The first salen-type ligands derived from 3',5'-diamino-3',5'-dideoxythymidine and -dideoxyxylothymidine and their corresponding copper(II) complexes

BACKGROUND: There are many nucleoside metal complexes known. According to observations made, only very few of them reveal their central ion to be co-ordinated by the sugar part of their molecules. The regio- and stereospecific exchange of the hydroxyl groups at the sugar moiety by chelating units improves its complexation ability and should give access to a new class of chiral ligands. RESULTS: In this paper we present the synthesis of 3',5'-diamino substituted thymidines with ribo- as well as xylo-configuration and the preparation of copper(II) complexes derived from their corresponding Schiff bases. Starting from thymidine, the amino derivatives were prepared in a three and four step reaction sequence respectively. The absolute configuration of the ligands was proved by the three-bond (1)H-(1)H spin spin coupling constants (3)J obtained by NMR-studies. Condensation of the amino derivatives with salicylic aldehydes resulted in the corresponding diimines, which represent a new class of chiral salen-type ligands. All ligands formed uncharged stable copper(II) complexes. The structure of 3',5'-bis(3,5-di-tert-butylsalicylaldiminato)-3',5'-dideoxyxylothymidine-copper(II) could be determined by single crystal X-ray structure analysis. The copper centre in this complex has distorted tetrahedral coordination geometry. CONCLUSION: For the synthesis of 3',5'-diamino-3',5'-dideoxy thymidines with xylo- as well as ribo-configuration an effective synthesis pathway has been developed. Their corresponding salicylidene imines form stable coordination compounds with copper(II) ions. They represent the first salen type complexes of nucleosides with this substitution pattern

Orthogonally Protected Artificial Amino Acid as Tripod Ligand for Automated Peptide Synthesis and Labeling with Tc-99m(OH2)(3)(CO)(3)](+)

1,2-Diamino-propionic acid (Dap) is a very strong chelator for the [(99m)Tc(CO)(3)](+) core, yielding small and hydrophilic complexes. We prepared the lysine based Dap derivative l-Lys(Dap) in which the ε-NH(2) group was replaced by the tripod through conjugation to its α-carbon. The synthetic strategy produced an orthogonally protected bifunctional chelator (BFC). The -NH(2) group of the α-amino acid portion is Fmoc- and the -NH(2) of Dap are Boc-protected. Fmoc-l-Lys(Dap(Boc)) was either conjugated to the N- and C-terminus of bombesin BBN(7-14) or integrated into the sequence using solid-phase peptide synthesis (SPPS). We also replaced the native lysine in a cyclic RGD peptide with l-Lys(Dap). For all peptides, quantitative labeling with the [(99m)Tc(CO)(3)](+) core at a 10 μM concentration in PBS buffer (pH = 7.4) was achieved. For comparison, the rhenium homologues were prepared from [Re(OH(2))(3)(CO)(3)](+) and Lys(Dap)-BBN(7-14) or cyclo-(RGDyK(Dap)), respectively. Determination of integrin receptor binding showed low to medium nanomolar affinities for various receptor subtypes. The IC(50) of cyclo-(RGDyK(Dap[Re(CO)(3)])) for α(v)β(3) is 7.1 nM as compared to 3.1 nM for nonligated RGD derivative. Biodistribution studies in M21 melanoma bearing nude mice showed reasonable α(v)β(3)-integrin specific tumor uptake. Altogether, orthogonally protected l-Lys(Dap) represents a highly versatile building block for integration in any peptide sequence. Lys(Dap)-precursors allow high-yield (99m)Tc-labeling with [(99m)Tc(OH(2))(3)(CO)(3)](+), forming small and hydrophilic complexes, which in turn leads to peptide radiopharmaceuticals with excellent in vivo characteristics

Orthogonally Protected Artificial Amino Acid as Tripod Ligand for Automated Peptide Synthesis and Labeling with [^99mTc(OH₂)₃(CO)₃]⁺

1,2-Diamino-propionic acid (Dap) is a very strong chelator for the [^99mTc­(CO)₃]⁺ core, yielding small and hydrophilic complexes. We prepared the lysine based Dap derivative l-Lys­(Dap) in which the ε-NH₂ group was replaced by the tripod through conjugation to its α-carbon. The synthetic strategy produced an orthogonally protected bifunctional chelator (BFC). The -NH₂ group of the α-amino acid portion is Fmoc- and the -NH₂ of Dap are Boc-protected. Fmoc-l-Lys­(Dap­(Boc)) was either conjugated to the N- and C-terminus of bombesin BBN(7–14) or integrated into the sequence using solid-phase peptide synthesis (SPPS). We also replaced the native lysine in a cyclic RGD peptide with l-Lys­(Dap). For all peptides, quantitative labeling with the [^99mTc­(CO)₃]⁺ core at a 10 μM concentration in PBS buffer (pH = 7.4) was achieved. For comparison, the rhenium homologues were prepared from [Re­(OH₂)₃(CO)₃]⁺ and Lys­(Dap)-BBN(7–14) or cyclo-(RGDyK­(Dap)), respectively. Determination of integrin receptor binding showed low to medium nanomolar affinities for various receptor subtypes. The IC₅₀ of cyclo-(RGDyK­(Dap­[Re­(CO)₃])) for α_vβ₃ is 7.1 nM as compared to 3.1 nM for nonligated RGD derivative. Biodistribution studies in M21 melanoma bearing nude mice showed reasonable α_vβ₃-integrin specific tumor uptake. Altogether, orthogonally protected l-Lys­(Dap) represents a highly versatile building block for integration in any peptide sequence. Lys­(Dap)-precursors allow high-yield ^99mTc-labeling with [^99mTc­(OH₂)₃(CO)₃]⁺, forming small and hydrophilic complexes, which in turn leads to peptide radiopharmaceuticals with excellent in vivo characteristics