Abstract:
:The Forkhead boX M1 (FOXM1) protein is an essential transcription factor required for the normal activation of human cell cycle. However, increasing evidence supports a correlation between FOXM1 overexpression and the onset of several types of cancer. Based on a previously reported molecular modeling and molecular dynamics simulations (MD) study, we hypothesized the role of an essential halogen-bonding interaction between the 4-fluorophenyl group in the forkhead domain inhibitor-6 (FDI-6) and an Arg297 residue inside the FOXM1-DNA binding domain (DBD). To prove the importance of this binding interaction, we synthesized and screened ten FDI-6 derivatives possessing different groups at the 4-fluorophenyl position of the lead molecule. Briefly, we found that derivatives possessing a 4-chlorophenyl, 4-bromophenyl, or a 4-iodophenyl group, were equipotent to the original 4-fluorophenyl moiety present in FDI-6, whereas derivatives without this 4-halogen moiety were inactive. We also observed that positional isomers in which the halogen was relocated to positions 2- or 3- on the phenyl group were significantly less active. These results provide evidence to support the essential role of a 4-halophenyl bonding interaction, with the Arg297 residue in the FOXM1-DBD, to exert inhibition of transcriptional activity.
journal_name
Bioorg Chemjournal_title
Bioorganic chemistryauthors
Tabatabaei Dakhili SA,Pérez DJ,Gopal K,Tabatabaei Dakhili SY,Ussher JR,Velázquez-Martínez CAdoi
10.1016/j.bioorg.2019.103269subject
Has Abstractpub_date
2019-12-01 00:00:00pages
103269eissn
0045-2068issn
1090-2120pii
S0045-2068(19)30400-6journal_volume
93pub_type
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