The Calabar Bean and its Alkaloids, 1st ed. 2018
From Magic, via Miracle, to Memory


Language: Anglais

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218 p. · 15.5x23.5 cm · Hardback

Investigations into Calabar beans (the dried ripe seeds of Physostigma venenosum) and their alkaloidal components compose a classical scientific journey throughout some one-and-a-half centuries and not only represent a fascinating aspect of the history of medicine but which is, moreover, still ongoing at the forefront of chemical and medical discovery. Those in particular involving its major such component, l-physostigmine, have led to an understanding of some of the fundamental mechanisms occurring in physiology, pharmacology and biochemistry and, either actually or potentially (by providing a template and thereby acting as a ?lead compound?) have provided a useful treatment for a variety of neurological disorders associated with irregularities in cholinergic transmission in which augmentation of cholinergic activity has proved to be beneficial.

Physostigma venenosum  is distributed throughout equatorial West Africa and having a colourful history ? by virtue of their former use as an ordeal poison in trials for witchcraft in the Efik society of Old Calabar ? are its dried ripe seeds (Calabar beans). The major toxic compound isolated from these, l-physostigmine, which is also known as eserine and is the only alkaloid as yet also to be isolated from a microbial source (along with l-N(8)-norphysostigmine) and is the first alkaloid found to contain a 1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole ring system, and the first natural product found to contain a carbamyl group. It also became one of the first examples whereby the mechanism of action of a drug could be defined at the molecular level relatively simply, played a crucial role in the Nobel Prize ? winning discovery of the mechanism of neurohumoral transmission, and has led to products for the treatment of a wide range of disorders associated with deficiencies in cholinergic transmission. Several other alkaloids have also been isolated from the Calabar bean. For some of these, structures have been established, syntheses effected and pharmacology investigated.

Chronology.-  Abbreviations.- Preface and acknowledgements.- 1. Introduction.- 2. l-Physostigmine (eserine).- 2.1. Natural occurrence.- 2.2. Structure elucidation.- 2.3. Synthesis of:- 2.3.1. by early approaches, including the first to be successful.- 2.3.2. l-physostigmine and the 3a-alkyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole ring system.- 2.3.3.  d-physostigmine.- 2.4. Absolute configuration, together with that of the other structurally-established alkaloids of the Calabar bean.- 2.5. Biogenesis.- 2.6. Ultraviolet absorption spectrum and reaction in an acidic medium.- 2.7. Mass spectrum.- 2.8. Detection, assay and instability.- 2.8.1. Qualitative and quantitative analysis.- 2.8.2. Rubreserine.- 2.8.3. Eserine blue.- 2.8.4. Eserine brown.- 3. l-Physovenine.- 3.1. Isolation and structure elucidation.- 3.2. Synthesis of the:- 3.2.1. racemate.- 3.2.2. l<- and d-enantiomers.- 3.2.3. 3a-alkyl-3,3a,8,8a-tetrahydro-2H<-furo[2,3-b]indole ring system.- 3.3. Biogenesis.- 4. l-Eseramine.- 4.1. Isolation and structure elucidation.- 4.2. Synthesis of the:- 4.2.1. racemate.- 4.2.2. l-enantiomer.- 5. l-N(8)-Norphysostigmine.- 5.1. Isolation and structure elucidation.- 5.2. Synthesis of the l-enantiomer.- 6. l-Geneserine.- 6.1. Isolation and structure elucidation.- 6.2. Synthesis of the l-enantiomer and the racemate.- 7. 1H-, 13C- and 15N-Nuclear magnetic resonance spectra of the alkaloids of the Calabar bean.- 8. Other alkaloids of, as yet, unknown structures that have been isolated, or allegedly so, from the Calabar bean.- 8.1. Calabarine.- 8.2. Eseridine.- 8.3. Isophysostigmine.- 8.4. Calabatine and calabacine.- 8.5. Investigations still to be effected.- 9. Non-alkaloidal components of the Calabar bean.- 10. Biological activities of the alkaloids of the Calabar bean.- 10.1. AntiAchE activity.- 10.1.1. AchE – its function in neurohumoral transmission, structure and inhibition.- 10.2. Pharmacology of l-physostigmine.- 10.3. Role of l-physostigmine in the discovery of the mechanism of neurohumoral transmission.- 10.4. AntiAchE activities of the minor alkaloids of the Calabar bean – the l-physostigmine pharmacophore.- 10.5. Clinical use of l-physostigmine in ophthalmology – miotic activity and the reduction of intraocular pressure in glaucoma.- 10.6. Clinical use of l-physostigmine in the treatment of:- 10.6.1. Myasthenia gravis.- 10.6.2. Paraplegic anejaculation.- 10.7. Use of l-physostigmine in the:- 10.7.1. Prophylactic protection against intoxication by organophosphates (including “nerve gases”).- 10.7.2. Enhancement of cognition and memory (including antiamnesic activity in dementia of the Alzheimer’s type – Alzheimer’s disease).- 10.8. Bactericidal and insecticidal activities of l-physostigmine.- 10.9. Prophylactic protection with d-physostigmine against intoxication by organophosphates (including “nerve gases”).- 10.10. Other clinical uses of l-physostigmine.- 10.11. Antinociceptive activity of l-eseroline and its synthetic analogues.- 10.12. Cytotoxicities of rubreserine and another structurally-related degradation product of l-physostigmine.- 10.13. Poisonings (either accidental or malicious) with the Calabar bean.- 11. Notes.- 12. References.- 13. Index.

One of the most exciting and interesting aspects of the study of natural products is the “field work” involving ethnological and ethnobotanical studies and which, where apposite, have been alluded to in the present treatise
Many texts on alkaloids are limited to chemical aspects, whereas the somewhat unique and therapeutically significant biological activities of the Calabar bean’s alkaloids (particularly l-physostigmine) has led to a detailed and through presentation of these facets in the present treatise

Throughout this present study, along with a detailed account of what has been done, investigations of what remains to be done have been high-lighted and approaches to effecting this are suggested, including the interpretations of already – published data