Thalidomide metabolites and analogues. 3. Synthesis and antiangiogenic activity of the teratogenic and TNFalpha-modulatory thalidomide analogue 2-(2,6-dioxopiperidine-3-yl)phthalimidine.
Versatile synthesis of the teratogenic, TNFalpha-modulatory, and antiangiogenic thalidomide analogue 2-(2,6-dioxopiperidine-3-yl)phthalimidine (1) and its direct antiangiogenic properties are described. With thalidomide or thalidomide derivatives as precursors, the synthesis involved either carbonyl reduction/thiation-desulfurization or carbonyl reduction/acyliminium ion reduction protocols. Compared to earlier studies with thalidomide, which was only active with microsomal treatment, 1 exhibited marginal inhibitory activity in the rat aortic ring assay, thereby demonstrating the requirement for metabolic activation.
Luzzio
Frederick A
FA
Department of Chemistry, University of Louisville, 2320 South Brook Street, Louisville, Kentucky 40292, USA. faluzz01@athena.louisville.edu
Mayorov
Alexander V
AV
Ng
Sylvia S W
SS
Kruger
Erwin A
EA
Figg
William D
WD
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D046508:Culture Techniques; D005260:Female; D008833:Microcirculation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000098:blood supply / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; C001079:2-(2,6-dioxopiperidin-3-yl)phthalimidine; D013792:Thalidomide