Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
2000-06-23
2003-10-21
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C424S001110, C424S001650, C424S009100, C534S010000, C534S011000, C534S014000, C534S015000
Reexamination Certificate
active
06635235
ABSTRACT:
TECHNICAL FIELD
The present invention relates to metallated biomolecules. More specifically, the present invention relates to the development of a new strategy for synthesizing biomolecules that can be used to form structure-specific metallated biomolecules.
BACKGROUND OF THE INVENTION
The transition metal chemistry of phosphines is diverse, resulting in a myriad of coordination compounds. The wealth of available data on the coordination chemistry of rhenium has provided a strong impetus in extending the chemistry to its diagonally related congener technetium-99. In fact, the demonstration that phosphine ligands produce well-defined, in vitro/in vivo stable complexes with technetium-99m (a &ggr;-emitter with 141 keV and t
½
=6.2 h) has resulted in the development of two Tc-99m-based radiopharmaceuticals being currently used for myocardial imaging in humans. [DeRosch et al., 1992; Forster et al., 1992]. Because most human cancer cells express a certain affinity for biomolecular vectors such as peptides or proteins, it is conceivable that radiolabeled receptor-avid peptides will provide new vehicles for delivering diagnostic or therapeutic radiations in site-directed treatments. Radiolabeling of receptor-avid peptides (or other bimolecular vectors) is best carried out by using bifunctional chelating agents. Radiolabeling with specific radioisotopes is done at the ligating unit of the bifunctional chelating agent, while functionalities such as —COOH or —NCS will incorporate a biomolecular vector within the bifunctional chelating agent to ultimately produce radiolabeled biomolecules. In this context, the utility of phosphines to construct new bifunctional chelating agents is attractive because of the potential applications of these ligands to produce well-defined complexes with radio-isotopes of diagnostic (Tc-99m) and therapeutic (Re-188, Au-199, Rh-105) value.
However, it is recognized that chemical transformations of traditional phosphine ligands (e.g. Ph
2
PCH
2
CH
2
PPh
2
, dppe or Me
2
PCH
2
CH
2
Pme
2
, dmpe) into bifunctional chelating agents are a challenge. Aryl phosphines (e.g. dppe) which are oxidatively stable are unsuitable for use under in vivo conditions because of their high lipophilicity. On the other hand, alkyl phosphines are oxidatively so unstable that backbone modification and their use in aqueous media would produce corresponding phosphine oxides. Therefore, in order to utilize the superior ligating properties of phosphine ligands in the construction of new bifunctional chelating agents, new strategies on the overall design of phosphine frameworks were needed.
The rich chemistry of phosphines with transition metals makes them well suited for constructing chelating frameworks on simple and complex molecular structures that can be used to form well-defined metallated biomolecules. Metallated biomolecules, where the metal is bound (chelated) in a site-specific and structure-specific manner, hold important potential for a variety of chemical and biomedical applications, including chiral catalysis and radiopharmaceuticals [Gilbertson et al., 1996; Liu et al., 1997; Lister-James, et al., 1996]. In this context, the utility of phosphines to construct metal chelating frameworks either appended to or incorporated within biomolecular structures at specific positions is particularly attractive.
However, it must be recognized that the incorporation of phosphine functionalities in biomolecules by current synthetic strategies is challenging and usually involves lengthy procedures and harsh reaction conditions that often damage (e.g., reduction with Raney nickel) the biomolecule [Gilbertson et al., 1994]. For example, Gilbertson, et al. 1994, employed a reaction pathway to append diphenylphosphine groups that used a diphenylphosphorous (V) sulfide intermediate. After the P═S derivatized peptide was made, reduction of the P═S to the phosphorous (III) phosphine was accomplished with Raney Ni [3] producing a mixture of products where the desired diphosphine-peptide product was produced in low yields. The resulting diphenylphosphine-peptide conjugate was subsequently used to selectively form the corresponding Rh(III) conjugate [Gilbertson et al., 1994].
Recent efforts have been successful in synthesis of bidentate and multidentate chelation frameworks that contain di-hydroxymethylene-phosphine (HMP) functionalities [i.e., —P(CH
2
OH)
2
] to facilitate formation of new transition metal complexes [Smith and Reddy et al., 1997; Smith and Katti et al., 1997; Smith and Li et al., 1997]. As a result of this work, the first bifunctional chelating agent containing HMP groups was synthesized, characterized, and used as a vehicle to conjugate metals to biomolecules. The synthesis of this bifunctional chelating agent system (i.e., carboxylate derivative of the di-HMP-diamido (P
2
N
2
) tetradentate ligand framework shown in Formula 1) was difficult and proceeded via a —P(V)=0 intermediate (similar to the Gillickson —P(V)=S intermediate) that had to be reduced with LiAIH
4
to a —P(III)H
2
intermediate in route to formation of the —P(CH
2
OH)
2
groups. However, the reduction conditions used would irreversibly alter most biomolecules precluding this approach for synthesis of most phosphine bioconjugates.
It would therefore be useful to develop HMP-containing ligand frameworks and —PR
2
containing biomolecules for use in formulating new diagnostic and therapeutic pharmaceuticals.
REFERENCES:
Scott R. Gilbertson et al. Synthesis of Phosphine-Rhodium Complexes Attached to a Standard Peptide Synthesis Resin (1996), Organometallics, vol. 15, pp. 4678-4680.
Shuang Liu et al.99mTc Labeling of Highly Potent Small Peptides (1997), Bioconjugate Chem. vol. 8, pp. 621-636.
J. Lister-James, et al. Small peptides radiolabed with99mTc (1996), QJ Nucl. Med. vol. 40, pp. 221-233.
Scott R. Gilbertson et al. Versatile Building Block for the Synthesis of Phosphine-Containing Peptides: The Sulfide of Diphenylphosphinoserine (1994), J Am, Chem. Soc., vol. 116, pp. 4481-4482.
C. Jeffrey Smith, et al. Synthesis and Coordination Chemistry of the First Water-Soluble Dithio-Bis(phosphine) Ligands . . . (1997), Inorg. Chem. vol. 36, pp. 3928-3935.
C. Jeffrey Smith, et al. Syntheses and Characterization of Chemically Flexible, Water-Soluble Dithio-Bis(phosphine) Compounds . . . (1997), Inorg. Chem, vol. 36, pp. 1786-1791.
C.J. Smith, et al. In Vitro and In Vivo Characterization of Novel Water-Soluble Dithio-Bisphosphine99mTc Complexes (1997), Nuclear Medicine & Biology, vol. 24, pp. 685-691.
Gali Hariprasad
Katti Kattesh V.
Pillarsetty Nagavara Kishore
Prabhu Kandikere R.
Volkert Wynn A.
Jones Dameron L.
Kohn & Associates PLLC
The Curators of the University of Missouri
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