute pericarditis [28]. In a β-, and γ-lumicolchicines [17,18]. Colchicine is soluble in water, single-center, open-label, randomized trial, called the Colchicine freely soluble in alcohol and in chloroform, and slightly soluble in for Acute Pericarditis (COPE) study, the addition of colchicine ether [19]. The optimum storage temperature for colchicines is