In this project, we first selected (1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-3-yl)(3,4,5-trimethoxyphenyl) methanone (1, compound RS6077) as a new pyrrole tubulin polymerization inhibitor (chart 1). In previous work, we noted that the presence of a 3-amino group of the 1-phenyl ring of 3-aroyl-1-arylpyrrole (2) increases the inhibition of MDR cell lines and suppresses the Hedgehog signaling pathway.1 Highlighted the effect of nitrogen atom we report the synthesis and first disclosure of RS6077.2 The promising inhibitor was evaluated in cancer cell culture and in a lymphoma TMD8 mouse xenograft model. Compound 1 showed a strong cell cycle arresting potential, blocking or dramatically delaying mitosis. In HeLa cultures, the cell cycle is strongly delayed prior to reaching mitosis. The mitotic arrest induced in RPE-1 non-transformed cells is not necessarily followed by cell death induction. In AHH-1 cell cultures 1 causes effective mitotic block suggesting that death actually occurs during mitotic arrest in cells that fail to complete mitosis. Compound 1 inhibits different lymphoma cell lines at nanomolar concentration. Most importantly, exposure to the different doses of 1 does not change cell viability of healthy cells, thus indicating this compound is not toxic for normal cells. In the lymphoma TMD8 mouse xenograft model, 1 reduces the tumor size after administration in 30% PEG400 by oral gavage at 100 mg/kg. These findings indicate that 1 has potential as novel therapeutic agent to treat lymphoma cancers. References 1. La Regina, G.; Bai, R.; Coluccia, A.; Famiglini, V.; Pelliccia, S.; Passacantilli, S.; Mazzoccoli, C.; Ruggieri, V.; Sisinni, L.; Bolognesi, A.; Rensen, W. M.; Miele, A.; Nalli, M.; Alfonsi, R.; Di Marcotullio, L.; Gulino, A.; Brancale, A.; Novellino, E.; Dondio, G.; Vultaggio, S.; Varasi, M.; Mercurio, C.; Hamel, E.; Lavia, P.; Silvestri, R. New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including Hedgehog-dependent cancer. J. Med. Chem. 2014, 57, 6531−6552. 2. Sebastiani, J.; Puxeddu, M.; Nalli, M.; Bai, R.; Altieri, L.; Rovella, P.; Gaudio, E.; Trisciuoglio, D.; Spriano, F.; Lavia, P.; Fionda, C.; Hamel, E.; Bertoni, F.; Silvestri, R.; La Regina, G. RS6077 induces mitotic arrest and selectively activates cell death in human cancer cell lines and in lymphoma tumor in vivo. Eur. J. Med. Chem. 2022, accepted.
RS6077 as novel and selective growth inhibitor of human cancer cell lines and lymphoma tumor / Puxeddu, M.; Sebastiani, J.; Hamel, E.; Fionda, Cinzia; C., Bertoni; Silvestri, R.; La Regina, G.. - (2022). (Intervento presentato al convegno XXVII National Meeting on Medicinal Chemistry - 14th Young Medicinal Chemists' Symposium tenutosi a Bari, Italy).
RS6077 as novel and selective growth inhibitor of human cancer cell lines and lymphoma tumor
Puxeddu, M.;Sebastiani, J.;Fionda;Silvestri, R.;La Regina, G.
2022
Abstract
In this project, we first selected (1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-3-yl)(3,4,5-trimethoxyphenyl) methanone (1, compound RS6077) as a new pyrrole tubulin polymerization inhibitor (chart 1). In previous work, we noted that the presence of a 3-amino group of the 1-phenyl ring of 3-aroyl-1-arylpyrrole (2) increases the inhibition of MDR cell lines and suppresses the Hedgehog signaling pathway.1 Highlighted the effect of nitrogen atom we report the synthesis and first disclosure of RS6077.2 The promising inhibitor was evaluated in cancer cell culture and in a lymphoma TMD8 mouse xenograft model. Compound 1 showed a strong cell cycle arresting potential, blocking or dramatically delaying mitosis. In HeLa cultures, the cell cycle is strongly delayed prior to reaching mitosis. The mitotic arrest induced in RPE-1 non-transformed cells is not necessarily followed by cell death induction. In AHH-1 cell cultures 1 causes effective mitotic block suggesting that death actually occurs during mitotic arrest in cells that fail to complete mitosis. Compound 1 inhibits different lymphoma cell lines at nanomolar concentration. Most importantly, exposure to the different doses of 1 does not change cell viability of healthy cells, thus indicating this compound is not toxic for normal cells. In the lymphoma TMD8 mouse xenograft model, 1 reduces the tumor size after administration in 30% PEG400 by oral gavage at 100 mg/kg. These findings indicate that 1 has potential as novel therapeutic agent to treat lymphoma cancers. References 1. La Regina, G.; Bai, R.; Coluccia, A.; Famiglini, V.; Pelliccia, S.; Passacantilli, S.; Mazzoccoli, C.; Ruggieri, V.; Sisinni, L.; Bolognesi, A.; Rensen, W. M.; Miele, A.; Nalli, M.; Alfonsi, R.; Di Marcotullio, L.; Gulino, A.; Brancale, A.; Novellino, E.; Dondio, G.; Vultaggio, S.; Varasi, M.; Mercurio, C.; Hamel, E.; Lavia, P.; Silvestri, R. New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including Hedgehog-dependent cancer. J. Med. Chem. 2014, 57, 6531−6552. 2. Sebastiani, J.; Puxeddu, M.; Nalli, M.; Bai, R.; Altieri, L.; Rovella, P.; Gaudio, E.; Trisciuoglio, D.; Spriano, F.; Lavia, P.; Fionda, C.; Hamel, E.; Bertoni, F.; Silvestri, R.; La Regina, G. RS6077 induces mitotic arrest and selectively activates cell death in human cancer cell lines and in lymphoma tumor in vivo. Eur. J. Med. Chem. 2022, accepted.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
