A new synthetic spiroketal: studies on antitumor activity on murine melanoma model In vivo and mechanism of action In vitro

The natural-like spiroketal, 2-hydroxy-8-methyl-1,7-dioxaspiro[5.5]undec-3-en-5-one (1) has been synthesised and has shown a potent antitumor activity against human tumor cells of different nature and histotype. We have now performed studies to verify its in vivo activity on a murine melanoma model and in vitro studies to shed some light on the mechanism of action. Spiroketal 1 have shown a potent dose-dependent antitumor efficacy in vivo in a syngenic murine model (C57Black mice) of melanoma (B16). The compound suppressed the tumor growth by an average of 90% at a dose of 5 mg/kg by intra-peritoneum administration at alternate days for 15 days. It also displayed high antitumor activity in vitro in the B16 cells with nanomolar IC₅₀ value. In addition to the proapoptotic and telomerase inhibition activities, compound 1 has shown to inhibit cell migration and to strongly reduce the HIF1alfa expression, that is considered a regulator of multiple cellular functions related to the progression from primary to metastatic cancer disease. Therefore, although the full mechanism of action of this molecule has yet to be completely elucidated, spiroketal 1 is a promising antitumor drug candidate for the clinical treatment of melanoma and various cancers.

References: Fuggetta, M. P.; De Mico, A.; Cottarelli, A.; Morelli, F.; Zonfrillo, M.; Ulgheri, F.; Peluso, P.; Mannu, A.; Deligia, F.; Marchetti, M.; Roviello, G.; Reyes Romero, A.; Dömling, A.; Spanu, P. Synthesis and Enantiomeric Separation of a Novel Spiroketal Derivative: A Potent Human Telomerase Inhibitor with High in Vitro Anticancer Activity. J. Med. Chem. 2016, 59, 9140−9149 and references quoted therein