Norditerpenoid Alkaloids from Medicinal Plants

Abstract

Norditerpenoid alkaloids are the main bioactive components of the medicinal plants of Aconitum and Delphinium. To achieve structure-activity relationship (SAR) studies of these natural products, especially of methyllycaconitine (MLA), investigation of their 3D structures is essential as the conformation of a molecule determines its bioactivities.

NMR spectroscopic data (1H, 13C, COSY, HSQC, HMBC and NOESY) of 5 commercially available norditerpenoid alkaloid free bases and 2 of their salts (aconitine HCl and lappaconitine HBr) were obtained. It is notable that basic norditerpenoid alkaloids and their analogues are partially protonated at neutral pH, e.g. in plasma or water. Therefore, essential studies on the solution conformations of the two alkaloid salts, which are bioactive conformations, were carried out in D2O. Solution conformation of these alkaloids were investigated with NOESY spectroscopies and key 1H signal coupling patterns. NMR analyses also demonstrated a rare through-space 1H NMR effect of steric compression in synthetic [3.3.1]azabicyclic analogues of MLA. This effect is shown in norditerpenoid alkaloids with uncommonly small intensity compared with that in the synthetic analogues, suggesting there are conformational differences between the alkaloids and their synthetic analogues. Singlecrystal X-ray diffraction (XRD) is one of the best methods for investigating configuration and conformation, if such high quality crystals are available. 15 single-crystals of norditerpenoid alkaloids and their synthetic analogues were obtained in this work and used for determining their crystal conformations, and then their conformational common features were summarized.

13C signal assignments reported in previous studies of the well-known lycoctonine, lappaconitine and crassicauline A norditerpenoid alkaloids are revised supported by 2D NMR spectroscopic data. Notably, a rare NMR effect of steric compression has been clearly demonstrated. Protonated norditerpenoid alkaloid salts adopt boat/chair conformations in crystals and in D2O, the same conformation of protonated [3.3.1]azabicycle in crystals, but that protonated [3.3.1]azabicycle adopts a chair/chair conformation in D2O.

Date of Award	30 Sept 2020
Original language	English
Awarding Institution	University of Bath
Supervisor	Ian Blagbrough (Supervisor) & Michael Rowan (Supervisor)