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A Bombesin Copper Complex Based on a Bifunctional Cyclam Derivative
Author(s) -
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,
Varvarigou Alexandra D.
Publication year - 2012
Publication title -
european journal of inorganic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.667
H-Index - 136
eISSN - 1099-0682
pISSN - 1434-1948
DOI - 10.1002/ejic.201200049
Subject(s) - chemistry , electrospray ionization , cyclam , nuclear magnetic resonance spectroscopy , electron paramagnetic resonance , peptide , circular dichroism , cystamine , nuclear chemistry , medicinal chemistry , mass spectrometry , stereochemistry , organic chemistry , metal , chromatography , biochemistry , physics , nuclear magnetic resonance
The reaction of the C ‐functionalized cyclam chelating agent 1,4,8,11‐tetraazacyclotetradecane‐6‐carboxylic acid ( 1 ) with CuCl 2 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 H 2 N‐(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 CuCl 2 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 Cu II 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 ( IC 50 ) values observed for 5 and 6 (0.30 ± 0.03 and 0.33 ± 0.03 n M , respectively) were similar to that of the [Tyr] 4 ‐BN peptide (0.45 ± 0.04 n M ), which was used as standard.