Synthesis and evaluation of tri-cyclic alkaloid-like compounds as anticancer agents

Publication Type:
Thesis
Issue Date:
2018
Full metadata record
As part of our ongoing research for anticancer agents, the synthesis of a library of tricyclic compounds using the Bridging Ritter reaction has been described in Chapter 2. Tricyclic imines 82a-c and amines (90a-b, 91a-b) were synthesised in good yields (> 70%). Eleven alkaloid-like compounds were successfully synthesised. Encouraged by the synthetic success described in Chapter 2, preparation of tricyclic caryophyllene derived alkaloid-like compounds was undertaken to provide new leads as described in Chapter 3. The synthesis focused on the use of β-caryophyllene 96 and caryophyllene monoepoxide 117 as key starting materials in the Ritter reaction. Treating 96 and 117 with various nitriles under strong acidic conditions afforded optically active tricyclic amides of caryolane 119a-i and clovane 120a-d skeletons. The formation of these skeletons proceeded via the acid catalysed Wagner-Meerwein rearrangement. The rations of the two structures depended on the reactivity of the nitriles that led to the more kinetically stable of the two skeletons. Caryolane 119c and clovane 120c and 126c were further used to generate complex alkaloid-like compounds through sequential amide cleavage and reductive alkylation. A total of 30 caryophyllene derived alkaloid-like compounds were successfully obtained and subjected to antiproliferative assays. Chapter 4 describes the biological activities of the synthesised compounds described in Chapter 2 and 3. In-house in vitro biological assays were used to assess the cytotoxicities of the synthesised compounds on breast cancer cell lines MCF-7 (ER+) as well as MDA-MB-231 (triple negative). Compound 63 was selected by the US National Cancer Institute (NCI) for their standard cytotoxicity screening program. It was shown to have significant anti-cancer activities with IC₅₀ in the μM range, across seven cancer types. The anti-cancer activities of 82c were found to be selective towards the aggressive and more challenging to treat triple negative (MDA-MB-231) cell line while exhibiting no antiproliferative activities towards the MCF-7 cells at the highest concentration tested (50 μM). The IC₅₀ of compound 82c was determined to be 7.9 μM for the MDA-MB-231 cell line. Furthermore, 82c arrested cell cycle at the G₂/M phase and induced apoptosis in a dose-dependent manner. Cytotoxicities of compounds 63 and 82c were tested against noncancerous mammalian cells (Vero cell line) and found to be approximately eight folds more selective towards MDA-MB-231 than the Vero cell line. From caryophyllene-derived compounds, eight compounds effectively decreased the proliferation and viability of MDA-MB-231, with observed IC₅₀ values ranging from 3.0 – 55.3 μM. Amongst the eight, 119c, 120c, and 126a were most active and selective towards the more aggressive triple negative (MDA-MB-231) over the MCF-7 cells. Furthermore, compounds 119c, 120c, and 126a also altered the distribution of cells throughout the cell cycle, as well as the ability to induce apoptosis in the MDA-MB-231 cells. This observed selectivity towards the harder to treat triple negative breast cancer cells make these compounds more ideal drug candidates for further development.
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