Keywords

pancreatic cancer, LAT1, FUBP1, piperazine, polyamines, leucine and methionine

Abstract

Pancreatic cancer is the sixth leading cause of cancer-related death and new therapies are needed. In this investigation two piperazine-based compound classes were discovered with anticancer activity against human pancreatic cancer cells. The use of piperazine moieties in medicinal chemistry has garnered increased interest because FDA-approved anticancer piperazine derivatives (i.e. Imatinib) have demonstrated significant impact in cancer treatment.

The first half of this study describes the discovery of a class of piperazine-based compounds that function as far upstream binding protein 1 (FUBP1) inhibitors. FUBP1 is a single-stranded DNA/RNA binding protein that functions as a master regulator of various genes, including c-Myc, which is overexpressed in pancreatic ductal adenocarcinoma. This report describes our initial discovery as well as development of a synthetic pathway to access these derivatives, and bioevaluation of these piperazine-based compounds in vitro.

The second half of this report describes a different class of piperazine-based compounds that function as large amino acid transporter 1 (LAT1) efflux agonists. LAT1, also known as solute carrier protein 7A5 (SLC7A5), is a Na+-independent amino acid transporter that regulates influx of essential amino acids. LAT1 expression is associated with decreased overall survival in pancreatic cancer. In previously published work, we demonstrated the ability of the lead compound to decrease leucine and methionine levels in human pancreatic cancer cells in vitro leading to inhibited cancer cell growth. This report describes our continued optimization of the LAT1 efflux agonist design through in silico modeling, development of a modular synthetic method using chiral piperazines to access new derivatives of our lead efflux agonist, and bioevaluation of these new compounds as anticancer therapies in vitro using relative growth measurements and a 3H-leucine efflux assay. Mapping our computational predictions to each compound’s actual in vitro performance is a major deliverable of this effort.

Completion Date

2024

Semester

Summer

Committee Chair

Otto Phanstiel, IV

Degree

Doctor of Philosophy (Ph.D.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Degree Program

Biomedical Sciences

Format

application/pdf

Identifier

DP0028877

URL

https://stars.library.ucf.edu/cgi/viewcontent.cgi?article=1404&context=etd2023

Language

English

Rights

In copyright

Release Date

2-15-2025

Length of Campus-only Access

None

Access Status

Doctoral Dissertation (Open Access)

Campus Location

Orlando (Main) Campus

Accessibility Status

Meets minimum standards for ETDs/HUTs

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