Design and development of novel phosphine-based chelating systems for chemical and biomedical motifs

A novel class of chelating frameworks based on dithio-bisphosphine (P ₂S₂COOH), trithio-bisphosphine(P₂S₃) and diamido-bisphosphine (BP₂N₂) were synthesized in good yields. An important accomplishment of these studies is the development of air-stable alkyl primary phosphines. In general, alkyl primary phosphines tend to be oxidatively unstable and require inert atmosphere for synthesis as well as storage. In contrast, the new chelating frameworks containing alkyl primary phosphines discussed here exhibited a much improved stability profile under a wide range of chemical conditions.; The conjugation of P₂S₂COOH bifunctional chelating agent (BFCA) with peptides (GlyGlyOEt, D-Lys6-LHRH and 5-Ava-BBN[7-14]) produced the first examples of peptide conjugates containing alkyl primary phosphines. Further, the hydrophilic derivatives of P₂S₂COOH and P₂S₂-peptide conjugates were produced via formylation of P-H bonds under mild conditions. The complexation of P₂S₂COOH and P₂S₂-GlyGlyOEt HMPs with Re(V) precursor yielded Re(V) complexes ReO₂-P₂ S₂COOH and ReO₂-P₂S₂-GlyGlyOEt with trans dioxo cores having metal to ligand ratio of 1:1. Further, ReO ₂-P₂S₂-5-Ava-BBN[7-14] was synthesized on a solid phase peptide synthesizer using standard fmoc chemistry. In vitro studies of ReO₂-P₂S₂COOH complex demonstrated its kinetic inertness and thermodynamic stability towards a wide range of physiological conditions. All the new compounds were characterized by 1H, 13C, and 31P NMR and IR spectroscopy and low/high-resolution FAB mass spectrometry.; Experimental protocols for in vitro radiochemical investigations of P₂S₂COOH HMP with technetium-99m/rhenium-188 were developed. Tracer level complexation with 99mTc/188 Re provided evidence for the formation of 99mTc/ 188Re-P₂S₂COOH complex in yields >95% under low ligand concentrations (1 × 10−5M), as a singular species evidenced by HPLC. The radio-metal complex was stable over a pH range of 5–9 over a period of >24 hours. The utility of the carboxylate side arm to conjugate with specific biomolecule via post-conjugation strategy was demonstrated by labeling a model peptide (GlyGlyOEt) with 99mTc. In vivo biodistribution analyses of the 99mTc/ 188Re-complexes in Srague-Dawley rats has provided evidence for an excellent in vivo stability and also for efficient clearance of the complexes via either the renal-urinary or hepatobiliary pathways. Subsequently, synthetic methods for labeling peptides with 99mTc/188Re via pre-conjugation strategy were also developed and demonstrated by labeling GlyGlyOEt and lutenizing hormone—releasing hormone analogue (D-Lys6-LHRH) with 99mTc and a bombesin analog (5-Ava-BBN[-14]) with 188Re. The results of this research demonstrated the potential utility of P₂S ₂-COOH as a bifunctional chelating agent in producing tumor-specific radiophamaceuticals for diagnosis and/or therapy of human cancers.