1. Benzothiopyranoindole- and pyridothiopyranoindole-based antiproliferative agents targeting topoisomerases.
- Author
-
Salerno S, La Pietra V, Hyeraci M, Taliani S, Robello M, Barresi E, Milite C, Simorini F, García-Argáez AN, Marinelli L, Novellino E, Da Settimo F, Marini AM, and Dalla Via L
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, DNA metabolism, Humans, Indoles chemical synthesis, Indoles chemistry, Indoles metabolism, Molecular Docking Simulation, Structure-Activity Relationship, Topoisomerase I Inhibitors chemical synthesis, Topoisomerase II Inhibitors chemical synthesis, Antineoplastic Agents chemical synthesis, Indoles pharmacology, Topoisomerase I Inhibitors chemistry, Topoisomerase II Inhibitors chemistry
- Abstract
New benzothiopyranoindoles (5a-l) and pyridothiopyranoindoles (5m-t), featuring different combinations of substituents (H, Cl, OCH
3 ) 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., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF