Inhibition of angiogenesis by THAM-derived cotelomers endowed with thalidomide moieties Sandrine Pe´rino, a Christiane Contino-Pe´pin, a, * Ronit Satchi-Fainaro, b Catherine Butterfield b and Bernard Pucci a, * a Laboratoire de Chimie Bioorganique et des Syste `mes Mole ´culaires Vectoriels, Faculte ´ des Sciences, 33, rue Louis Pasteur, 84000, Avignon, France b Harvard Medical School, Surgical Research, Children’s Hospital, 300 Longwood Avenue, Boston MA 02115, USA Received 16 July 2003; revised 1 October 2003; accepted 27 October 2003 Abstract—The synthesis of a tris(hydroxymethyl)acrylamidomethane (THAM)-derived cotelomer endowed with thalidomide units and a preliminary assessment of its biological activity are described. 4-Carboxy thalidomide and 4-(N-acryloyl) lysine thalidomide derivatives were prepared. The polymerization of these compounds with THAM in the presence of octanethiol as transfer reagent provided a water-soluble telomer bearing several thalidomide units. The ability of this telomer to inhibit angiogenesis in a mouse model of corneal neovascularization was compared to 4-carboxy thalidomide and thalidomide. A significant inhibition in area of neovascularization stimulated by a bFGF pellet was observed only in the mice treated with the telomer. # 2003 Elsevier Ltd. All rights reserved. Thalidomide, a hypnosedative drug introduced in the 1950s, was first launched to prevent nausea in pregnant women. Its use was abruptly halted in 1961 with the discovery of its potential for causing severe birth defects in children whose mothers were exposed to the drug during the first trimester of pregnancy. 1 3 However, numerous attractive properties of thalidomide have been observed since then. It was approved in 1998 by the Food and Drug Administration for the short- term treatment of cutaneous manifestations of moderate to severe erythema nodosum leprosum, a complication of leprosy (Hansen’s disease). 4,5 Recently, it was descri- bed as a promising drug in the treatment of a number of cancers (in particular for multiple myeloma therapy) 1,6 8 and inflammatory- or immune-based com- plications of HIV infection and other diseases. 9 In the field of medical oncology, one of its most pro- mising properties is its antiangiogenic effect. It has been shown that thalidomide can inhibit angiogenesis induced by angiogenic cytokines such as basic fibroblast growth factor (bFGF) in the rabbit cornea and vascular endothelial growth factor (VEGF) in the corneas of mice. 10 12 Moreover for a few years, numerous metabolites or thalidomide derived compounds have been assayed to better understand the thalidomide activity and to specify their potentialities in medical oncology, notably as inhibi- tors of angiogenesis, TNF-a production or cyclooxygenase 13 16 or for the suppression of liver injury. 17 In the course of our previous research, we focused on the phenomenon of angiogenesis, hypothesized 30 years ago to be an absolute requirement for the growth and metastasis of solid tumors. 18 20 We validated the ther- apeutic potential of oligomeric prodrugs of Ara-C called ‘telomers’ bearing RGD peptidic sequences known to be selectively recognized by specific receptors over- expressed on angiogenic sites. 21 23 Moreover, we obtained interesting biological results with telomeric carriers endowed with chemotherapeutics like Ara-C or 5-Fluorouracil 24,25 which prompted us to apply this concept of drug delivery to the design of macro- molecular derivatives of thalidomide. We predicted that the introduction of multiple thalido- mide units on a telomeric carrier through an appropriate peptidic spacer arm would provide a macromolecule with antiangiogenic properties. Such a conjugate could 0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2003.10.045 Bioorganic & Medicinal Chemistry Letters 14 (2004) 421–425 Keywords: Thalidomide; Telomers; Angiogenesis; Prodrug. *Corresponding authors. Tel.: +33-490-144442; fax: +33-490-144449 (B.P); tel.: +33-490-144435; fax: +33-490-144449 (C.C.-P.); e-mail: bernard.pucci@univ-avignon.fr; christine.contino@univ-avignon.fr