Synthesis and biological evaluation of natural and synthetic ganoderic acids

Jaramillo Forcada, Tatiana (2017) Synthesis and biological evaluation of natural and synthetic ganoderic acids. PhD thesis, University of Nottingham.

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Abstract

Ganoderma lucidum also known as lingzhi or mushroom of immortality in East Asia countries, has been known for over 2000 years. Ganoderic acids (GA), which are important secondary metabolites of this mushroom, are highly oxygenated lanostane-type entities with extraordinary pharmacological properties. GA are biosynthesised from lanosterol by a still unknown mechanism.

The synthesis of thirteen GA analogues and the biological evaluation of ten of them against prostate cell-lines is described in this thesis. Analogues with different functionalities at C-3, C-7, C-8, C-9, C-11, C-23, C-24, C-25 and C-26 of the lanostane frame have been synthesised. As functional groups, alcohols, acetates, ketones, carboxylic acids and single and conjugated double bonds have been introduced. For their preparation, aldehyde 89 was formed from commercial lanosterol in up to 47% overall yield over a 3 or 4 step sequence. Wittig olefination, Reformatsky reaction and direct oxidation of aldehyde 89 provided the precursors from which the analogues were achieved. Analogues were prepared after a total of six to eight steps in 7-44% overall yield.

GA and their analogues inhibited the cell viability of prostate cell-lines. However, they were less effective in the inhibition than Taxotere® (docetaxel). Besides, by comparing their IC50 values and thus, building a structure activity relationship (SAR) analysis, the most important positions for activity were determined. Interestingly, some of the ganoderic acids, GA-H (24), and analogues 3-ketone 108 and 7,11-diketone 146, were less toxic for the normal prostate cells than for the pre-malignant ones, conferring on them prophylactic activity. It is believed that ketones at C-3, C-7 and C-11 could be responsible for this behaviour.

Ganoderma lucidum is rare in nature. However, due to its great demand, it is now being farmed. For their cultivation sawdust, logs or cork is used. New substrates, otherwise disposed as waste, are being investigated to produce high quality mushrooms, among them oil palm fibres such as mesocarp or empty fruit bunch fibres. Therefore, to unveil new cultivation methods, the triterpene composition of the mushroom grown at different stages, with different substrates or conditions has been assessed and their biological activity evaluated against prostate cancer cell-lines. Cultivating the mushroom in mesocarp or empty fruit bunch fibres produced similar results to those of sawdust. However, poor ventilated conditions reduced their biological activity against prostate cancer cell-lines. Likewise, it was established that triterpene composition varied during different stages and for different target body parts, their biological activity also varied with age, increasing as the mushroom aged during the 2- to 8-week period studied.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Thomas, Neil R.
Grabowska, Anna
Keywords: Ganoderic acid, ganoderma lucidum, prostate cancer, sar analysis
Subjects: Q Science > QD Chemistry > QD241 Organic chemistry
R Medicine > RS Pharmacy and materia medica
Faculties/Schools: UK Campuses > Faculty of Science > School of Chemistry
Item ID: 43313
Depositing User: Jaramillo Forcada, Tatiana
Date Deposited: 28 Jul 2017 12:42
Last Modified: 23 Oct 2017 07:30
URI: http://eprints.nottingham.ac.uk/id/eprint/43313

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