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Chromophore-modified bis-benzo[g]indole carboxamides: synthesis and antiproliferative activity of bis-benzo[g]indazole-3-carboxamides and related dimers

Pinna, Gérard Aimé and Pirisi, Maria Antonietta and Mussinu, Jean-Mario and Murineddu, Gabriele and Loriga, Giovanni and Pau, Amedeo and Grella, Giuseppe Enrico (2003) Chromophore-modified bis-benzo[g]indole carboxamides: synthesis and antiproliferative activity of bis-benzo[g]indazole-3-carboxamides and related dimers. Il Farmaco, Vol. 58 (9), p. 749-763. ISSN 0014-827X. Article.

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DOI: 10.1016/S0014-827X(03)00131-9

Abstract

Tricyclic pyrazole dimers that comprise two kinds of CONH---(CH2)n---N(CH3)---(CH2)n---NHCO bridges to which are linked potential DNA-intercalating groups such as 1H-benzo[g]indazole, 2H-benzo[g]indazole and 1,4-dihydroindeno[1,2-c]pyrazole were designed, synthesized and some of them evaluated in vitro by NCI (Bethesda, USA) against nine types of cancer cells. Compounds 2a, 2fi and 2or demonstrated significant antiproliferative activity, all with GI50 values in the low micromolar range. Preliminary analysis of the structure–activity relationship for dimers 2 indicated that: (i) in the ground terms (2a and 2k) antitumor activities were strongly related to the type of chromophore, (ii) in contrast, either 1H-benzo[g]indazole- or 1,4-dihydroindeno[1,2-c]pyrazole-dimers when bore a N1-aryl group (2g, 2h, 2i, 2o, 2p, 2q and 2r) generally showed a good level of antitumor potency and (iii) for the most representative compounds (pairs of compounds: 2g,2h; 2o,2p and 2q,2r) the length of the bridges did not significantly contribute to the variations in cytotoxicity. Two members of this series, 2f and 2q, were selected and tested in the hollow fiber cell assay to evaluate in a preliminary fashion their in vivo antitumor activity. Finally, viscosity measurement of 2f with poly(dA-dT)2, confirmed that these promising compounds behaved as typical DNA-intercalating agents.

Item Type:Article
ID Code:2552
Status:Published
Refereed:Yes
Uncontrolled Keywords:Tricyclic pyrazole, cytotoxic activity, viscosity
Subjects:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Divisions:001 Università di Sassari > 01 Dipartimenti > Farmaco, chimico, tossicologico
Publisher:Elsevier
ISSN:0014-827X
Copyright Holders:© 2003 Éditions scientifiques et médicales Elsevier
Deposited On:18 Aug 2009 10:08

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