title: Novel styryl-indoles as small molecule inhibitors of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1): Synthesis and biological evaluation.
abstract: The synthesis of a series of imidazole styrylindoles and sulfonyl styrylindoles derivatives is described. Evaluation of binding affinity and inhibitory activity against CYP24A1 identified the imidazole styrylindoles as potent inhibitors with activity greater or comparable with the standard ketoconazole. Flexible alignment and docking studies of the inhibitors in the CYP24A1 enzyme active site confirmed that complete occupation of the vitamin D access tunnel is essential to inhibitory activity, allowing exposure to multiple hydrophobic binding interactions and optimal conformation for the interaction of the imidazole nitrogen lone pair and the active site haem.
authors.affiliation: Medicinal Chemistry, School of Pharmacy & Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Ferla
authors.affiliation: Medicinal Chemistry, School of Pharmacy & Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Gomaa
authors.affiliation: Medicinal Chemistry, School of Pharmacy & Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706-1544, USA.
authors.forename: Jinge
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706-1544, USA.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Ochalek
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706-1544, USA.
authors.forename: Hector F
authors.initials: HF
authors.lastname: DeLuca
authors.affiliation: Medicinal Chemistry, School of Pharmacy & Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK. Electronic address: SimonsC@Cardiff.ac.uk.
authors.forename: Claire
authors.initials: C
authors.lastname: Simons
mesh_terms: D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D020058:Styrene / Q000737:chemistry*; D065668:Vitamin D3 24-Hydroxylase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D054852:Small Molecule Libraries; D020058:Styrene; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase
keywords: CYP24A1; Imidazole styrylindoles; Molecular modelling; Sulfonyl styrylindoles; Vitamin D