Synthesis, cytotoxic activity, DNA topoisomerase-II inhibition, molecular modeling and structure-activity relationship of 9-anilinothiazolo[5,4-b]quinoline derivatives

Marco A. Loza-Mejía, Susana Olvera-Vázquez, Karina Maldonado-Hernández, Teresita Guadarrama-Salgado, Ignacio González-Sánchez, Fernando Rodríguez-Hernández, José D. Solano, Rogelio Rodríguez-Sotres, Alfonso Lira-Rocha

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Some novel 9-anilinothiazolo[5,4-b]quinoline derivatives were synthesized and their cytotoxic activities were examined. The inhibition of some of the most active compounds over human topoisomerase II (Topo II) activity was assessed with the kDNA decatenation assay. The novel compounds differ in the substituents attached to the anilino ring, a dialkylamino alkylamino group, a saturated heterocyclic moiety, a methylthio group at position 2 and a fluorine atom present or absent at 7-position. According to the data, compounds with a diethylaminopropylamino group and a chlorine atom at 4′-position of the anilino ring were the most cytotoxic. The molecular models of all compounds indicated a correlation between hydrophobicity and cytotoxic activity although the direction and magnitude of the dipole moment also had a significant influence on its cytotoxicity. The 2-dialkylaminoalkylamino substituent is flexible and is known to facilitate the crossing of cell membranes; thus, this last barrier may be a limiting step in the mechanisms mediating the cytotoxicity. On the other hand, the activity of 2-methylthio derivatives seems to rely more on the electronic effects brought about by the substitution of the aniline ring. The synthesis, cytotoxicity against cancer cell lines, in vitro inhibition of human topoisomerase II, molecular modeling and the preliminary analysis of structure-activity relationships are presented.

Original languageEnglish
Pages (from-to)3266-3277
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number9
DOIs
StatePublished - 1 May 2009
Externally publishedYes

Keywords

  • Cytotoxic activity
  • DNA topoisomerase-II inhibition
  • Molecular modeling
  • Structure-activity relationship
  • Thiazolo[5,4-b]quinoline

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