Synthesis of Thapsigargin

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Background Thapsigargin (Tp) is found in the Mediterranean weed Thapsia garganica. The roots and fruit from this plant have long been used to treat rheumatism, female infertility and pulmonary illnesses. Tp is a sub-nanomolar inhibitor of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA). The SERCA pump plays a critical role in regulating calcium homeostasis. It uses the energy of ATP hydrolysis to pump Ca2+ ions from the cytoplasm into the sarcoplasmic reticulum maintaining low cytosolic Ca2+ concentrations. This Ca2+ distribution in the cell is responsible for regulation of proliferation, gene transcription and apoptosis. SERCA isoforms have been implicated in a variety of cancers and neurodegenerative diseases. Tp promotes ER stress by depleting luminal calcium stores and inducing apoptosis. The high cytotoxicity of Tp has led to its development as a novel anticancer agent and it is currently being investigated as an anti-viral agent for SARS-CoV-2. Currently Tp is Isolated from the plant and is laborious and expensive. There is need for a commercially feasible synthetic route to synthesize this compound and to find more potent Tp analogs . Technology Overview Queen’s researchers have developed a synthetic method for the synthesis of Tp and its analogs. Previously, the synthetic route was 42 steps with <1% yield. This improved route is only 11 steps, one-third of the number of steps required by Ley, but with >40 fold greater yield than Baran’s method. Additionally, novel analogs have been developed 18 of which are currently being tested for SERCA activity. This method is rapid and scalable and could provide the basis for a manufacturing route for this compound and the rapid preparation of a Tp analog library.