SYNTHESIS OF THIOPHENE-CONTAINING HETEROCYCLES AND THEIR APPLICATION AS ANTICANCER AGENTS

摘要

Five-membered heterocycles represent a privileged scaffold in drug discovery and are the focus of analog design. The first chapter presents the synthesis and biological evaluation of analogs of NSC 652287, which targets the renal carcinoma cell line A498. The Pd-catalyzed Suzuki-Miyaura cross-coupling with halogenated furan, thiophene, and selenophene led to generally high overall yields for the construction of heterocyclic triads. C-H bond activation provided an efficient strategy for the Pd-catalyzed cross-coupling at C(2) of oxazoles. Further analog variation was achieved with a copper-catalyzed azide-alkyne cycloaddition to form a 1,4-substituted 1,2,3-triazole. Potency and selectivity of the final hydroxymethyl products were determined in the NCI-60 cell assay. Two lead compounds were tested in vivo and compared to NSC 652287. The evaluation of these compounds continues with a thermal shift assay coupled with differential mass spectrometry for biological target identification. The chemical stability of select triads are also discussed.udThe second chapter details the synthesis of thienopyridone and thienopyrimidine dione analogs as inhibitors of protein tyrosine phosphatase 4A3 (PTP4A3), an attractive anticancer target. Derivatization by photooxygenation led to a compound with a unique structural motif, high potency, and excellent selectivity towards PTP4A3. An automated synthesis strategy using Lilly’s Automated Synthesis Lab was employed for analog synthesis.