Photoflow Preparation of PTP4A3 Inhibitors, and Concise Total Syntheses of Ergot and Clavine Alkaloids

The first section of this thesis describes the photooxygenation of a thienopyridone to generate a potent, novel PTP4A3 inhibitor bearing an iminopyridinedione pharmacophore. A scalable flow process was developed to facilitate throughput of the lead inhibitor JMS-053 and to enable structure-activity-relationship studies in collaboration with a fellow researcher, and a convergent imination was implemented to simplify purification of final products. Several analogs were synthesized and are described, and a preliminary binding pose is proposed. The second section describes the total syntheses of several ergot, clavine, and unnatural alkaloids and a C(3) indole alkylation methodology. The methyl lysergates, which are direct precursors to tetracyclic ergot and clavine alkaloids, are synthesized in four steps (28% overall yield). An expedited synthesis delivers methyl lysergates with only one chromatographic purification. A transition metal-free Hydrogen Autotransfer (HA) reaction to alkylate C(3) of indole was discovered, developed, and implemented in the synthesis, and the mechanism of this transformation was investigated. The rapid synthesis was expanded to several alkaloids, including lysergic acid, lysergol, isolysergol, lysergene, lysergine, isolysergine, and festuclavine. Structural isomers of the clavine alkaloids were discovered during these efforts, and the scaffolds were expanded to lysergic acid diethylamide and lysergol analogs. Studies toward developing an asymmetric synthesis of the methyl lysergates are detailed. Finally, several alkaloids and unnatural products were evaluated for their ability to bind and activate 5-HT receptors

Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer

High grade serous ovarian cancer (OvCa) frequently becomes drug resistant and often recurs. Consequently, new drug targets and therapies are needed. Bioinformatics-based studies uncovered a relationship between high Protein Tyrosine Phosphatase of Regenerating Liver-3 (PRL3 also known as PTP4A3) expression and poor patient survival in both early and late stage OvCa. PTP4A3 mRNA levels were 5–20 fold higher in drug resistant or high grade serous OvCa cell lines compared to nonmalignant cells. JMS-053 is a potent allosteric small molecule PTP4A3 inhibitor and to explore further the role of PTP4A3 in OvCa, we synthesized and interrogated a series of JMS-053-based analogs in OvCa cell line-based phenotypic assays. While the JMS-053 analogs inhibit in vitro PTP4A3 enzyme activity, none were superior to JMS-053 in reducing high grade serous OvCa cell survival. Because PTP4A3 controls cell migration, we interrogated the effect of JMS-053 on this cancer-relevant process. Both JMS-053 and CRISPR/Cas9 PTP4A3 depletion blocked cell migration. The inhibition caused by JMS-053 required the presence of PTP4A3. JMS-053 caused additive or synergistic in vitro cytotoxicity when combined with paclitaxel and reduced in vivo OvCa dissemination. These results indicate the importance of PTP4A3 in OvCa and support further investigations of the lead inhibitor, JMS-053