The chemoselective reactions of tyrosine-containing G-protein-coupled receptor peptides with [Cp*Rh(H2O)3](OTf)2, including 2D NMR structures and the biological consequences.
The bioconjugation of organometallic complexes with peptides has proven to be a novel approach for drug discovery. We report the facile and chemoselective reaction of tyrosine-containing G-protein-coupled receptor (GPCR) peptides with [Cp*Rh(H(2)O)(3)](OTf)(2), in water, at room temperature, and at pH 5-6. We have focused on three important GPCR peptides; namely, [Tyr(1)]-leu-enkephalin, [Tyr(4)]-neurotensin(8-13), and [Tyr(3)]-octreotide, each of which has a different position for the tyrosine residue, together with competing functionalities. Importantly, all other functional groups present, i.e., amino, carboxyl, disulfide, phenyl, and indole, were not prominent sites of reactivity by the Cp*Rh tris aqua complex. Furthermore, the influence of the Cp*Rh moiety on the structure of [Tyr(3)]-octreotide was characterized by 2D NMR, resulting in the first representative structure of an organometallic-peptide complex. The biological consequences of these Cp*Rh-peptide complexes, with respect to GPCR binding and growth inhibition of MCF7 and HT29 cancer cells, will be presented for [(η(6)-Cp*Rh-Tyr(1))-leu-enkephalin](OTf)(2) and [(η(6)-Cp*Rh-Tyr(3))-octreotide](OTf)(2).
Bioinorganic Chemistry 1, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, Bochum, Germany.
H Bauke
HB
Albada
Florian
F
Wieberneit
Ingrid
I
Dijkgraaf
Jessica H
JH
Harvey
Jennifer L
JL
Whistler
Raphael
R
Stoll
Nils
N
Metzler-Nolte
Richard H
RH
Fish
D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000188:drug therapy; D005260:Female; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism; D012238:Rhodium / Q000737:chemistry*; D014443:Tyrosine / Q000737:chemistry*
D009942:Organometallic Compounds; D010455:Peptides; D043562:Receptors, G-Protein-Coupled; D014443:Tyrosine; D012238:Rhodium