N-Benzylpolyamines as Vectors of Boron and Fluorine for Cancer Therapy and Imaging:  Synthesis and Biological Evaluation

• Published in: Journal of medicinal chemistry 2001-10, Vol.44 (22), p.3653-3664
• Main Authors: Martin, Bénédicte, Possémé, Françoise, Le Barbier, Caroline, Carreaux, François, Carboni, Bertrand, Seiler, Nikolaus, Moulinoux, Jacques-Philippe, Delcros, Jean-Guy
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Biological Transport, Active; Boron Compounds - chemical synthesis; Boron Compounds - metabolism; Boron Neutron Capture Therapy; Cell Line; DNA - chemistry; General aspects; Medical sciences; Pharmacology. Drug treatments; Putrescine - analogs & derivatives; Putrescine - chemical synthesis; Putrescine - metabolism; Spermidine - analogs & derivatives; Spermidine - chemical synthesis; Spermidine - metabolism; Spermine - analogs & derivatives; Structure-Activity Relationship; Tomography, Emission-Computed; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010897q

Cancer cells have high-affinity polyamine uptake systems with a low stringency for structural features. Putrescine, spermidine, and spermine have, therefore, been considered as potential vectors for the selective accumulation in tumors of therapeutically or diagnostically useful structures and elements. We envisaged N-benzyl derivatives of the polyamines as vectors of 10B and 18F for boron neutron capture therapy (BNCT) and tumor imaging by positron emission tomography (PET), respectively. In the present work, the synthesis, transport characteristics, DNA-binding properties, and cytotoxicity of several N-benzyl derivatives of putrescine and spermidine are described. The fluorinated spermidine derivative N-{3-[(4-aminobutyl)amino]propyl}[(4-fluorophenyl)methyl]amine (N -4-Fbz-spd) may be useful for PET because of its high accumulation in cancer cells via the polyamine transport system. Among the boron-containing benzyl polyamines, N-(4-aminobutyl){[4-(dihydroxyboryl)phenyl]methyl}amine (4-Bbz-put) and N-{3-[(4-aminobutyl)amino]propyl}{[4-(dihydroxyboryl)phenyl]methyl}amine (N 1 -4-Bbz-spd) should be suitable for BNCT, because their accumulation in B16 melanoma cells was more efficient than that of borocaptate and borophenylalanine, two reference compounds used in BNCT.