AbstractNorditerpenoid alkaloids (NDA) are the main bioactive components of the medicinal plants of Delphinium and Aconitum. This research project is focussed on the characterization of NDA in their natural sources by isolation, some aspects of quantification, and detailed analytical chemistry which leads to a better understanding of their possible 3D-conformations in biological fluids. The synthesis of small molecule AE-bicyclic NDA analogues gave a better understanding of their structure-activity relationships (SAR).
The phytochemical investigation of D. elatum seeds results in the isolation of four NDA: methyllycaconitine (MLA), shawurensine A, shawurensine B, which is reported for the first time, and delpheline where the crystal structure is reported for the first time. The safety and effectiveness have been assessed for five Aconitum TCM preparations (Zhi’cao’wu, Zhi’chuan’wu, Yan’fu’zi, Bai’fu’pian, and Hei’shun’pian) through the quantification of six norditerpenoid markers. It was found that the total diester diterpenoid alkaloids (DDA) amount is within the Chinese Pharmacopeia limit and therefore they can be safely used. On the other hand, only Zhi’cao’wu met the Chinese Pharmacopeia limit for the total monoester diterpenoid alkaloids (MDA) amount which ensures the preparation efficacy.
The in-solution characterization of NDA using NMR spectroscopy and mass spectrometry (MS) was accomplished where it was observed using NMR spectroscopy that the A-ring in 1-OH NDA adopts a boat conformation compared to a chair conformer in 1-OMe NDA due to the intramolecular H-bonding between that 1-OH group and the piperidine nitrogen. The stability of the NDA skeleton was studied using atmospheric pressure chemical ionization mass spectrometry (APCI-MS) where it was shown that 1-OH NDA are more stable compared to 1-OMe NDA. In addition, the effect of carbon 1 substituent configuration was studied by the synthesis of 1-epi-condelphine where it was found that it is less stable in the MS compared to condelphine as the nitrogen is no longer hydrogen bonded to the β-OH at position 1.
The synthesis of AE-bicyclic analogues of methyllycaconitine (MLA) was accomplished with different nitrogen and ester side-chains to get a better SAR understanding of their activity at human α7 nAChR.
|Date of Award||16 Nov 2022|
|Supervisor||Ian Blagbrough (Supervisor) & Michael Rowan (Supervisor)|