Benzothiopyranoindole- and pyridothiopyranoindole-based antiproliferative agents targeting topoisomerases

  • Eur J Med Chem. 2019 Mar 1:165:46-58. doi: 10.1016/j.ejmech.2019.01.015.
Silvia Salerno  1 ,  Valeria La Pietra  2 ,  Mariafrancesca Hyeraci  3 ,  Sabrina Taliani  4 ,  Marco Robello  5 ,  Elisabetta Barresi  1 ,  Ciro Milite  6 ,  Francesca Simorini  1 ,  Aída Nelly García-Argáez  7 ,  Luciana Marinelli  8 ,  Ettore Novellino  2 ,  Federico Da Settimo  1 ,  Anna Maria Marini  1 ,  Lisa Dalla Via  3
Affiliations
  • 1. Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126, Pisa, Italy.
  • 2. Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, 80131, Napoli, Italy.
  • 3. Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131, Padova, Italy.
  • 4. Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126, Pisa, Italy. Electronic address: [email protected].
  • 5. Synthetic Bioactive Molecules Section LBC, NIDDK, NIH, 8 Center Dr., 20982, Bethesda, MD, USA.
  • 6. Dipartimento di Farmacia, Università di Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Salerno, Italy.
  • 7. Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131, Padova, Italy; Fondazione per la Biologia e la Medicina della Rigenerazione T.E.S., Via Marzolo 13, 35131, Padova, Italy.
  • 8. Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, 80131, Napoli, Italy. Electronic address: [email protected].
PMID: 30660826 DOI: 10.1016/j.ejmech.2019.01.015
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 μM) 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.

Keywords
Antiproliferative activity; Benzothiopyranoindoles; Pyridothiopyranoindoles; Topoisomerase I poisons; Topoisomerases.