Synthesis and pharmacophore modeling of naphthoquinone derivatives with cytotoxic activity in human promyelocytic leukemia HL-60 cell line

Elisa Pérez-Sacau, Raquel G. Díaz-Peńate, Ana Estévez-Braun, Angel G. Ravelo, Jose M. García-Castellano, Leonardo Pardo, Mercedes Campillo

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116 Citations (Scopus)

Abstract

Catalyst/HypoGen pharmacophore modeling approach and three-dimensional quantitative structure-activity relationship (3D-QSAR)/comparative molecular similarity indices analysis (CoMSIA) methods have been successfully applied to explain the cytotoxic activity of a set of 51 natural and synthesized naphthoquinone derivatives tested in human promyelocytic leukemia HL-60 cell line. The computational models have facilitated the identification of structural elements of the ligands that are key for antitumoral properties. The four most salient features of the highly active β-cycled-pyran-1,2-naphthoquinones [0.1 μM < IC50 < 0.6 μM] are the hydrogen-bond interactions of the carbonyl groups at C-1 (HBA1) and C-2 (HBA2), the hydrogen-bond interaction of the oxygen atom of the pyran ring (HBA3), and the interaction of methyl groups (HYD) at the pyran ring with a hydrophobic area at the receptor. The moderately active 1,4-naphthoquinone derivatives accurately fulfill only three of these features. The results of our study provide a valuable tool in designing new and more potent cytotoxic analogues. © 2007 American Chemical Society.
Original languageEnglish
Pages (from-to)696-706
JournalJournal of Medicinal Chemistry
Volume50
DOIs
Publication statusPublished - 22 Feb 2007

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