Synthesis and characterization of time-resolved fluorescence probes for the potential detection and improved study of melanoma cancer

A multi-part fluorescent probe was designed for the development of new clinical tools for the detection and treatment of melanoma skin cancer. It has been proposed that the addition of a fluorescent tag to a melanocyte stimulating hormone would create a luminescent probe with potential for the detection and study of melanoma skin cancer. The proposed design involves attaching a luminescent lanthanide probe to an MSH (4) peptide substrate using a flexible polyethylene glycol linker. The individual portions of the proposed molecule (luminescent probe, PEGO linker, and MSH (4) peptide) have been synthesized and characterized using a combination of FTIR, NMR, GCMS, HPLC, UV-Vis, and Fluorescent spectroscopy. Luminescent probe synthesis involved the nitration and subsequent reduction of 1,10-phenanthroline followed by complexation with Eu(TTA)3. Synthesis of the PEGO linker was accomplished by the reaction of tetraethylene glycol with tert-butyl bromoacetate to form a diacid through a t-butyl protected intermediate. MSH (4) peptide synthesis proceeded on solid phase following a f-moc protocol and using a Mars6 microwave synthesizer. Future work will focus on the construction of the final molecule using the components obtained though this thesis research

Synthesis and Pharmacology of Halogenated δ-Opiod Selective [\u3csub\u3eD\u3c/sub\u3eAla\u3csup\u3e2\u3c/sup\u3e] Deltorphin II Peptide Analogs

Deltorphins are naturally occurring peptides produced by the skin of the giant monkey frog (Phyllomedusa bicolor). They are δ-opioid receptor-selective agonists. Herein, we report the design and synthesis of a peptide, Tyr-d-Ala-(pI)Phe-Glu-Ile-Ile-Gly-NH2 3 (GATE3-8), based on the [d-Ala2]deltorphin II template, which is δ-selective in in vitro radioligand binding assays over the μ- and κ-opioid receptors. It is a full agonist in [35S]GTPγS functional assays and analgesic when administered supraspinally to mice. Analgesia of 3 (GATE3-8) is blocked by the selective δ receptor antagonist naltrindole, indicating that the analgesic action of 3 is mediated by the δ-opioid receptor. We have established a radioligand in which 125I is incorporated into 3 (GATE3-8). The radioligand has a KD of 0.1 nM in Chinese hamster ovary (CHO) cells expressing the δ receptor. Additionally, a series of peptides based on 3 (GATE3-8) was synthesized by incorporating various halogens in the para position on the aromatic ring of Phe3. The peptides were characterized for binding affinity at the μ-, δ-, and κ-opioid receptors, which showed a linear correlation between binding affinity and the size of the halogen substituent. These peptides may be interesting tools for probing δ-opioid receptor pharmacology