A Bombesin Copper Complex Based on a Bifunctional Cyclam Derivative

The reaction of the C‐functionalized cyclam chelating agent 1,4,8,11‐tetraazacyclotetradecane‐6‐carboxylic acid (1) with CuCl2 generated a stable and neutral complex 2, which was characterized by elemental analysis, UV/Vis and IR spectroscopy, electrospray ionization mass spectrometry (ESI‐MS), EPR spectroscopy and X‐ray crystallography. The secondary amine groups of 1 were protected to generate 3, which was further conjugated with the bombesin (BN) derivative H2N‐(Ornithine)3‐BN(2–14) by a solid phase peptide synthesis method. After cleavage from the resin and deprotection, the resulting product 5 was obtained and characterized with ESI‐MS and NMR spectroscopy, and was subsequently complexed under mild conditions with CuCl2 to generate complex 6 in high yield. Complex 6 was characterized with UV/Vis spectroscopy, ESI‐MS and EPR spectroscopy. The stability of complexes 2 and 6 was tested against cysteine, histidine and glutathione, and both complexes were found to be stable. The cyclam BN conjugate 5 and its CuII complex 6 were suitable for targeting the gastrin releasing peptide receptors (GRPrs) that are over expressed on PC‐3 cells. Both 5 and 6 showed high binding affinity to GRPrs during in vitro cell assays with human PC‐3 prostate cancer cells. The half maximal inhibitory concentration (IC50) values observed for 5 and 6 (0.30 ± 0.03 and 0.33 ± 0.03 nM, respectively) were similar to that of the [Tyr]4‐BN peptide (0.45 ± 0.04 nM), which was used as standard. A new bombesin copper complex based on a bifunctional cyclam derivative was synthesized, characterized, and evaluated for its binding affinity to bombesin receptors through in vitro cell assays with PC‐3 cells.