Exploring the spliceosome using hinokiflavone based probes

Kreinin, Helmi (2018) Exploring the spliceosome using hinokiflavone based probes. PhD thesis, University of Glasgow.

Abstract

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.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: biflavonoid, natural product, spliceosome, total synthesis, analogues, SENP inhibitor, SUMO accumulation.
• Subjects: Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Supervisor's Name: Hartley, Professor Richard C.
• Date of Award: 2018
• Embargo Date: 26 January 2022
• Depositing User: Miss Helmi Kreinin
• Unique ID: glathesis:2018-8705
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 29 Jan 2018 10:44
• Last Modified: 16 Feb 2024 10:03
• Thesis DOI: 10.5525/gla.thesis.8705
• URI: https://theses.gla.ac.uk/id/eprint/8705