N-Benzylpolyamines as vectors of boron and fluorine for cancer therapy and imaging: synthesis and biological evaluation.
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 (10)B and (18)F 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(1)-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.
Martin
B
B
Groupe de Recherche en Thérapeutiques Anticancéreuses, Faculté de Médecine, UPR ESA CNRS 6027, 2 Avenue du Pr. Léon Bernard, F35043 Rennes Cedex, France.
Possémé
F
F
Le Barbier
C
C
Carreaux
F
F
Carboni
B
B
Seiler
N
N
Moulinoux
J P
JP
Delcros
J G
JG
D000818:Animals; D001693:Biological Transport, Active; D001896:Boron Compounds / Q000138:chemical synthesis* / Q000378:metabolism; D016754:Boron Neutron Capture Therapy; D002460:Cell Line; D004247:DNA / Q000737:chemistry; D011700:Putrescine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism; D013095:Spermidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism; D013096:Spermine / Q000031:analogs & derivatives; D013329:Structure-Activity Relationship; D014055:Tomography, Emission-Computed; D014407:Tumor Cells, Cultured
D001896:Boron Compounds; C438864:N-(3-((4-aminobutyl)amino)propyl)((4-(dihydroxyboryl)phenyl)methyl)amine; C438863:N-(3-((4-aminobutyl)amino)propyl)((4-fluorophenyl)methyl)amine; C438865:N-(4-aminobutyl)((4-(dihydroxyboryl)phenyl)methyl)amine; D013096:Spermine; D004247:DNA; D013095:Spermidine; D011700:Putrescine