Abstract
Narciclasine, pancratistatin and narciprimine are natural products obtained from the bulbs of various Amaryllidaceae plants. Narciclasine and pancratistatin both display powerful activity against a wide range of cancers, with little toxicity to normal cells. Narciprimine is not active, however this may be due to its planar nature or lack of hydroxy groups, hence the need to investigate the synthesis of analogues.Limited availability from natural sources and complex chemical synthesis of the natural products and related analogues has, however, prevented detailed biological evaluation of anti-brain tumour activities and clinical development.
Synthesis of narciprimine analogues began with assembling the A-C bicyclic ring precursor. Suzuki coupling of the boronic acid and corresponding bromide afforded the A-C ring in 58-92% yields. Ring-closure was attempted using an already established procedure; this, however, failed to furnish the desired ABC product. In an alternative approach, the amide was first synthesised in good yields and subsequent Heck coupling successfully afforded the desired analogue in 55-75% yield. Upon further investigations, double C-H activation and selective demethylation was successfully achieved in one pot, affording the desired narciprimine analogue. Preliminary attempts were made to furnish the C-ring with hydroxy groups, using gallic acid as starting material. This route will be explored in future.
A one-pot synthetic method to generate the narciclasine/pancratistatin core was previously developed in a single high-yielding step, from the corresponding dihydrocinnamic acid, via a modified Curtius rearrangement. Formation and capture of an isocyanate intermediate with a Lewis acid by the electron-rich aromatic ring forms the desired lactam, initially as a BF2-complex. Upon applying this method, a series of dihydroisoquinolinones as simplified AB-ring analogues were synthesised in 55-81 % yields.
Using shikimic acid as a cheap and readily available starting material, synthesis of the functionalised C-ring with fixed stereochemistry and decorated with hydroxy groups began with MOM protection of the shikimic acid and subsequent hydrolysis of the ester. This was achieved in quantitative yields. The A-C ring was made by optimising a palladium-catalysed cross-coupling reaction to afford the highly functionalised cyclisation precursor. Reduction of the αβ-unsaturated coupled ester gave the corresponding saturated product in quantitative yields as a mixture of epimers in 3:2 ratio. This was followed by saponification of the ester, formation of the acyl azide, subsequent Curtius rearrangement to generate the isocyanate intermediate and formation of the methyl carbamate, all in excellent yields. Ring-closure was achieved using Banwell’s protocol followed by selective demethylation to reveal the free phenol and exposure of hydroxy groups, thereby furnishing the analogue of narciclasine/pancratistatin as a single epimer in 11 steps, in 4% overall yield from shikimic acid.
The natural product and synthesised analogues have been evaluated against glioblastoma cell lines and tested on a novel blood-brain-barrier (BBB) model in collaboration with Exeter Medical School with promising results.
| Date of Award | 23 Mar 2022 |
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| Original language | English |
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| Supervisor | Lorenzo Caggiano (Supervisor) & Michael Threadgill (Supervisor) |