Alkaloid-like molecules as AChE inhibitors

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The alkaloid class of natural compounds is extensively known for their variety of biological activities. A high percentage of currently employed chemotherapeutic drugs - more than 60% for cancer are of plant origin, and many are alkaloids.[1] Synthetic compounds that display similar structures to alkaloids are known as alkaloid-like molecules. Alkaloids are commonly documented to poses pharmacological properties such as acetylcholinesterase (AChE) inhibitory and antineoplasticity. The Aristotelia alkaloids (1, 2, 3) have a broad spectrum of biological activities,[2] several of which contain the same 3-aza-bicyclo[3.3.1]nonane (4) core structure architecture. As these Alkaloids are both rare and require complex isolation, it is more resourceful to generate libraries of molecules with the same core scaffold through synthetic pathways, such as the Bridging Ritter reaction.[3] Through the use of the Bridging Ritter reaction with (-)-β-pinene (5) and various nitriles, a small library of alkaloid-like molecules has be synthesized and purified. Their activity against AChE is then tested. AChE inhibitors are currently the front line of drugs used for relieving the symptoms of Alzheimer’s disease (AD). Through reducing the natural decomposition of the neurotransmitter acetylcholine (ACh) by AChE, in the synapse of AD suffers, cognitive function lost due to decreased levels of ACh can be restored.[4] There are currently only three AChE inhibitors approved for use in Australia, all of which are not without undesirable side-effects. With the mortality rate reported to be 11,000 people in Australia alone in 2013, and that number expected to increase as the baby boomer generation enters the age bracket in which most people develop the disease. A library of 27 alkaloid-like molecules has been synthesised and tested using the TLC bioautographic method[5] for initial rapid screening. The IC50 values of the inhibitors were determined using the Ellman Assay.[6] The recent finding of our work will be presented in details in this presentation. References [1] D. J. Newman and G. M. Cragg, Journal of Natural Products 2012, 75, 311-335. [2] M. Silva and M. Bittner, Química de la Flora de Chile 1992, 153-164. [3] A. T. Ung, S. G. Williams, A. Angeloski, J. Ashmore, U. Kuzhiumparambil, M. Bhadbhade and R. Bishop, Monatshefte für Chemie-Chemical Monthly 2014, 145, 983-992. [4] H. Yu, W.-M. Li, K. K. Kan, J. M. Ho, P. R. Carlier, Y.-P. Pang, Z.-M. Gu, Z. Zhong, K. Chan and Y.-T. Wang, Journal of pharmaceutical and biomedical analysis 2008, 46, 75-81. [5] A. Marston, J. Kissling and K. Hostettmann, Phytochemical Analysis 2002, 13, 51-54. [6] G. L. Ellman, K. D. Courtney and R. M. Featherstone, Biochemical pharmacology 1961, 7, 88-95.
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