Peptide Targeting of Platinum Anti-Cancer Drug and Synthesis of Water Soluble Monofunctional Pt(II) Complexes Useful for Biological Labeling

Abstract

Platinum has been used as an inorganic medicinal agent with various applications such as anti cancer agents. Several new targeted Pt(II) conjugates were synthesized having the NGR and LHRH targeting motif. The platinum conjugates bearing the NGR motif revealed selective delivery and destruction of cancer cells that had CD13 receptors compared to untargeted carboplatin drug. The development of targeted chemotherapeutic has opened a new approach for efficient delivery of antitumor toxins with minimal exposure to normal cells. Several peptide sequences are known to have the ability to target tumors, for instance NGR motif which home specifically in solid tumors and has receptors aminopeptidase N (APN), also referred to as CD13 which binds specifically to NGR peptides. Luteinizing hormone-releasing hormone (LHRH), another targeting moiety, has been found to be more prevalent in tumor cells than normal cells and has receptors. LHRH sequence was used in the synthesis of targeted curcumin, phthalocyanine and platinum conjugate. Another set of platinum complexes synthesized are monofuctional platinum (II) complexes. The monofuctional platinum complexes are useful in understanding the chemistry of cisplatin which is bifunctional and forms various adducts on interaction with DNA which are not well understood. To monitor and understand the interaction of nucleotide with platinum complexes, complexes with only one reactive sight were synthesized. The tridentate ligands were characterized by X-ray crystallography, fluorescence and NMR spectroscopy. Interaction of platinum complexes and nucleotide (5¡ä-GMP) was monitored by NMR to reveal different rate of rotation about the Pt¨CN(7) bond depending on the platinum complex studied. These new complexes have desirable features for assessing the potential of tridentate platinum complexes for investigating selective monocoordination of metal complexes to DNA and peptides.