السلام عليكم ورحمة الله وبركاته
ان شاء الله الموضوع ده يكون متجدد
دائما وسلسلة تربط الفيتو والمديسنال والفارما
مع بعضها البعض
مشاركاتكم مرحب بيها طبعا
مع الألتزام بذكر المصدر بالطريقة الموضحة فى أسفل المقال
ووضع ملخص باللغة العربية والكلمات الدلاليةKEYWORDS
المقالة منقولة كبداية للسلسلة
ونشرت عام 98
وصدق او لاتصدق كاتبها كان خريج فى ذاك الوقت
دون ان يحصل على ماجستير حتى..
انا عارف ان المقالة اللى هتشوفوها دلوقتى
مقالة تخض شوية
بس هى بالنسبة للفرقة الثالثة والرابعة
مفروض تكون مفهمة الى حد كبير
المقالة بتناقش الكولشيسين
وهو الكالويد طبيعى ذو اهمية
فى علاق مرض النقرس وتجرى ابحاث حديثة
على استخدامه كعلاج للسرطان
المشكلة الأساسية ان هذا المركب له نافذة علاجية ضيقة
للغاية-narrow therapeutic window
مما يقلل من فرص استخدامه لفترات طويلة ويظل المريض مراقب بشكل كافى لمراقبة
اثار السمية الناتجة
الجملة باللون الأحمر فى المقالة ولكن طبعا غير مقبولة
لأنها مخالفة للدين الأسلامى
تستعرض المقالة ايضا العلاقة بين الفاعلية والمركب
ومقارنة بين الايسومر المختلفة للكولشيسين
حيث ان المركب له نشاط ضوئى
بسبب اللا تماثل الموجود فى الكربون
رقم 7 فى الحلقة السباعية الأليفاتية
ايضا تستعرض المقالة التفرقة بين الأيسومر المختلفة بعمل ENERGY MINIMIZATION
باستخدام برنامج سيبيل تريبوس
ويتضح فى الشكل ثلاثى الأبعاد مدى
اختلاف وضعية مجموعةالأسيتاميد فى الفراغ
والذى بلاشك يؤثر تأثير كبيرا على التأثير الدوائى للمركب
(الشكل الثلاثى الأبعاد والزوايا بين ذرات الكربون والحلقات المتصلة
مهم لتحقيق الأرتباط مع التيوبيولين (TUBULIN(
وفى النهاية تضع المقالة مخططا لأهم النقاط فى العلاقة بين التركيب الكيميائى
والفاعلية الدوائية واهم المحاولات التى ادت لأكتشافSAR لهذا المركب
KEY WORDS:-COLCHICINE,STEREO ISOMERS,GOUT,URIC ACID, TUBULIN AND SAR
,
colchicine
"
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]5,6]. In humans and other primates, uric acid is the final m e tabolite in the breakdown of purines
when this hyperurecosia, or elevated bloof levels of uric acid, causes the common symptoms of the gout m etabolic 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 m etaphase, 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 stereoisomer,as shown in Figure3.each pair has either the R or S configuration at C-7. (-)-(aS,7S)-colchicine,the natural isomer,can interconvert between the two conformational isomer 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 up) and (aR,7S)-colchicine down).
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"
References
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. 1) Weede, R.P. 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) c ook, 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.