Isolation, semisynthesis, covalent docking and transforming growth factor beta-activated kinase 1 (TAK1)-inhibitory activities of (5Z)-7-oxozeaenol analogues.
(5Z)-7-Oxozeanol and related analogues were isolated and screened to explore their activity as TAK1 inhibitors. Seven analogues were synthesized and more than a score of natural products isolated that examined the role that different areas of the molecule contribute to TAK1 inhibition. A novel nonaromatic difluoro-derivative was synthesized that had similar potency compared to the lead. This is the first example of a nonaromatic compound in this class to have TAK1 inhibition. Covalent docking for the isolated and synthesized analogues was carried out and found a strong correlation between the observed activities and the calculated binding.
Department of Chemistry and Biochemistry, Natural Products and Drug Discovery Center, University of North Carolina at Greensboro, Greensboro, NC 27402, USA.
Lara
L
Fakhouri
Department of Chemistry and Biochemistry, Natural Products and Drug Discovery Center, University of North Carolina at Greensboro, Greensboro, NC 27402, USA.
Tamam
T
El-Elimat
Department of Chemistry and Biochemistry, Natural Products and Drug Discovery Center, University of North Carolina at Greensboro, Greensboro, NC 27402, USA.
Dow P
DP
Hurst
Department of Chemistry and Biochemistry, Natural Products and Drug Discovery Center, University of North Carolina at Greensboro, Greensboro, NC 27402, USA.
Patricia H
PH
Reggio
Mycosynthetix, Inc., 505 Meadowlands Drive, Suite 103, Hillsborough, USA.
Cedric J
CJ
Pearce
Department of Chemistry and Biochemistry, Natural Products and Drug Discovery Center, University of North Carolina at Greensboro, Greensboro, NC 27402, USA.
Nicholas H
NH
Oberlies
Department of Chemistry and Biochemistry, Natural Products and Drug Discovery Center, University of North Carolina at Greensboro, Greensboro, NC 27402, USA.
Mitchell P
MP
Croatt
D001665:Binding Sites; D006801:Humans; D020128:Inhibitory Concentration 50; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015025:Zearalenone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000008:administration & dosage; D000099151:MAP Kinase Kinase Kinase 7; D007783:Lactones; D012118:Resorcinols
D020930:MAP Kinase Kinase Kinases; D047428:Protein Kinase Inhibitors; D015025:Zearalenone; D000099151:MAP Kinase Kinase Kinase 7; C505734:7-oxozeanol; D007783:Lactones; D012118:Resorcinols
(5Z)-7-Oxozeaenol; Covalent docking; Resorcylic acid lactone; Selectfluor®; TAK1