title: Synthesis and pharmacophore modeling of naphthoquinone derivatives with cytotoxic activity in human promyelocytic leukemia HL-60 cell line.
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.
authors.affiliation: Instituto Universitario de Bio-OrgAnica "Antonio GonzAlez", Universidad de La Laguna, Avda. Astrofísico Fco. SAnchez 2, 38206 La Laguna, Tenerife, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Pérez-Sacau
authors.forename: Raquel G
authors.initials: RG
authors.lastname: Díaz-Peñate
authors.forename: Ana
authors.initials: A
authors.lastname: Estévez-Braun
authors.forename: Angel G
authors.initials: AG
authors.lastname: Ravelo
authors.forename: Jose M
authors.initials: JM
authors.lastname: García-Castellano
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pardo
authors.forename: Mercedes
authors.initials: M
authors.lastname: Campillo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D008958:Models, Molecular; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010616:Phenanthrenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D009285:Naphthoquinones; D010616:Phenanthrenes; D011714:Pyrans