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Physostigmine salicylate U.S.P. medicalcorps.org |
Physostigmine (also known as eserine from éséré, West African name for the Calabar bean) is a parasympathomimetic, specifically, a reversible cholinesterase inhibitor alkaloid of the Calabar bean. The chemical was synthesized for the first time in 1935 by the chemists Percy Lavon Julian and Josef Pikl. It is available in the U.S. under the trade names Antilirium, Eserine Salicylate, Isopto Eserine, and Eserine Sulfate.
[edit] MechanismBy interfering with the metabolism of acetylcholine, physostigmine indirectly stimulates both nicotinic and muscarinic receptors. [edit] Syntheses The first total synthesis of physostigmine was achieved by Julian and Piki in 1935. It was summarized in the Figure 3. The main goal of Julian’s physostigmine synthesis was to get the intermediate key compound, l- eseroline 10. Then, 10 would be easily converted to physostigmine2. In one of his earlier work “Studies in the Indole Series II,”15 Julian synthesized the ring of physostigmine from starting material, 1-methyl-3-formyl oxindole, which was discovered by Friedlander. However, he faced that the starting material was expensive, and the reduction of a nitrile to an amine (similar to the reaction of 6 to 7) with sodium and alcohol did not result in good yield.14,15 In his second work “Studies in the Indole Series III,” he had improved the yield of amine from nitrile significantly by using palladium and hydrogen.3 The Julian’s physostigmine synthesis was started from phenacetin 1 because 1 was inexpensive. First, 1 was added to sodium powder and dimethyl sulfate under xylene while being heat to produce 2. Then, 2 was converted to anilide 3 by reacting with -bromopropionyl bromide. When 3 was treated with an excess of aluminum chloride, the ethoxyl group of 3 was cleaved, and then heating and working up of the mass was done to give a high yield of 4. Next, 4 was ethylated by ethyl sulfate to produce 5. 5 was then treated with chloroacetoniltrile and sodium ethoxide or sodium to yield 6. The nitrile of 6 was reduced to the amine to give 7 by Palladium and hydrogen. The amine of 7 was methylated, then reacting with methyl iodide followed by hydrolysis to produce 8. By successive action of d-camphorsulfonic acid and d-tartaric acid, this amine was resolved into its enantiomers in excellent yield. As a result, l-amine of 8 was reduced by sodium and alcohol and yielded more than 80% of l-eserethole 9 . Because the yields of all above steps were very good and those reactions requires a little time, l-eserethole was easy to achieve.4 9 was then converted to l-eseroline 10 smoothly by dissolved it in petroleum ether and anhydrous aluminum chloride while gently boiling the mixture. The conversion of l-eseroline into physostigmine was easy to achieve by treating with methyl isocynate, which was described by Polonovski and Nitzberg.2 As a result, Julian had completely synthesized d,l-eserethole for the first time. Consequently, the first synthesis of physostigmine was completed. However, there are drawbacks in Julian’s synthesis. First, the chemical resolution of 8 is unreliable, and the chemical resolution of d,l-eserethole 9 gives optically pure enantiomers after eight times of recrystallization of its tartrate salt. Second, the reaction from 8 to 9 requires a large amount of Na.12 As a result, Julian’s synthesis needs to be improved.  Most recently, Mukund and his groups have described a powerful method to construct quaternary carbon center by using the Wittig olefination-Claisen rearrangement. The synthesis starts with the Wittig olefination of o-nitroacetophenone 11. 11 is reacted with allyloxymethylenetriphenylphosphorane to produce an allyl vinyl ether 12. 12 is an inseparable mixture of E- and Z- isomer, but the NMR signals of E- and Z-isomer are well separated in the olefinic region. Therefore, the ratio (5:1) of these isomers is identified. The allyl vinyl ether 12 is then refluxed in xylene. This reaction goes through the Claisen rearrangement to yield 85% of 13. The aldehyde group of 13 is protected by adding p-TSA, ethylene glycol, and toluene while refluxing. Then, ozone gas and dimethyl sulfide are added into the solution in DCM at 00C and give 14 with new aldehyde. This aldehyde is reduced to alcohol 15 by reacting with sodium borohydride in aqueous THF. The alcohol of 15 is converted into amine 16 by adding DIAD and triphenyl phosphine, followed by phthalimide. The reaction is later reacted with methylamine while refluxing. The nitro of 16 is then reacted with methanol, Raney nickel, and hydrogen to give diamine 17 with 82% yield. Acetal of 17 is hydrolyzed with p-TSA in refluxing aqueous THF to produce tricyclic compound 18 in 65% yields. 19 is easy to achieve by adding ethyl acetate, aqueous formalin and followed 10% catalytic, Pd-C, under hydrogen.16 Then, 19 is converted to esermethole 20, an intermediate in the synthesis of physostigmine.1,16 Esermethole 20 is achieved in 70% yield by adding N-bromosuccinimide (NBS) to DMF at 00C, and then sodium methoxide is added in the presence of cuprous iodide while being heat. Finally, esermethole 20 is demethylated with boron tribromide; then the mixture is treated with phenol, NaH, THF, and methylisocyanate result the crystals product, Physostigmine.16 As a result, a new and efficient synthesis of physostigmine is successfully synthesized. [edit] Clinical usesPhysostigmine is used to treat myasthenia gravis, glaucoma, Alzheimer's disease and delayed gastric emptying. It has been shown to improve the short term memory (Krus et al. 1968). Recently, it has begun to be used in the treatment of orthostatic hypotension. Because it is a tertiary amine (and thus does not hydrogen bond, making it more hydrophobic), it can cross the blood-brain barrier, and physostigmine salicylate is used to treat the central nervous system effects of atropine, scopolamine and other anticholinergic drug overdoses. Physostigmine is the antidote of choice for datura stramonium poisoning. It is also an antidote for atropa belladonna poisoning, the same as for atropine.[1] It has been also used as an antidote for poisoning with GHB as well,[2] but is poorly effective and often causes additional toxicity, so is not a recommended treatment.[3] [edit] BioactivityPhysostigmine is functioned as an acetylcholinesterase inhibitor.6 Its mechanism is to prevent the hydrolysis of acetylcholine by acetylcholinesterase at the transmitted sites of acetylcholine. Therefore, the effect of acetylcholine is enhanced.13 Since physostigmine enhanced the effect of acetalcholine, it is useful for the treatment of cholinergic disorders and myasthenia gravis.11 More recently, physostigmine has been used to improve the memory of Alzheimer’s patients because it is a highly potent anticholinesterase. However, the drug form of physostigmine, physostigmine salicylate, needs to be prepared more effective dosage form because of its poor bioavailability.7,10 Not only physostigmine is functioned as acetyl cholinesterase inhibitor, but also it has miotic function, which help contract the pupil of the eyes. Consequently, it is used to treat mydriasis. Moreover, physostigmine helps increase outflow of the aqueous humor in the eye; thus, it is useful in the treatment of glaucoma13. Recently, physostigmine has been proposed as antidote for gamma hydroxybutyrate (GHB) intoxication, a potent sedative-hypnotic agent that people who take it will lose their consciousness, muscle control, and even death. Physostigmine could treat GHB because it capable produces a nonspecific state of arousal in the treatment of sedative-hypnotic toxicity.8,9 In addition, physostigmine also has other proposals; it could reverse undesired side effects induced by benzodiazepines such as diazepam, alleviation of anxiety and tension; another proposal is it could reverse the effects of barbiturates, any of a group of barbituric acid derived which is used as sedatives or hypnotics.20 However, there are not enough scientific evidences to prove physostigmine could treat GHB toxicity.8,9,20 Finally, physostigmine has a quaternary center; this quaternary center has caused difficulty in synthesizing physostigmine. Therefore, constructing a quaternary center is crucial to synthesize physostigmine. There are 71 systheses of physostigmine, 33 racemic and 38 chiral have been reported.16 [edit] Side effectsAn overdose can cause cholinergic syndrome. Other side effects may include nausea, vomiting, diarrhea, anorexia, dizziness, headache, stomach pain, sweating and dyspepsia.[4] [edit] References
[edit] References for Bioactivity and syntheses1 Bui, T.; Syed, S.; Barbas, C. F. Thiourea-Catalyzed Highly Enantio- and Diastereoselective Additions of Oxindoles to Nitroolefins: Application to the Formal Synthesis of (+)- Physostigmine. J. Am. Chem. Soc. 2009, 131, 8758-8759. 2 Julian, P. L.; Pikl, J. Studies in the Indole Series. V. The Complete Synthesis of Physostigmine (Eserine). J. Am. Chem. Soc. 1935, 57, 755-757. 3 Julian, P. L.; Pikl, J. Studies in the Indole Series. Iii. On the Synthesis of Physostigmine. J. Am. Chem. Soc. 1935, 57, 539-544. 4 Julian, P. L.; Pikl, J. Studies in the Indole Series. Iv. The Synthesis of D,L-Eserethole. J. Am. Chem. Soc. 1935, 57, 563-566. 5 Kawahara, M.; Nishida, A.; Nakagawa, M. An Efficient Synthesis of Optically Active Physostigmine from Tryptophan Via Alkylative Cyclization. Org. Lett. 2000, 2, 675-678. 6 Morales-Rios, M. S.; Santos-Sanchez, N. F.; Joseph-Nathan, P. Efficient Formal Total Synthesis of Physostigmine and Physovenine: Conformational Analysis of Key Intermediates. J. Nat. Prod. 2002, 65, 136-141. 7 Popović, M.; Popović, N.; Jovanova-Nešć, K.; Bokonjić, D.; Dobrić, S.; Kostić, V. S.; Rosić, N. Effect of Physostigmine and Verapamil on Active Avoidance in an Experimental Model of Alzheimer's Disease. J. Neurosci. 1997, 90, 87-97. 8 Traub, S. J.; Nelson, L. S.; Hoffman, R. S. Physostigmine as a Treatment for Gamma-Hydroxybutyrate Toxicity: A Review. Clin. Toxicol. 2002, 40, 781-787. 9 Zvosec, D. L.; Smith, S. W.; Litonjua, R.; Westfal, R. E. J. Physostigmine for Gamma-Hydroxybutyrate Coma: Inefficacy, Adverse Events, and Review. Clin. Toxicol. 2007, 45, 261-265. 10 Bolourchian, N.; Hadidi., N.; Foroutan., S. M.; Shafaghi., B. Development and Optimization of a Sublingual Tablet Formulation for Physostigmine Salicylate. Acta. Pharm. 2009, 59, 301-312. 11 Ashimori, A.; Matsuura, T.; Overman, L. E.; Poon, D. J. Catalytic Asymmetric Synthesis of Either Enantiomer of Physostigmine. Formation of Quaternary Carbon Centers with High Enantioselection by Intramolecular Heck Reactions of (Z)-2-Butenanilides. J. Org. Chem. 2002, 58, 6949-6951. 12 Brossi, A.; Pei, X.-F.; Greig, N. H. Invited Review. Phenserine, a Novel Anticholinesterase Related to Physostigmine: Total Synthesis and Biological Properties. Aust. J. Chem. 1996, 49, 171-181. 13 Dewick, P. M. Medicinal Natural Products: A Biosynthetic Approach. 3rd ed.; John Wiley & Sons: Chichester, 2009; p 385-387. 14 Julian, P. L.; Pikl, J. Studies in the Indole Series. I. The Synthesis of Alpha-Benzylindoles. J. Am. Chem. Soc. 1933, 55, 2105-2110. 15 Julian, P. L.; Pikl, J.; Boggess, D. Studies in the Indole Series. Ii. The Alkylation of 1-Methyl-3-Formyloxindole and a Synthesis of the Basic Ring Structure of Physostigmine1. J. Am. Chem. Soc. 1934, 56, 1797-1801. 16 Kulkarni, M. G.; Dhondge, A. P.; Borhade, A. S.; Gaikwad, D. D.; Chavhan, S. W.; Shaikh, Y. B.; Ningdale, V. B.; Desai, M. P.; Birhade, D. R.; Shinde, M. P. A Novel and Efficient Total Synthesis of (±)-Physostigmine. Tetrahedron Lett. 2009, 50, 2411-2413. 17 LLoyd, J. U.; Cincinnati, O. Physostigma Venenosum (Calabar). The Western Druggist. 1897, 19, 249-251. 18 Rege, P. D.; Johnson, F. Application of Vicarious Nucleophilic Substitution to the Total Synthesis of Dl- Physostigmine. J. Org. Chem. 2003, 68, 6133-6139. 19 Smith, R.; Livinghouse, T. An Expedient Synthetic Approach to the Physostigmine Alkaloids Via Intramolecular Formamidine Ylide Cycloadditions. J. Org. Chem. 2002, 48, 1554-1555. 20 Jastak, J. T. Physostigmine: An Antidote for Excessive Central Nervous System Depression or Paradoxical Rage Reactions Resulting from Intravenous Diazepam. Anesth Prog. 1985, 32, 87-92. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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