RT journal article
T1 Exploring novel aromatase cytochrome P450-binding ligands: Molecular docking and QSAR study of phorbol esters as aromatase inhibitors
A1 Ezzanad, Abdellah
A1 Escobar Montaño, Felipe
A1 Sánchez Márquez, Jesús
A1 Zorrilla Cuenca, David
A1 Coca, Victor
A1 McCann, Glen J.P.
A1 Horley, Neill
A1 Botubol Ares, José Manuel
A1 Durán Patrón, Rosa María
A1 Macías Sánchez, Antonio José
A1 Hunter, Alan Christy
A1 Hernández Galán, Rosario
A2 Química Física
A2 Química Orgánica
K1 Phorbol
K1 Molecular docking
K1 3D-QSAR
K1 Euphorbia resinifera
K1 Aromatase
K1 CYP19A1
AB A library comprising thirty-three natural and semi-synthetic phorbol derivatives was constructed and subsequently evaluated for aromatase (CYP19A1) inhibitory activity. The primary goal was to identify novel aromatase inhibitors through selective esterifications at the C-12, C-13 and C-20 positions of the phorbol skeleton. Twenty-two phorbol esters, fifteen of which were previously undescribed (5–9, 12 and 16–24), were obtained via semi-synthetic modifications. Additionally, ten 12-deoxyphorbol esters (25–34), four bearing an extra acyloxy chain at C-16, isolated from Euphorbia resinifera, were tested. Inhibition studies revealed that 12,13-diesters bearing medium-sized ester moieties (such as isobutyrate, tigliate or phenylacetate) exhibited the highest potency (IC50 = 0.9–6.4 μM). Conversely, shorter or longer ester chains significantly reduced activity (IC50 values ranging from 22.4 to 29.8 μM). An enhancement of potency was observed upon reduction of the α,β-unsaturated ketone at C-3 to an allylic alcohol. Molecular docking suggested that the phorbol derivatives bind within the aromatase activator-binding pocket, exerting their inhibitory actions through hydrogen-bond interactions with protein residues, independent of the heme group. The inhibitory potency correlated with the ability to establish these interactions. The activities of the most potent compounds are comparable to nonsteroidal, non-heme-binding aromatase inhibitors, such as stilbene and coumarin derivatives. Moreover, 3D-QSAR models were developed, with the most robust model (R2 = 0.908) highlighting the molecular descriptors NQC14 and AP as crucial modulators of the anti-aromatase activity. These findings provide a framework for future optimization of phorbol ester as selective aromatase inhibitors.
PB Elsevier
SN 1768-3254
YR 2026
FD 2026-02
LK http://hdl.handle.net/10498/39142
UL http://hdl.handle.net/10498/39142
LA eng
DS Repositorio Institucional de la Universidad de Cádiz
RD 05-nov-2026