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Spiropyrrolizidine and piperazine derivatives: Synthesis and evaluation on kras expression levels in human colon cancer cells
Victor P. Liu (author)Chow Lee (thesis advisor)Tina Bott (thesis advisor)University of Northern British Columbia College of Science and Management (Degree granting institution)Guy Plourde (committee member)Kerry Reimer (committee member)
Master of Science (MSc)
1 online resource (160 pages)
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.
Colon (Anatomy)--Cancer--TreatmentColonic NeoplasmsPyrrolizidinesPyrrolizidine Alkaloids--therapeutic usePiperazine--therapeutic use