Colchicine

English Info.

Colchicine

Mesajgönderen Birsel tarih Sal Eyl 04, 2007 10:57 pm

Colchicine is a highly poisonous alkaloid, originally extracted from plants of the genus Colchicum (Autumn crocus, also known as the "Meadow saffron"). Originally used to treat rheumatic complaints and especially gout, it was also prescribed for its cathartic and emetic effects. Its present medicinal use is mainly in the treatment of gout; as well, it is being investigated for its potential use as an anti-cancer drug. It can also be used as initial treatment for pericarditis and preventing recurrences of the condition.


History
Colchicum extract was first described as a treatment for gout in De Materia Medica by Padanius Dioscorides in the first century CE.

The colchicine alkaloid was first isolated in 1820 by the two French chemists P.S. Pelletier and J. Caventon.[1]

It was later identified as a tricyclic alkaloid, and its pain-relieving and anti-inflammatory effects for gout were linked to its ability to bind with tubulin.


[edit] Pharmacology

[edit] Biological function
Colchicine inhibits microtubule polymerization by binding to tubulin, one of the main constituents of microtubules. Availability of tubulin is essential to mitosis, and therefore colchicine effectively functions as a "mitotic poison" or spindle poison.[2] Since one of the defining characteristics of cancer cells is a significantly increased rate of mitosis, this means that cancer cells are significantly more vulnerable to colchicine poisoning than are normal cells. It should be noted, however, that the therapeutic value of colchicine against cancer is (as is typical with chemotherapy agents) limited by its toxicity against normal cells.

Apart from inhibiting mitosis, a process heavily dependent on cytoskeletal changes, colchicine also inhibits neutrophil motility and activity, leading to a net anti-inflammatory effect.


[edit] Colchicine as medicine
Colchicine is Food and Drug Administration (FDA)-approved for the treatment of gout and also for familial Mediterranean fever, secondary amyloidosis(AA), and scleroderma.

The Australian biotechnology company Giaconda has developed a combination therapy to treat constipation-predominant irritable bowel syndrome which combines colchicine with the anti-inflammatory drug olsalazine.

Colchicine has a relatively low therapeutic index.

Colchicine is "used widely" off-label by naturopaths for a number of treatments, including the treatment of back pain.[3]


[edit] Side effects
Side effects include gastro-intestinal upset and neutropenia. High doses can also damage bone marrow and lead to anemia. Note that all of these side effects can result from hyper-inhibition of mitosis.


[edit] Toxicity
Colchicine poisoning has been compared to arsenic poisoning: symptoms start 2 to 5 hours after the toxic dose has been ingested and include burning in the mouth and throat, fever, vomiting, diarrhea, abdominal pain and kidney failure. Death from respiratory failure can follow. There is no specific antidote for colchicine, although various treatments do exist.


[edit] Botanical use
Since chromosome segregation is driven by microtubules, colchicine is also used for inducing polyploidy in plant cells during cellular division by inhibiting chromosome segregation during meiosis; half the resulting gametes therefore contain no chromosomes, while the other half contain double the usual number of chromosomes (i.e., diploid instead of haploid as gametes usually are), and lead to embryos with double the usual number of chromosomes (i.e. tetraploid instead of diploid). While this would be fatal in animal cells, in plant cells it is not only usually well tolerated, but in fact frequently results in plants which are larger, hardier, faster growing, and in general more desirable than the normally diploid parents; for this reason, this type of genetic manipulation is frequently used in breeding plants commercially. In addition, when such a tetraploid plant is crossed with a diploid plant, the triploid offspring will be sterile (which may be commercially useful in itself by requiring growers to buy seed from the supplier) but can often be induced to create a "seedless" fruit if pollinated (usually the triploid will also not produce pollen, therefore a diploid parent is needed to provide the pollen). This is the method used to create seedless watermelons, for instance. On the other hand, colchicine's ability to induce polyploidy can be exploited to render infertile hybrids fertile, as is done when breeding triticale from wheat and rye. Wheat is typically tetraploid and rye diploid, with the triploid hybrid infertile. Treatment with colchicine of triploid triticale gives fertile hexaploid triticale.


[edit] References
^ Pelletier PS, Caventon J. Ann. Chim. Phys. 1820;14:69
^ http://biotech.icmb.utexas.edu/botany/colch.html
^ "Deaths sound an Rx alert", The Portland Tribune, Apr 20, 2007
ya zirvelerden gelen su gibi duru;
ya da kavrulmus ormanlar gibi kuru

hayat senin...ne istiyorsan o ol.....
Birsel
Site Admin
 
Mesajlar: 1412
Kayıt: Sal Haz 20, 2006 6:34 pm
Konum: Seligenstadt

Mesajgönderen Birsel tarih Sal Eyl 04, 2007 11:04 pm

Colchicine

--------------------------------------------------------------------------------

Matthew J. Dowd, Graduate Student
Department of Medicinal Chemistry
Medical College of Virginia Campus
Virginia Commonwealth University




"No other pain is more severe than this, not iron screws, nor cords, not the wound of a dagger, nor burning fire."[1] Imagine feeling this pain, as described by Aretaeus, the Greek physician of the second century. Thomas Sydenham, a 17th Century physician, described the pain as "a violent stretching and tearing of the ligaments - now it is a gnawing pain, like that of a dog."[1] The disease gout is the source of these vivid descriptions. Through the centuries, gout has been a debilitating afflicton most associated with a decadent lifestyle, middle-aged men, and alcohol. The major symptom is an intense, burning pain of the joint of the big toe. Because of its long history, gout has been the target of a number of effective and some not-so-effective treatments. Some of the less beneficial treatments include rest and relaxation until the pain subsides, consumption of wine or alcoholic punch, and even vibration-generated heat from a glass boot. With the age of modern medicine came also more effective treatments for gout, such as the drugs probenecid, allopurinol, cortisone, and nonsteroidal antiinflammatory drugs (NSAIDS) such as ibuprofen and indomethacin. Clearly, the antigout agent with the longest history is colchicine.


FIGURE 1. Colchicum autumnale
(-)-Colchicine (1), which was first used over 2000 years ago in the form of preparations of the meadow saffron Colchicum autumnale (Fig. 1), is still one of the more effective treatments for the intense pain associated with a gout attack. Padanius Dioscorides, a Greek surgeon in the Roman Army during the rule of Nero (AD 54-68), first described the meadow saffron in his influential De Materia Medica, a pharmacopeia which systematically described about 600 plants[2]. Throughout the years, many historians, physicians, and pharmacopeias have noted the beneficial effects of Colchicum extracts for the treatment of gout.
It was not until 1820 when (-)-colchicine, the pharmacologically active constituent of the plant, was isolated by the French chemists Pelletier and Caventon.[3] The absolute configuration was determined by Corrodi and Hardegger in 1955.[4] As can be seen, colchicine is a tricyclic alkaloid, the main features of which include a trimethoxyphenyl ring (A ring), a seven membered ring (B ring) with an acetamide at the seven position, and a tropolonic ring (C ring).
1

The goal of most colchicine research is a more thorough understanding of the cause of gout, which is often thought of as a disease of rich living. However, as many victims will testify, the affliction does not limit itself to this lifestyle. Gout, from the Latin gutta, meaning drop, was used to describe the symptoms because physicians presumed the disease was caused by the dropping of phlegm into the big toe.[1] Hyperurecosia, or elevated blood levels of uric acid, causes the common symptoms of gout[5,6]. In humans and other primates, uric acid is the final metabolite in the breakdown of purines. When this metabolic pathway becomes overwhelmed, from either an enzymatic deficiency or an increase in dietary purines, uric acid cannot be efficiently elimated from the body. The poorly soluble uric acid crystalizes, initiating a response from macrophages and leukocytes. The phagocytosis of urate crystals by the macrogphages and leukocytes stimulates the release of cytokines and interleukins, leading to inflammation and the distinctive symptoms.

The precise mechanism by which colchicine relieves the intense pain of gout is not known.[5] However, it is believed that the major relief of pain involves colchicine's major pharmacological action: binding to tubulin dimers. Tubulin (MW approximately 10,000 Dalton) is a protein consisting of two forms, alpha and beta. Alpha and beta tubulin form dimers, and these dimers polymerize to form long filaments of microtubules. When colchicine binds to the tubulin dimers, the dimers are unable to form the microtubules. The microtubules are vital for formation of spindle fibers during mitosis and meiosis, intracellular transport of vesicles and proteins, flagella reassembly, ameboid motility, and other cellular processes. Inhibition of ameoboid motility prevents macrophage and leokocyte migration and phagocytosis, thereby presumably preventing the inflammation and pain of gout. Because colchicine disrupts mitosis, halting the process at metaphase, scientists have also evaluated colchicine as an anticancer agent. However, serious toxicities prevent the use of colchicine in antineoplastic therapies.


FIGURE 2. Chiral substitued biphenyl.
One insight into the molecular action of colchicine has been the determination of the biologically active conformation [7,8]. (-)-Colchicine has only one stereogenic center: carbon -7. The designation of this carbon is S, according to the common Cahn-Ingold-Prelog rules. However, colchicine is also asymmetric due to axial chirality.
The single bond between the A and C rings is rotationally restricted, in a similar manner to certain substituted biphenyls (Figure 2). This restriction adds a degree of asymmetry to the molecule. In 1933, Kuhn designated this type of stereoisomerism as atropisomerism (from Greek - "a" meaning not; "tropos" meaning turn)[9]. The designation of this asymmetry is "aS or aR," according to the rules of molecular asymmetry, in which the "a" stands for axial chirality.[10] In colchicine, the C-C bond between the A and C rings is the chiral axis.

FIGURE 3. Stereoisomers of Colchicine.

In light of this molecular asymmetry, colchicine has four stereoisomers, as shown in Figure 3. Each pair has either the R or S configuration at C-7. (-)-(aS,7S)-Colchicine, the natural isomer, can interconvert between the two conformational isomers aR and aS, given enough energy. The energy barrier of rotation in colchicine, approximately 22-24 kcal/mol [8], is large enough to allow the synthesis and isolation of the conformations as stereoisomers. The research of many medicinal chemists, in particular Arnold Brossi, has led to the conclusion that the counterclockwise aS conformation is that of the naturally occuring alkaloid.[7,8,11-14] Shown in Figure 4 are energy-minimized models of the atropisomers of (7S)-colchicine (Constructed using Sybyl 6.4, Tripos, Inc). Note the very different arrangement of the acetamide group in the two conformations.


FIGURE 4. (aS,7S)-colchicine (left) and (aR,7S)-colchicine (right).

In the search for more effective agents than those provided by Mother Nature, medicinal chemists have synthesized hundreds of analogs of colchicine and colchicine-like compounds. Analysis of these data has yielded infomation about the optimal structural requirements for binding to tubulin and inhibiting tubulin polymerization. The basic, although not comprehensive, structure-activity relationships (SARs) are summarized in Fig 5, adapted from Boye and Brossi [8]. (+)-(aR,7R)-Colchicine (see Figure 4), the unnatural enantiomer of (-)-colchicine, is devoid of tubulin binding activity. The appropriate torsion angle (about 53 degrees) between rings A and C is required for tubulin binding ability. Removal or demethylation of the methoxy groups decreases potency. On the B ring, the acetamide can be replaced by other alkyl amides with retention of potency; however, the free amine has decreased antitubulin activity. The acetamide can be elimated altogether, and activity is retained. On the C ring, demethylation to the 10 -OH (i.e., colchiceine) destroys activity. Replacement of the 10-methoxy with SCH3 or NR2 leads to increased potency. Reversal of the oxygen pattern (i.e., 9-methoxy and 10-keto) produces isocolchicine, which is inactive. It is apparent that the tropolonic functionality contributes to activity. This seven membered C ring can, however, be replaced with a an anisole ring, producing a bridged biphenyl, which retains tubulin binding activity, as long as the torsion angle between the rings A and C is acceptable.

FIGURE 5. Structure-Activity Relationships of Colchicine Analogs.
Present and future work in the design of colchicine analogs and other agents that inhibit tubulin polymerization will attempt to make agents wth reduced toxicities and a larger therapeutic window[15]. These analogs may more successfully treat diseases in which colchicine is presently used, such as familial Mediterranean fever (FMF)[16], chronic constipation [17], immunosuppresion, and several other pathophysiological processes. Another major goal is to determine the precise interaction between colchicine and tubulin dimers. Knowledge of the tubulin-colchicine interactions at the atomic level may lead to the design of better drugs, preventing future generations from experiencing the pain "more severe than iron screws and burning fire."
Date posted: April 30, 1998

References



1) Weede, R.P. Poison in the Pot: The Legacy of Lead Southern Illinois University Press: Carbondale and Edwardsville, 1984, 83.
2) Singer, C. A History of Scientific Ideas Barnes and Nobles, 1996.
3) Pelletier, P.S.; Caventon, J. Ann. Chim. Phys. 1820, 14, 69.
4) Corrodi, H.; Hardegger, E. Die Konfiguration des Colchicins und verwandter Verbindungen Helv. Chem. Acta 1955, 38, 2030-2033.
5) Katzung, B.G. Basic and Clinical Pharmacology; B.G. Katzung, Ed.; Apleton and Lange: Norwalk, 1995, 536-559.
6) Voet, D.; Voet. J.G. Biochemistry John Wiley and Sons, Inc.: New York, 1990, 758-762.
7) Capraro, H. G.; Brossi, A. The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1984; Vol. 23, 1-70.
8) Boye, O.; Brossi, A. The Alkaloids; Brossi, A., Cordell, G.A., Eds.; Academic Press: New York, 1992; Vol. 41, 125-178.
9) Kuhn, R. "Molekulare Asymmetrie" in Stereochemie; Frendenberg, K. Ed.; Franz Deutike: 1933, p.803.
10) Eliel, E.L.; Wilen, S.H. Stereochemistry of Organic Compounds; John Wiley and Sons, Inc.: New York, 1994, 1119-1122.
11) Brossi, A. Bioactive Alkaloids. 4. Results of Recent Investigations with Colchicine and Physostigmine. J. Med. Chem. 1990, 33, 2311-2319.
12) Wildman, W.C. The Alkaloids; Manske, R.H.F., Holmes, H.L., Eds.; Academic Press: New York, 1968; Vol. 11, 407-456.
13) Cook, J. W.; Loudon, J. D. The Alkaloids; Manske, R.H.F., Holmes, H.L., Eds.; Academic Press: New York, 1952; Vol.2, 261-330.
14) Wildman, W.C. The Alkaloids; Manske, R.H.F., Ed.; Academic Press: New York, 1960I>; Vol.6, 220-246.
15) Chen, K.; Kuo, S.C.; Hsieh, M.C.; Mauger, A.; Lin, C.M.; Hamel, E.; Lee, K.H. Antitumor Agents. 178. Synthesis and Biological Evaluation of Substituted 2-Aryl-1,8-naphthyridin-4(1H)-ones as Antitumor Agents That Inhibit Tubulin Polymerization. J. Med. Chem. 1997, 40, 3049-3056.
16) Buskila, D.; Zaks, N.; Neumann, L.; Livneh, A.; Greenberg, S.; Pras, M. Langevitz, P. Quality of life of patients with familial Mediterranean fever. Clin. Exp. Rheumatol. 1997, 15, 355-360.
17) Verne, G.N.; Eaker, E.Y.; Davis, R.H.; Sninksy, C.A. Colchicine is an effective treatment for patients with chronic constipation: an open-label trial. Dig. Dis. Sci. 1997, 42, 1959-1963.
ya zirvelerden gelen su gibi duru;
ya da kavrulmus ormanlar gibi kuru

hayat senin...ne istiyorsan o ol.....
Birsel
Site Admin
 
Mesajlar: 1412
Kayıt: Sal Haz 20, 2006 6:34 pm
Konum: Seligenstadt


Dön English

Kimler çevrimiçi

Bu forumu gezen kullanıcılar: Hiç bir kayıtlı kullanıcı yok ve 1 misafir