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 beta-cycled-pyran-1,2-naphthoquinones [0.1 microM < IC50 < 0.6 microM] 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.
Subject(s)
Antineoplastic Agents/chemical synthesis , Models, Molecular , Naphthoquinones/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , Furans/chemical synthesis , Furans/chemistry , Furans/pharmacology , HL-60 Cells , Humans , Naphthoquinones/chemistry , Naphthoquinones/pharmacology , Phenanthrenes/chemical synthesis , Phenanthrenes/chemistry , Phenanthrenes/pharmacology , Pyrans/chemical synthesis , Pyrans/chemistry , Pyrans/pharmacology , Structure-Activity RelationshipABSTRACT
A large series of alkyl C-glycosides was synthesized from D-glucal or D-galactal. These compounds were screened against the human promyelocytic leukemia cell line (HL60), showing significant activity and apoptosis. Up to 13 C-glucopyranosides, but no C-galacto- or C-mannopyranosides, exhibited inhibitory concentrations (IC(50) values) below 20 microM, five of them in the range 4-8 microM. Preliminary structure-activity relationships were established.
