Benzothiopyranoindole-Based Antiproliferative Agents: Synthesis, Cytotoxicity, Nucleic Acids Interaction, and Topoisomerases Inhibition Properties

VIA, Lisa Dalla ; MARCIANI MAGNO, Sebastiano ; et al.

In: Journal of medicinal chemistry (Print), Jg. 52 (2009), Heft 17, S. 5429-5441

academicJournal - print, 68 ref

Novel benzo[3',2':5,6]thiopyrano[3,2-b]indol-10(11H)-ones la—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 IC50 values in the low micromolar range. Linear dichroism measurements showed that all 11-dialkylaminoalkyl substituted derivatives le—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.

Titel:	Benzothiopyranoindole-Based Antiproliferative Agents: Synthesis, Cytotoxicity, Nucleic Acids Interaction, and Topoisomerases Inhibition Properties
Autor/in / Beteiligte Person:	VIA, Lisa Dalla ; MARCIANI MAGNO, Sebastiano ; DI GIOVANNI, Carmen ; BRANCATO, Giuseppe ; BARONE, Vincenzo ; NOVELLINO, Ettore ; GIA, Omella ; MARINI, Anna Maria ; DA SETTIMO, Federico ; SALERNO, Silvia ; LA MOTTA, Concettina ; SIMORINI, Francesca ; TALIANI, Sabrina ; LAVECCHIA, Antonio
Link:	E-Journal im Bestand der UB Hagen? View record from PASCAL Archive
Zeitschrift:	Journal of medicinal chemistry (Print), Jg. 52 (2009), Heft 17, S. 5429-5441
Veröffentlichung:	Columbus, OH: American Chemical Society, 2009
Medientyp:	academicJournal
Umfang:	print, 68 ref
ISSN:	0022-2623 (print)
Schlagwort:	Pharmacology drugs Pharmacologie, galénique Sciences biologiques et medicales Biological and medical sciences Sciences medicales Medical sciences Pharmacologie. Traitements medicamenteux Pharmacology. Drug treatments Anticancéreux Antineoplastic agents Généralités General aspects Enzyme Enzima Isomerases Agent intercalant Intercalating agent Agente intercalante Amine primaire Primary amine Amina primaria Antineoplastic agent Anticanceroso Cellule tumorale Tumor cell Célula tumoral Col utérus Uterine cervix Cuello útero Composé aromatique Aromatic compound Compuesto aromático Composé tétracyclique Tetracyclic compound Compuesto tetracíclico Cytotoxicité Cytotoxicity Citotoxicidad Cétone Ketone Cetona DNA topoisomerase (ATP-hydrolysing) DNA topoisomerase DNA Fixation biologique Biological fixation Fijación biológica Homme Human Hombre Hétérocycle soufre azote Sulfur nitrogen heterocycle Heterociclo azufre nitrógeno In vitro Inhibiteur de la topoisomérase I Topoisomerase I inhibitor Inhibidor topoisomerase I Inhibiteur de la topoisomérase II Topoisomerase II inhibitor Inhibidor topoisomerase II Inhibiteur enzyme Enzyme inhibitor Inhibidor enzima Leucémie promyélocytaire Promyelocytic leukemia Leucemia promielocítica Lignée HL60 HL60 cell line Línea HL60 Lignée HeLa Hela cell line Célula HeLa Lignée cellulaire Cell line Línea celular Relation structure activité Structure activity relation Relación estructura actividad Synthèse chimique Chemical synthesis Síntesis química Benzothiopyranoindole Fixation DNA [1]Benzothiopyrano[3,2-b]indol-11-one(10-[2-(diméthylamino)éthyl]-3-méthoxy)
Sonstiges:	Nachgewiesen in: PASCAL Archive Sprachen: English Original Material: INIST-CNRS Document Type: Article File Description: text Language: English Author Affiliations: Dipartimento di Scienze Farmaceutiche, Università di Padova, via Marzolo 5, 1-35131 Padova, Italy ; Dipartimento di Chimica Farmaceutica e Tossicalogica, Università di Napoli Federico II, Via D. Montesano 40, 80131 Napoli, Italy ; Scuola Normale Superiore, Piazza dei Cavalieri 7, 1-56100, Pisa and Istituto per i Processi Chimico-Fisici del Consiglio Nazionale delle Ricerche (IPCF-CNR), Area della Ricerca, Via G. Moruzzi 1, 1-56124 Pisa, Italy ; Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, 1-56126 Pisa, Italy Rights: Copyright 2015 INIST-CNRS ; CC BY 4.0 ; Sauf mention contraire ci-dessus, le contenu de cette notice bibliographique peut être utilisé dans le cadre d’une licence CC BY 4.0 Inist-CNRS / Unless otherwise stated above, the content of this bibliographic record may be used under a CC BY 4.0 licence by Inist-CNRS / A menos que se haya señalado antes, el contenido de este registro bibliográfico puede ser utilizado al amparo de una licencia CC BY 4.0 Inist-CNRS Notes: Pharmacological treatments

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