Design and Synthesis of Novel Serotonin Receptor Ligands

Novel and potent ligands to the serotonin7 (5-HT7) receptor have been synthesized. The synthesized compounds include a set of substituted pyrimidines which show high affinity to the 5-HT7 receptor, synthesized by previously described methods [1,2] in high yield. Comparing the affinities of substituted pyrimidines to previously calculated models [3,4] yielded new hypotheses about the nature of interaction between the pyrimidine ligands and the 5-HT7 binding site. Several new series of compounds were synthesized by various methods to validate these hypotheses, including a conjugate addition to vinylpyrimidines [5]. These compounds include benzofurans, oximes, hydrazones, as well as a group of substituted piperazines. All series of compounds show affinity to the 5-HT7 receptor comparable to previously synthesized 5-HT7 ligands. Several of the synthesized ligands show affinity which exceeds that of currently available ligands. The synthesized compounds were evaluated quantitatively by calculating a three-dimensional quantitative structure-affinity relationship (3D-QSAR) for the 5-HT7 receptor. Evaluation of the calculated model validated qualitative assumptions about the data set as well as described regions of interaction in greater detail than previously available. These observations give further insight on the nature of ligand-binding site interactions with highly potent ligands such as 4-(3-furyl)-2-(N-methylpiperazino)pyrimidine which will lead to more potent 5-HT7 receptor ligands. Additionally, a model was calculated for affinity to the 5-HT2a receptor. Comparing this model to that calculated for affinity to the 5-HT7 receptor identified two regions which may be exploited in future sets of ligands to increase selectivity to the 5HT7 receptor

Synthetically Tailored Cyanines for Imaging and Therapy

This dissertation focuses on two fundamental yet unanswered questions in human health and disease concerning both diagnostics and therapeutics. The first half addresses the lack of optimized near-infrared fluorophores for image-guided surgery. Fluorescence imaging cameras and intraoperative imaging systems lack appropriately engineered contrast agents that allow the detection of sensitive normal tissue (i.e. endocrine and exocrine glands) for surgical avoidance. After systematically probing various fluorophore classes, we discovered promise in cyanine-based contrast agents. By altering functional groups of cyanine fluorophores, we, for the first time, report the selective targeting of many endocrine glands, exocrine glands, cartilage and bone using NIR fluorescence to visualize the targeted tissue. Secondly, this dissertation elaborates a new pathway for developing functional and fluorescent chemotherapeutics based on the targeting, stabilization and imaging of G-quadruplex DNA – a folding pattern commonly associated with cancer cell proliferation through telomerase over-expression and oncogene promoter regions. Chromophores modified to assume quadruplex binding characteristics – planar cationic structures – have been developed that stabilize the quadruplex as evaluated through several complementary methods toward developing novel theranostic agents in the NIR visualization and treatment of human cancers