Spiropyrrolizidine and piperazine derivatives: Synthesis and evaluation on kras expression levels in human colon cancer cells

Summary

Description / Synopsis	Description / Synopsis KRAS-driven cancers are notoriously difficult to treat due to poor pharmacodynamics of downstream inhibitors and resistance to anti-EGFR drugs. IMP-1 is a post-transcriptional regulator of KRAS mRNA. As a novel therapeutic approach, the targeting of the IMP-1-KRAS mRNA complex with a spiropyrrolizidine derivative (UNBC152), was studied. LC-MS analysis of UNBC152 indicated presence of impurities. The purpose of this study was to synthesize UNBC152 and determine the responsible bioactive molecule within the impurities. LC-MS and TLC suggested the presence of a bioactive [3+3] cycloaddition side product (SPOPP) in UNBC152. SPOPP suppressed KRAS expression in human colorectal cancer cells. Fluorescence polarization determined that SPOPP did not impact the IMP-1-KRAS mRNA interaction. SPOPP induced G2/M cell cycle arrest as shown by flow cytometry. MTT assay confirmed the SPOPP-induced growth inhibition in SW480 (IC50 = 4.17 μM) and HT29 (IC50 = 6.76 μM). These findings represent a first reporting on the bioactivity of SPOPP.
Persons	Persons Author (aut): Liu, Victor P. Thesis advisor (ths): Lee, Chow Thesis advisor (ths): Bott, Tina Degree committee member (dgc): Plourde, Guy Degree committee member (dgc): Reimer, Kerry
Degree Name	Degree Name Master of Science (MSc)
Department	Department Biochemistry
DOI	DOI https://doi.org/10.24124/2019/58964
Collection(s)	Collection(s) Dissertations and Theses

Origin Information

Date Created/Date Issued	2019
Publisher	University of Northern British Columbia
Issuance	monographic

Organizations

Degree Level

Subjects and Classifications

Subject Topic	Subject Topic Colon (Anatomy)--Cancer--Treatment Colonic Neoplasms Pyrrolizidines Pyrrolizidine Alkaloids--therapeutic use Piperazine--therapeutic use
Keywords	Keywords kras cancer colon inhibitors anti-egfr drugs

Resource Description

Extent	Extent 1 online resource (160 pages)
Physical Form	Physical Form electronic
Physical Description Note	Physical Description Note PUBLISHED
Content type	Content type Digital Document
Resource Type	Resource Type Text
Genre	Genre thesis
Language	Language English

Access and Rights

Use and Reproduction	Use and Reproduction author
Rights Statement	Rights Statement IN COPYRIGHT

Language	English
Name	Spiropyrrolizidine and piperazine derivatives
Authored on	2025-03-20
MIME type	application/pdf
File size	5577711
Media Use	Original File

Download