Synthesis of water soluble organophosphines and phosphine-peptide conjugates: Investigations on the biomedical utility of their transition metal complexes.

摘要

A series of bidentate (P₂), tridentate (S₂P, NP ₂), and tetradentate (N₂P₂, N₂SP) water-soluble hydroxymethyl phosphine (HMP) ligands have been synthesized and characterized. The complexation properties of these novel ligands with rhenium at the macroscopic level and technetium at the tracer level were investigated. In vitro stability and in vivo biodistribution studies of 99mTc complexes of these HMP ligands were performed. The ligands S ₂P and N₂P₂, whose Re and 99mTc complexes exhibited favorable characteristics such as fast complexation, high kinetic stability under challenging conditions, in vitro/ in vivo stability, and favorable bio-clearance pathways, were chosen and the backbones modified to incorporate a carboxylate functional group, which was later utilized to conjugate to receptor specific biomolecules. Ligands S₂P-COOH, N₂P₂-COOH were synthesized and conjugated to Gastrin Releasing Peptide (GRP) receptor specific (7–14) bombesin (BBN) fragment to yield S₂PBBN and N₂P ₂BBN. Biodistribution and stability studies were carried out on radioactive 99mTc complex of S₂PBBN. The studies reveal that the 99mTc complex is in vitro and in vivo stable and is able to target GRP receptor expressing cells in vivo , with no significant uptake in non target organs.; As part of an effort to develop new chemotherapeutic agents, the HMP based gold compound, [Au(P(CH₂OH)₃)₄]Cl, was synthesized using a modified procedure to afford large scale synthesis and investigated for its antitumor properties. In vitro/ in vivo studies have been performed and the studies demonstrate that the gold compound is active against various cancer cell lines.