Synthesis and anticancer activity of NDGA and analogues

McDonald, Russell Walker (2000) Synthesis and anticancer activity of NDGA and analogues. PhD thesis, University of Glasgow.

Abstract

There is an urgent need to develop novel therapeutic strategies for common solid tumours including small cell lung cancer where the five year survival rate is less than 5%. The natural product nordihydroguaiaretic acid (NDGA) (A) has been shown to block the growth of small cell lung cancer in vitro and in vivo. In order to realise the potential of NDGA as an effective anti-cancer agent we set up a collaboration with Dr. M. Seckl (Hammersmith Hospital) with the goal of producing a more potent analogue. Initially we concentrated on the synthesis of the racemate of NDGA (B) which would ascertain whether the stereochemistry of the methyl groups was important for activity. Our four step synthesis employed a pinacol coupling as the key step affording (B) in low overall yield. The preliminary test results showed (B) to be equipotent to NDGA suggesting that the stereochemistry of the methyl groups is not important for activity.To help in the determination of structural activity relationships we synthesised a series of analogues of NDGA having different bridging distances between the aromatic nuclei. The synthesis of a series of mono phenolic compounds was also undertaken following the same procedures. The diarylbutane derivative (C) was found to be 10 fold more potent than NDGA in vitro suggesting that the methyl groups of (A) hindered its activity or that improved activity was due to decreased lipophilicity. A number of amide derivatives were also synthesised allowing access to more conformationally restricted analogues. The test results showed that the secondary amide (D) was four times more potent than NDGA. However the corresponding N-Me derivative was less active. The poor aqueous solubility of NDGA has hampered its development as an effective anti-cancer agent. With this in mind, we have been working on the synthesis of a water soluble conjugate of NDGA which would release the active component over a period of time. The tetra glycyl salt (E) was synthesised. This is water soluble as expected but has slighty less activity than the parent compound. On the other hand, the ammonium salt (F) was found to be water soluble and twice as potent as NDGA and is currently undergoing in vivo testing.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Pharmacology, organic chemistry.
• Subjects: Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Supervisor's Name: Robins, Professor David
• Date of Award: 2000
• Depositing User: Enlighten Team
• Unique ID: glathesis:2000-71251
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 10 May 2019 10:49
• Last Modified: 02 Nov 2022 21:00
• Thesis DOI: 10.5525/gla.thesis.71251
• URI: https://theses.gla.ac.uk/id/eprint/71251