Synthesis and Enantiomeric Separation of a Novel Spiroketal Derivative: A Potent Human Telomerase Inhibitor with High in Vitro Anticancer Activity.
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.
Istituto di Farmacologia Traslazionale, Consiglio Nazionale delle Ricerche, Via Fosso del Cavaliere, 00133 Roma, Italy.
Maria Pia
MP
Fuggetta
Istituto di Biologia e Patologia Molecolare, Consiglio Nazionale delle Ricerche, Piazzale Aldo Moro 5, 00185 Roma, Italy.
Antonella
A
De Mico
Istituto di Farmacologia Traslazionale, Consiglio Nazionale delle Ricerche, Via Fosso del Cavaliere, 00133 Roma, Italy.
Andrea
A
Cottarelli
Istituto di Genetica e Biofisica, Consiglio Nazionale delle Ricerche, Via Pietro Castellino 111, 80131 Napoli, Italy.
Franco
F
Morelli
Istituto di Farmacologia Traslazionale, Consiglio Nazionale delle Ricerche, Via Fosso del Cavaliere, 00133 Roma, Italy.
Manuela
M
Zonfrillo
Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Trav. La Crucca 3, 07100 Sassari, Italy.
Fausta
F
Ulgheri
Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Trav. La Crucca 3, 07100 Sassari, Italy.
Paola
P
Peluso
Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Trav. La Crucca 3, 07100 Sassari, Italy.
Alberto
A
Mannu
Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Trav. La Crucca 3, 07100 Sassari, Italy.
Francesco
F
Deligia
Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Trav. La Crucca 3, 07100 Sassari, Italy.
Mauro
M
Marchetti
Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, Via Mezzocannone 16, 80134 Naples, Italy.
Giovanni
G
Roviello
Department of Drug Design, School of Pharmacy, University of Groningen , Antonius Deusinglaan 1 Postbus 196, 9700 AD, Groningen, The Netherlands.
Atilio
A
Reyes Romero
Department of Drug Design, School of Pharmacy, University of Groningen , Antonius Deusinglaan 1 Postbus 196, 9700 AD, Groningen, The Netherlands.
Alexander
A
Dömling
Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Trav. La Crucca 3, 07100 Sassari, Italy.
Pietro
P
Spanu
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054856:G-Quadruplexes / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005663:Furans; D013141:Spiro Compounds; C520774:spiroketal; D019098:Telomerase