Comparative Molecular Field Analysis and Comparative Molecular Similarity Indices Analysis of Thalidomide Analogues as Angiogenesis Inhibitors

Erin R. Lepper, Sylvia S.W. Ng, Michael Gütschow, Michael Weiss, Sunna Hauschildt, Thomas K. Hecker, Frederick A. Luzzio, Kurt Eger, William D. Figg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

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 r2 values of 0.924 and 0.996, respectively. The cross-validated q2 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.

Original languageEnglish
Pages (from-to)2219-2227
Number of pages9
JournalJournal of Medicinal Chemistry
Volume47
Issue number9
DOIs
StatePublished - 22 Apr 2004

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