Synthesis and Enantiomeric Separation of a Novel Spiroketal Derivative: A Potent Human Telomerase Inhibitor with High in Vitro Anticancer Activity

• Published in: Journal of medicinal chemistry Vol. 59; no. 19; pp. 9140 - 9149
• Main Authors: Fuggetta, Maria Pia, De Mico, Antonella, Cottarelli, Andrea, Morelli, Franco, Zonfrillo, Manuela, Ulgheri, Fausta, Peluso, Paola, Mannu, Alberto, Deligia, Francesco, Marchetti, Mauro, Roviello, Giovanni, Reyes Romero, Atilio, Dömling, Alexander, Spanu, Pietro
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.10.2016; Amer Chemical Soc
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Chemistry, Medicinal; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Furans - chemical synthesis; Furans - chemistry; Furans - pharmacology; G-Quadruplexes - drug effects; Humans; Life Sciences & Biomedicine; Models, Molecular; Molecular Docking Simulation; Neoplasms - drug therapy; Neoplasms - metabolism; Pharmacology & Pharmacy; Science & Technology; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Stereoisomerism; Structure-Activity Relationship; Telomerase - antagonists & inhibitors; Telomerase - metabolism; RESVERATROL; REVEROMYCINS; BIOLOGICAL-ACTIVITY; EUKARYOTIC CELL-GROWTH; PHARMACOPHORE; OKADAIC ACID; STRUCTURE-BASED DESIGN
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b01046

The synthesis, the enantiomeric separation, and the characterization of new simple spiroketal derivatives have been performed. The synthesized compounds have shown a very high anticancer activity. Cell proliferation assay showed that they induce a remarkable inhibition of cell proliferation in all cell lines treated, depending on culture time and concentration. The compounds have also shown a potent nanomolar human telomerase inhibition activity and apoptosis induction. CD melting experiments demonstrate that spiroketal does not affect the G-quadruplex (G4) thermal stability. Docking studies showed that telomerase inhibition could be determined by a spiroketal interaction with the telomerase enzyme.