Liolios, Christos C., Zikos, Christos, Fragogeorgi, Eirini, Benaki, Dimitra, Pelecanou, Maria, Pirmettis, Ioannis, Ioannidis, Nikolaos, Sanakis, Yiannis, Raptopoulou, Catherine P., Psycharis, Vassilis, Terzis, Aris, Boschetti, Frédéric, Papadopoulos, Minas S., Sivolapenko, Gregory, and Varvarigou, Alexandra D.
The reaction of the C‐functionalized cyclam chelating agent 1,4,8,11‐tetraazacyclotetradecane‐6‐carboxylic acid (1) with CuCl2generated 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 1were 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 5was obtained and characterized with ESI‐MS and NMR spectroscopy, and was subsequently complexed under mild conditions with CuCl2to generate complex 6in high yield. Complex 6was characterized with UV/Vis spectroscopy, ESI‐MS and EPR spectroscopy. The stability of complexes 2and 6was tested against cysteine, histidine and glutathione, and both complexes were found to be stable. The cyclam BN conjugate 5and its CuIIcomplex 6were suitable for targeting the gastrin releasing peptide receptors (GRPrs) that are over expressed on PC‐3 cells. Both 5and 6showed 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 5and 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.