title: Comparative molecular field analysis and comparative molecular similarity indices analysis of thalidomide analogues as angiogenesis inhibitors.
abstract: Thalidomide, 2-(2,6-dioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione, has been shown to inhibit angiogenesis, the formation of new blood vessels from existing vasculature. As a result, there is renewed interest in this drug as a potential therapy for solid tumors. Thalidomide forms a number of metabolites and has been shown to require metabolic activation for antiangiogenic activity. A series of 39 compounds, based upon the structure of some of these metabolites, was synthesized and tested for their ability to inhibit microvessel growth in the rat aortic ring assay. The results of this testing have been used as the basis for a three-dimensional quantitative structure-activity relationship (3D-QSAR) study, utilizing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) procedures. The best resulting CoMFA and CoMSIA models have conventional r(2) values of 0.924 and 0.996, respectively. The cross-validated q(2) values are 0.666 and 0.635, respectively. These models offer insight into the structural requirements for activity of thalidomide analogues as angiogenesis inhibitors, since there is only speculative knowledge of the target. Additionally, it appears as though there is more than one active site or mechanism of action.
authors.affiliation: Molecular Pharmacology Section, Cancer Therapeutics Branch and Clinical Pharmacology Research Core, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Erin R
authors.initials: ER
authors.lastname: Lepper
authors.forename: Sylvia S W
authors.initials: SS
authors.lastname: Ng
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
authors.forename: Michael
authors.initials: M
authors.lastname: Weiss
authors.forename: Sunna
authors.initials: S
authors.lastname: Hauschildt
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Hecker
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Luzzio
authors.forename: Kurt
authors.initials: K
authors.lastname: Eger
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D008958:Models, Molecular; D008968:Molecular Conformation; D009131:Muscle, Smooth, Vascular / Q000098:blood supply / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D013792:Thalidomide