title: Benzothiopyranoindole-based antiproliferative agents: synthesis, cytotoxicity, nucleic acids interaction, and topoisomerases inhibition properties.
abstract: Novel benzo[3',2':5,6]thiopyrano[3,2-b]indol-10(11H)-ones 1a-v were synthesized and evaluated for their antiproliferative activity in an in vitro assay of human tumor cell lines (HL-60 and HeLa). Compounds 1e-v, substituted at the 11-position with a basic side chain, showed a significant ability to inhibit cell growth with IC(50) values in the low micromolar range. Linear dichroism measurements showed that all 11-dialkylaminoalkyl substituted derivatives 1e-v behave as DNA-intercalating agents. Fluorimetric titrations demonstrated their specificity in binding to A-T rich regions, and molecular modeling studies were performed on the most active derivatives (1e, 1i, 1p) to characterize in detail the complexation mechanism of these benzothiopyranoindoles to DNA. A relaxation assay evidenced a dose-dependent inhibition of topoisomerase II activity that appeared in accordance with the antiproliferative capacity. Finally, for the most cytotoxic derivative, 1e, a topoisomerase II poisoning effect was also demonstrated, along with a weak inhibition of topoisomerase I-mediated relaxation.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Padova, Padova, Italy. lisa.dallavia@unipd.it
authors.forename: Lisa
authors.initials: L
authors.lastname: Dalla Via
authors.forename: Sebastiano Marciani
authors.initials: SM
authors.lastname: Magno
authors.forename: Ornella
authors.initials: O
authors.lastname: Gia
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Marini
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.forename: Silvia
authors.initials: S
authors.lastname: Salerno
authors.forename: Concettina
authors.initials: C
authors.lastname: La Motta
authors.forename: Francesca
authors.initials: F
authors.lastname: Simorini
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Carmen
authors.initials: C
authors.lastname: Di Giovanni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Brancato
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Barone
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000737:chemistry; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology* / Q000633:toxicity; D005470:Fluorometry; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology* / Q000633:toxicity; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D011789:Quantum Theory; D013816:Thermodynamics; D017186:Titrimetry; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II