Cytotoxic Cyclolignans Obtained by the Enlargement of the Cyclolignan Skeleton of Podophyllic Aldehyde, a Selective Podophyllotoxin-Derived Cyclolignan
Pablo A. García,
Ángela-Patricia Hernández,
Mª Antonia Gómez-Zurita,
José M. Miguel del Corral,
Marina Gordaliza,
Andrés Francesch,
Arturo San Feliciano,
Mª Ángeles Castro
Affiliations
Pablo A. García
Departamento de Ciencias Farmacéuticas, Área de Química Farmacéutica, Facultad de Farmacia, CIETUS/IBSAL, University of Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain
Ángela-Patricia Hernández
Departamento de Ciencias Farmacéuticas, Área de Química Farmacéutica, Facultad de Farmacia, CIETUS/IBSAL, University of Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain
Mª Antonia Gómez-Zurita
Departamento de Ciencias Farmacéuticas, Área de Química Farmacéutica, Facultad de Farmacia, CIETUS/IBSAL, University of Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain
José M. Miguel del Corral
Departamento de Ciencias Farmacéuticas, Área de Química Farmacéutica, Facultad de Farmacia, CIETUS/IBSAL, University of Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain
Marina Gordaliza
Departamento de Ciencias Farmacéuticas, Área de Química Farmacéutica, Facultad de Farmacia, CIETUS/IBSAL, University of Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain
Andrés Francesch
PharmaMar S.A., Avda de los Reyes, 1, 28770 Colmenar Viejo, Spain
Arturo San Feliciano
Departamento de Ciencias Farmacéuticas, Área de Química Farmacéutica, Facultad de Farmacia, CIETUS/IBSAL, University of Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain
Mª Ángeles Castro
Departamento de Ciencias Farmacéuticas, Área de Química Farmacéutica, Facultad de Farmacia, CIETUS/IBSAL, University of Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain
Podophyllotoxin, a cyclolignan natural product, has been the object of extensive chemomodulation to obtain better chemotherapeutic agents. Among the obtained podophyllotoxin derivatives, podophyllic aldehyde showed very interesting potency and selectivity against several tumoral cell lines, so it became our lead compound for further modifications, as described in this work, oriented toward the enlargement of the cyclolignan skeleton. Thus, modifications performed at the aldehyde function included nucleophilic addition reactions and the incorporation of the aldehyde carbon into several five-membered rings, such as thiazolidinones and benzo-fused azoles. The synthesized derivatives were evaluated against several types of cancer cells, and although some compounds were cytotoxic at the nanomolar range, most of them were less potent and less selective than the parent compound podophyllic aldehyde, with the most potent being those having the lactone ring of podophyllotoxin. In silico ADME evaluation predicted good druggability for most of them. The results indicate that the γ-lactone ring is important for potency, while the α,β-unsaturated aldehyde is necessary to induce selectivity in these cyclolignans.
