Norditerpenoid alkaloids have important biological activities. Many of them are potent ligands and therefore promising leads for novel selective antagonists and/or agonists of subtypes of nicotinic acetylcholine receptors (nAChR) and voltage-gated sodium channels. Aconitum, Consolida, and Delphinium are important sources of norditerpenoid alkaloids. This thesis is focussed on the chemistry of norditerpenoid alkaloids from these three genera, starting with a review of those recently isolated from Aconitum, Consolida, and Delphinium with brief aspects of taxonomy, biological activities, and modes of action. Selected aspects of the uses in traditional medicine of Delphinium and Aconitum are presented, including data on both toxicity and detoxification. In this thesis, chemical constituents of the seeds of Delphinium cultivar Pacific Giant and the seeds ofAconitum lycoctonum were investigated. To extract the crude alkaloidal material, Soxblet extraction was used for Delphinium cv Pacific Giant seeds and room temperature extraction for A. lycoctonum seeds. The crude extracts were purified by repeated column chromatography (over silica and alumina gels), yielding five known norditerpenoid alkaloids from Delphinium cv Pacific Giant (delavaines A and B, delpheline, methyllycaconitine (MLA), and pacinine) and two from A. lycoctonum (lycaconitine and N-succinylanthranoyl lycoctonine) which were analysed by detailed spectroscopic methods. X-Ray crystallographic analysis of aconitine, mesaconitine, lycoctonine, and delpheline was also studied. Three compounds were obtained from semisynthesis starting with MLA: lycoctonine by basic hydrolysis, inuline by acidic hydrolysis and by esterification of lycoctonine, and elatine by methylenedioxy acetal fonnation. These known alkaloids were structurally elucidated by a variety of spectroscopic techniques. MLA is a selective competitive antagonist at 0.7 sub-type nAChR. From collaborative studies, the results of biological activity for methyl esters delavaines A and B (a 3:2 mixture), delpheline'iand pacinine (the B-ring C6-ketone of delpheline) are reported in this thesis. Their biological activities were detennined in competitive o.-bungarotoxin binding assays for 0.7 nAChR in rat brain membranes. Delavaines A and B were potent ligands (ICso = 50 nM, cfMLA ICso =-1-2 nM), whereas delpheline and pacinine displayed only modest activity at 0.7 nAChR (ICso = -1 JlM). After studying N-ethylpiperidine as a model alkaloid, the pKa (a key physico-chemical parameter) ofMLA was measured by IH NMR as 7.15. A brief comparison with pKa data reported in the literature IS made across closely related norditerpenoid alkaloids.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:485128 |
| Date | January 2007 |
| Creators | Saensuk, Pilan |
| Publisher | University of Bath |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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