The spliceosome is the cellular machinery involved in producing mature messenger RNA from pre-mRNA before it is translated into protein by the cells. Improved understanding of this vital cellular process would allow us to design better drugs to combat diseases that depend on splicing mismanagement. Small molecules that affect splicing would be useful in furthering our understanding of this complex cellular mechanism. Hinokiflavone, a biflavonoid natural product, was found to affect splicing in cells. In this work we describe the total synthesis of hinokiflavone, after exploring alternative synthetic routes. Several different series of hinokiflavone analogues were also designed and three of these structural analogues displayed the same bioactivity as hinokiflavone. Various biological assays in which hinokiflavone and the analogues were active were then examined. It was found that these molecules modulate splicing by inhibiting SENP activity. The SENP enzyme removes SUMO, a post-translational modification involved in the cellular control over splicing, hence its inhibition has a marked effect on cellular metabolism.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:732779 |
| Date | January 2018 |
| Creators | Kreinin, Helmi |
| Publisher | University of Glasgow |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://theses.gla.ac.uk/8705/ |
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