Automated synthesis of 18F radiolabelled indole containing Oncrasin-like molecules; a comparison of iodonium salts and boronic ester chemistry

Alexander F Mcdonald,Yit Wooi Goh,Andrew M Scott,Jonathan M White,Uwe Ackermann

doi:10.1186/s41181-020-00104-x

Abstract

BackgroundOncrasin-1 is a small molecule which was identified from a screen of KRAS mutant cancer cells and has shown specificity for KRAS mutant cell killing. We aimed to develop a radiolabelled form of Oncrasin-1 to enable in-vivo imaging of mutant KRAS expression in malignant tumours. This work outlines the synthesis of 3 fluorinated derivatives and development of iodonium salt and boronic ester precursors for radiolabelling with the 18F isotope.ResultsIn our hands, synthesis of iodonium salts were not easily accessible due to the 3-carbaldehyde indole structure being preferentially oxidized by conditions required for iodonium salt formation, rather than benzyl iodide. Synthesis and radiolabelling of boronic acid pinacol ester precursors were successful, with the products being obtained in yields of 10.76% ± 0.96% (n = 5), 14.7% ±8.58% (n = 3) and 14.92% ±3.9% (n = 3) for 18F KAM001, 18F KAM002 and 18F KAM003 respectively, with radiochemical purity of greater than 99%.ConclusionsThe successful synthesis of these tracers has been undertaken utilizing boronic ester radio-fluorination methods and will allow for investigation of Oncrasin based molecules as potential diagnostics for cancers expressing mutant KRAS protein.

Highlights

Oncrasin-1 is a small molecule which was identified from a screen of Kirsten Rat Sarcoma (KRAS) mutant cancer cells and has shown specificity for KRAS mutant cell killing
Miyarua borylation A standard Miyaura borylation was utilized for generation of the parasubstituted boronic acid pinacol ester precursor from an iodine substituted intermediate to afford the product in a 72% yield
Boronic acid pinacol ester precursors were successfully synthesized and radiolabelled utilizing modified reaction conditions reported by Mossine and co-workers

Summary

Introduction

Oncrasin-1 is a small molecule which was identified from a screen of KRAS mutant cancer cells and has shown specificity for KRAS mutant cell killing. The high frequency of mutation in cancer has made this gene family a target of significant interest within the field of oncology, despite extensive efforts to exploit these proteins as potential therapeutic targets, molecules designed for RAS mutant therapies have not made progress into the clinic. Since identification of this oncogenic driver, efforts to develop new molecules to target KRAS have been ongoing; a molecule, denoted Oncrasin-1 shown, being discovered in 2008 through a synthetic lethal screen with KRAS mutation in breast cancer cell lines (Guo et al 2008).

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