Alkaloid-like Molecules for Drug Discovery

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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 antineoplasticity and acetylcholinesterase (AChE) inhibition. The Aristotelia alkaloids (1 and 2) have a broad spectrum of biological activities,[2] several of which contain the same 3-aza-bicyclo[3.3.1]nonane core structure architecture, seen in blue in Figure 2. Figure 1: Aristotelia alkaloids, 1 and 2. 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 (3) and various nitriles, a small library of alkaloid-like molecules has been synthesized. Figure 2: The bridging Ritter reaction of (-)-β-pinene with various nitriles. AChE inhibitors are currently the front line of drugs used for relieving the symptoms of Alzheimer’s disease (AD) by restoring natural levels neurotransmitter acetylcholine, found to be low in the synapse of AD suffers.[4] All of the currently approved AChE inhibitors have severe undesirable side-effects and with the diseases mortality rate expected to increase greatly, it is imperative that more suitable drug candidates be developed. Therefore, these alkaloid-like compounds were screened for AChE inhibitory activity using The TLC bioautographic method[5] and Ellman Assay[6]. A library of 27 alkaloid-like molecules has been synthesised. The library is currently undergoing in-house anticancer testing using the MTS assay[7] against the MDA-MB-231 breast cancer cell line. External screening has revealed one series of compounds to show potent inhibition properties against MCF-7 and one inparticular to be inactive against healthy mammalian (Vero cell line) and human oral cavity carcinoma (KB) respectively. Screening against AChE showed that the current library act only as weak inhibitors but combined with molecular modeling, has provided useful SAR data to guide the synthesis of more potent hits. Of significant interest is the importance the alkene functionality plays in providing activity. The recent finding of our work will be presented in details in this presentation.
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