A new series of N,N-bis(alkanol)amine aryl diesters was synthesized and studied as dual P-glycoprotein (P-gp) and carbonic anhydrase XII inhibitors (CA XII). These hybrids should be able to synergistically overcome P-gp mediated multidrug resistance (MDR) in cancer cells. It was reported that the effux activity of P-gp could be modulated by CA XII, as the pH reduction caused by CA XII inhibition produces a significant decrease in P-gp ATPase activity. The new compounds reported here feature both P-gp and CA XII binding moieties. These hybrids contain a N,N-bis(alkanol)amine diester scaffold found in P-glycoprotein ligands and a coumarin or benzene sulfonamide moiety to target CA XII. Many compounds displayed a dual activity against P-gp and CA XII being active in the Rhd 123 uptake test on K562/DOX cells and in the hCA XII inhibition test. On LoVo/DOX cells, that overexpress both P-gp and CA XII, some coumarin derivatives showed a high MDR reversal effect in Rhd 123 uptake and doxorubicin cytotoxicity enhancement tests. In particular, compounds 7 and 8 showed higher activity than verapamil and were more potent on LoVo/DOX than on K562/DOX cells overexpressing only P-gp. They can be considered as valuable candidates for selective P-gp/CA XII inhibition in MDR cancer cells.

Dual P-glycoprotein and CA XII inhibitors: A new strategy to reverse the P-gp Mediated Multidrug Resistance (MDR) in cancer cells y / Teodori E.; Braconi L.; Bua S.; Lapucci A.; Bartolucci G.; Manetti D.; Romanelli M.N.; Dei S.; Supuran C.T.; Coronnello M.. - In: MOLECULES. - ISSN 1420-3049. - STAMPA. - 25:(2020), pp. 1-26. [10.3390/molecules25071748]

Dual P-glycoprotein and CA XII inhibitors: A new strategy to reverse the P-gp Mediated Multidrug Resistance (MDR) in cancer cells y

Teodori E.;Braconi L.;Bua S.;Lapucci A.;Bartolucci G.;Manetti D.;Romanelli M. N.;Dei S.
;
Supuran C. T.;Coronnello M.
2020

Abstract

A new series of N,N-bis(alkanol)amine aryl diesters was synthesized and studied as dual P-glycoprotein (P-gp) and carbonic anhydrase XII inhibitors (CA XII). These hybrids should be able to synergistically overcome P-gp mediated multidrug resistance (MDR) in cancer cells. It was reported that the effux activity of P-gp could be modulated by CA XII, as the pH reduction caused by CA XII inhibition produces a significant decrease in P-gp ATPase activity. The new compounds reported here feature both P-gp and CA XII binding moieties. These hybrids contain a N,N-bis(alkanol)amine diester scaffold found in P-glycoprotein ligands and a coumarin or benzene sulfonamide moiety to target CA XII. Many compounds displayed a dual activity against P-gp and CA XII being active in the Rhd 123 uptake test on K562/DOX cells and in the hCA XII inhibition test. On LoVo/DOX cells, that overexpress both P-gp and CA XII, some coumarin derivatives showed a high MDR reversal effect in Rhd 123 uptake and doxorubicin cytotoxicity enhancement tests. In particular, compounds 7 and 8 showed higher activity than verapamil and were more potent on LoVo/DOX than on K562/DOX cells overexpressing only P-gp. They can be considered as valuable candidates for selective P-gp/CA XII inhibition in MDR cancer cells.
2020
25
1
26
Goal 3: Good health and well-being for people
Teodori E.; Braconi L.; Bua S.; Lapucci A.; Bartolucci G.; Manetti D.; Romanelli M.N.; Dei S.; Supuran C.T.; Coronnello M.
File in questo prodotto:
File Dimensione Formato  
molecules-25-01748.pdf

accesso aperto

Descrizione: Articolo principale
Tipologia: Pdf editoriale (Version of record)
Licenza: Open Access
Dimensione 2.62 MB
Formato Adobe PDF
2.62 MB Adobe PDF

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

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1190124
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 29
  • ???jsp.display-item.citation.isi??? 24
social impact