New benzothiopyranoindoles (5a-l) and pyridothiopyranoindoles (5m-t), featuring different combinations of substituents (H, Cl, OCH3) at R2-R4 positions and protonatable R1-dialkylaminoalkyl chains, were synthesized and biologically assayed on three human tumor cell lines, showing significant antiproliferative activity (GI50 values spanning from 0.31 to 6.93 mM) and pro-apoptotic effect. Linear flow dichroism experiments indicate the ability of both chromophores to form a molecular complex with DNA, following an intercalative mode of binding. All compounds displayed a moderate ability to inhibit the relaxation activity of both topoisomerases I and II, reasonably correlated to their intercalative capacities. Cleavable assay performed with topoisomerase I revealed a significant poisoning effect for compounds 5g, 5h, 5s, and 5t. A theoretical model provided by hydrated docking calculations clarified the role of the R1-R4 substituents on the topoisomerase I poison activity, revealing a crucial role of the R2- OCH3 group.

Benzothiopyranoindole- and pyridothiopyranoindole-based antiproliferative agents targeting topoisomerases

Salerno, Silvia
Primo
;
Taliani, Sabrina
;
Barresi, Elisabetta;Simorini, Francesca;Da Settimo, Federico;
2019-01-01

Abstract

New benzothiopyranoindoles (5a-l) and pyridothiopyranoindoles (5m-t), featuring different combinations of substituents (H, Cl, OCH3) at R2-R4 positions and protonatable R1-dialkylaminoalkyl chains, were synthesized and biologically assayed on three human tumor cell lines, showing significant antiproliferative activity (GI50 values spanning from 0.31 to 6.93 mM) and pro-apoptotic effect. Linear flow dichroism experiments indicate the ability of both chromophores to form a molecular complex with DNA, following an intercalative mode of binding. All compounds displayed a moderate ability to inhibit the relaxation activity of both topoisomerases I and II, reasonably correlated to their intercalative capacities. Cleavable assay performed with topoisomerase I revealed a significant poisoning effect for compounds 5g, 5h, 5s, and 5t. A theoretical model provided by hydrated docking calculations clarified the role of the R1-R4 substituents on the topoisomerase I poison activity, revealing a crucial role of the R2- OCH3 group.
2019
Salerno, Silvia; La Pietra, Valeria; Hyeraci, Mariafrancesca; Taliani, Sabrina; Robello, Marco; Barresi, Elisabetta; Milite, Ciro; Simorini, Francesca; García-Argáez, Aída Nelly; Marinelli, Luciana; Novellino, Ettore; Da Settimo, Federico; Marini, Anna Maria; Dalla Via, Lisa
File in questo prodotto:
File Dimensione Formato  
Eur J Med Chem 165 (2019) 46-58.pdf

non disponibili

Tipologia: Versione finale editoriale
Licenza: NON PUBBLICO - accesso privato/ristretto
Dimensione 1.79 MB
Formato Adobe PDF
1.79 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Eur J Med Chem 2019_manuscript.pdf

accesso aperto

Tipologia: Documento in Post-print
Licenza: Creative commons
Dimensione 2.03 MB
Formato Adobe PDF
2.03 MB Adobe PDF Visualizza/Apri

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/11568/987472
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 5
  • ???jsp.display-item.citation.isi??? 5
social impact