Long-term survivors of glioblastoma multiforme (GBM) are at high risk of developing second primary neoplasms, including leukemia. For these patients, the use of classic tyrosine kinase inhibitors (TKIs), such as imatinib mesylate, is strongly discouraged, since this treatment causes a tremendous increase of tumor and stem cell migration and invasion. We aimed to develop agents useful for the treatment of patients with GBM and chronic myeloid leukemia (CML) using an alternative mechanism of action from the TKIs, specifically based on the inhibition of tubulin polymerization. Compounds 7 and 25, as planned, not only inhibited tubulin polymerization, but also inhibited the proliferation of both GMB and CML cells, including those expressing the T315I mutation, at nanomolar concentrations. In in vivo experiments in BALB/cnu/nu mice injected subcutaneously with U87MG cells, in vivo, 7 significantly inhibited GBM cancer cell proliferation, in vivo tumorigenesis, and tumor growth, tumorigenesis and angiogenesis. Compound 7 was found to block human topoisomerase II (hTopoII) selectively and completely, at a concentration of 100 μM.

Discovery of pyrrole derivatives for the treatment of glioblastoma and chronic myeloid leukemia / Puxeddu, M.; Shen, H.; Bai, R.; Coluccia, A.; Bufano, M.; Nalli, M.; Sebastiani, J.; Brancaccio, D.; Da Pozzo, E.; Tremolanti, C.; Martini, C.; Orlando, V.; Biagioni, S.; Sinicropi, M. S.; Ceramella, J.; Iacopetta, D.; Coluccia, A. M. L.; Hamel, E.; Liu, T.; Silvestri, R.; La Regina, G.. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 221:(2021), pp. 1-18. [10.1016/j.ejmech.2021.113532]

Discovery of pyrrole derivatives for the treatment of glioblastoma and chronic myeloid leukemia

Puxeddu M.;Coluccia A.;Bufano M.;Nalli M.;Sebastiani J.;Orlando V.;Biagioni S.;Silvestri R.;La Regina G.
2021

Abstract

Long-term survivors of glioblastoma multiforme (GBM) are at high risk of developing second primary neoplasms, including leukemia. For these patients, the use of classic tyrosine kinase inhibitors (TKIs), such as imatinib mesylate, is strongly discouraged, since this treatment causes a tremendous increase of tumor and stem cell migration and invasion. We aimed to develop agents useful for the treatment of patients with GBM and chronic myeloid leukemia (CML) using an alternative mechanism of action from the TKIs, specifically based on the inhibition of tubulin polymerization. Compounds 7 and 25, as planned, not only inhibited tubulin polymerization, but also inhibited the proliferation of both GMB and CML cells, including those expressing the T315I mutation, at nanomolar concentrations. In in vivo experiments in BALB/cnu/nu mice injected subcutaneously with U87MG cells, in vivo, 7 significantly inhibited GBM cancer cell proliferation, in vivo tumorigenesis, and tumor growth, tumorigenesis and angiogenesis. Compound 7 was found to block human topoisomerase II (hTopoII) selectively and completely, at a concentration of 100 μM.
2021
Glioblastoma; Leukemia; Pyrrole; Synthesis; Tubulin
01 Pubblicazione su rivista::01a Articolo in rivista
Discovery of pyrrole derivatives for the treatment of glioblastoma and chronic myeloid leukemia / Puxeddu, M.; Shen, H.; Bai, R.; Coluccia, A.; Bufano, M.; Nalli, M.; Sebastiani, J.; Brancaccio, D.; Da Pozzo, E.; Tremolanti, C.; Martini, C.; Orlando, V.; Biagioni, S.; Sinicropi, M. S.; Ceramella, J.; Iacopetta, D.; Coluccia, A. M. L.; Hamel, E.; Liu, T.; Silvestri, R.; La Regina, G.. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 221:(2021), pp. 1-18. [10.1016/j.ejmech.2021.113532]
File allegati a questo prodotto
File Dimensione Formato  
Puxeddu_Discovery_2021.pdf

solo gestori archivio

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 3.16 MB
Formato Adobe PDF
3.16 MB Adobe PDF   Contatta l'autore

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1554523
Citazioni
  • ???jsp.display-item.citation.pmc??? 6
  • Scopus 11
  • ???jsp.display-item.citation.isi??? 10
social impact