2. Academic Validation
  3. Benzothiopyranoindole- and pyridothiopyranoindole-based antiproliferative agents targeting topoisomerases

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

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: sabrina.taliani@unipi.it.
  • 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: lmarinel@unina.it.
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.

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