The Forkhead box M1 protein (FOXM1) belongs to a family of evolutively conserved transcription regulators, which controls a broad range of normal biologically essential functions such as DNA damage repair, cellular proliferation, cell cycle progression, cellular renovation, cellular differentiation, cellular migration and angiogenesis. As a transcription factor FOXM1 expression is frequently overregulated in practically all types of cancer. Additionally, it has been observed that the in vitro inhibition of the transcriptional FOXM1 activity is associated with a decrease in cellular proliferation for many different types of cancer cells; thus, this transcription factor is considered a good target for fighting this disease with utility both as a radiotracer for diagnosis and as a drug for therapy. Carlos Velásquez group, in University of Alberta, Canada, previously reported a series of docking and molecular dynamic studies, in which an important interaction between the Forkhead Domain Inhibitor-6 (FDI-6) and the Arg297 residue inside the FOXM1-DNA binding domain (DBD) was observed. In order to prove the importance of this interaction, in this work we synthesized a series of new FDI-6 derivatives possessing a 4-iodophenyl with different substituents at position 2 of the phenyl group, whose anticancerogenic activity will be determined. Additionally, an easily accessible methodology to substitute the iodine for a fluorine atom (19F) in the newly synthesized compounds is being studied. This methodology could be used with radioactive fluorine (18F) and the radioactive compounds can be assessed as radiotracers. To support the experimental observations a complementary docking studies between the compounds and one of the FOXM1 protein domains were carried out in order to know more about the need of the different substituents at positions 2 and 4, of the phenyl moiety, of FDI drugs. Progresses of these studies are presented in this work.

Synthesis of new FDI-6 derivatives as inhibitors and radiotracers of FOXM1

2019 Fall National Meeting

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