Novel styryl-indoles as small molecule inhibitors of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1): Synthesis and biological evaluation

Ferla, Salvatore; Gomaa, Mohamed S.; Brancale, Andrea; Zhu, Jinge; Ochalek, Justin T.; DeLuca, Hector F.; Simons, Claire

doi:10.1016/j.ejmech.2014.09.035

Cited by 5 publications

(1 citation statement)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Product 2i was obtained as a light yellow crystalline solid (26 mg, 48%): 1 H NMR (400 MHz, CDCl (E)-5-Styryl-1H-indole (2j). 36 The reaction was performed according to Method B using 5-(phenylethynyl)-1H-indole (131 mg, 0.6 mmol), RuCl 2 (DMSO) 4 (29 mg, 0.06 mmol), tBuOK (34 mg, 0.3 mmol), 2-propanol (0.46 mL, 6.0 mmol), and toluene (1.54 mL) with a reaction time of 72 h. NMR yield: 75%. Flash chromatography gradient: petroleum ether/EtOAc, 96:4 to 92:8 (10 column volumes) to 92:8 (8 column volumes).…”

Section: -(Phenylethynyl)aniline (1h)mentioning

confidence: 99%

Ruthenium-Catalyzed E-Selective Alkyne Semihydrogenation with Alcohols as Hydrogen Donors

2020

View full text Add to dashboard Cite

Selective direct ruthenium-catalyzed semihydrogenation of diaryl alkynes to the corresponding E-alkenes has been achieved using alcohols as the hydrogen source. The method employs a simple ruthenium catalyst, does not require external ligands, and affords the desired products in > 99% NMR yield in most cases (up to 93% isolated yield). Best results were obtained using benzyl alcohol as the hydrogen donor, although biorenewable alcohols such as furfuryl alcohol could also be applied. In addition, tandem semihydrogenation–alkylation reactions were demonstrated, with potential applications in the synthesis of resveratrol derivatives.

show abstract

Section: -(Phenylethynyl)aniline (1h)mentioning

confidence: 99%

Ruthenium-Catalyzed E-Selective Alkyne Semihydrogenation with Alcohols as Hydrogen Donors

2020

View full text Add to dashboard Cite

show abstract

Synthesis, molecular modelling and CYP24A1 inhibitory activity of novel of ( E )- N -(2-(1 H -imidazol-1-yl)-2-(phenylethyl)-3/4-styrylbenzamides

Taban

Zhu

DeLuca

et al. 2017

Bioorganic & Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

CYP24A1 (25-hydroxyvitamin D-24-hydroxylase) is a useful enzyme target for a range of medical conditions including cancer, cardiovascular and autoimmune disease, which show elevated CYP24A1 levels and corresponding reduction of calcitriol (the biologically active form of vitamin D). A series of (E)-N-(2-(1H-imidazol-1-yl)-2-(phenylethyl)-3/4-styrylbenzamides have been synthesised using an efficient synthetic route and shown to be potent inhibitors of CYP24A1 (IC 0.11-0.35μM) compared with the standard ketoconazole. Molecular modelling using our CYP24A1 homology model showed the inhibitors to fill the hydrophobic binding site, forming key transition metal interaction between the imidazole nitrogen and the haem Fe and multiple interactions with the active site amino acid residues.

show abstract

Analysis of the binding sites of vitamin D 1α-hydroxylase (CYP27B1) and vitamin D 24-hydroxylase (CYP24A1) for the design of selective CYP24A1 inhibitors: Homology modelling, molecular dynamics simulations and identification of key binding requirements

Taban

Zhu

DeLuca

et al. 2017

Bioorganic & Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

A homology model of human CYP27B1 was built using MOE and was further optimised by molecular dynamics simulations of the hCYP27B1 homology model and a hCYP27B1-SDZ-88357 complex. Docking results from the hCYP27B1-SDZ-88357 complex showed amino acids Arg107, Asn387 and Asp320 have an important role in binding interaction, with Asp320 part of the important acid-alcohol pair situated in the I-helix with the conserved sequence (A/G) GX (E/D) (T/S), which assumes an essential role in the binding of an oxygen molecule for catalysis. Additional docking experiments with selective hCYP27B1 or hCYP24A1 inhibitors using both the hCYP27B1 model and a triple mutant hCYP24A1 model provided further support for the importance of H-bonding interactions with the three identified active site amino acids. To confirm the role of Arg107, Asn387 and Asp320 in the active site of hCYP27B1 compounds were designed that would form H-bonding interactions, as determined from docking experiments with the hCYP27B1 model. Subsequent synthesis and CYP24A1 and CYP27B1 enzyme assays of the designed compounds 1a and 1b showed a∼5-fold selectivity for CYP27B1 confirming the importance of Asp320 in particular and also Asn387 and Arg107 as important amino acids for CYP27B1 inhibitory activity.

show abstract

Novel styryl-indoles as small molecule inhibitors of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1): Synthesis and biological evaluation

Cited by 5 publications

References 34 publications

Ruthenium-Catalyzed E-Selective Alkyne Semihydrogenation with Alcohols as Hydrogen Donors

Ruthenium-Catalyzed E-Selective Alkyne Semihydrogenation with Alcohols as Hydrogen Donors

Synthesis, molecular modelling and CYP24A1 inhibitory activity of novel of ( E )- N -(2-(1 H -imidazol-1-yl)-2-(phenylethyl)-3/4-styrylbenzamides

Analysis of the binding sites of vitamin D 1α-hydroxylase (CYP27B1) and vitamin D 24-hydroxylase (CYP24A1) for the design of selective CYP24A1 inhibitors: Homology modelling, molecular dynamics simulations and identification of key binding requirements

Contact Info

Product

Resources

About