I. Synthetic Progress Towards the Total Synthesis of Rhodojaponin III II. Design and Synthesis of Novel ENT Inhibitors

Affecting 1 in 5 Americans, chronic pain has become the most common reason individuals seek out medical care. Those suffering from daily pain often endure mobile restrictions, anxiety, depression, and an overall reduced quality of life. Currently, pain management relies heavily on non-steroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics, but these options only provide relief for ~25% of patients. Opioids, which are considered the most effective at relieving pain, are associated with very serious side effects such as addiction, dependence, and tolerance. As a result of their addictive properties, we now face an epidemic of opioid overdose. Since 1999 the number of deaths resulting from opioid overdose has steadily increased with ~70,000 deaths in 2020. Consequently, the discovery of safe, effective, and non-addictive analgesics is imperative to end this epidemic and treat those suffering from daily pain. As natural products have had a long-standing role in the identification of bioactive compounds for drug development, they may provide an excellent starting point for the development of non-opioid analgesics. Grayanane-type natural products are diterpenoids extracted from the plants of the Ericaceae family. They exhibit a unique 5/7/6/5 ring system and a wide variety of bioactivities. Among them, rhodojaponin III has recently been reported to possess potent analgesic activity in an acute, inflammatory, and diabetic neuropathic pain model. Notably, rhodojaponin III does not affect the endogenous opioid peptidergic system but it’s mechanism of action has yet to be established. As the total synthesis of rhodojaponin III has yet to be reported, we aim to develop an efficient route to access rhodojaponin III for further development as an analgesic and a chemical probe for mechanistic studies. Our synthetic strategy relies on a convergent approach in which two fragments are synthesized separately and then coupled together to provide the skeleton of grayanane-type natural products. Herein, the synthesis of the two fragments will be discussed with an emphasis on the enantioselective construction of the key bicyclo[3.2.1]octane fragment. Synthesis of the bicycle is centered around a copper(I)-mediated conjugate addition to a shielded enoate, cyclization of an alkynyl ketone via Mn(III)-mediated radical cyclization and a stereoselective ketone reduction with SmI2. In addition to natural product synthesis, our efforts towards the development of non-opioid analgesics includes the structure-guided design of adenosine reuptake inhibitors (AdoRIs). The analgesic effect of adenosine has gained recent attraction as an alternative approach for pain-relief. One tactic for increasing extracellular adenosine is to inhibit the intracellular transport by equilibrative nucleoside transporters (ENTs). Consequently, our work takes advantage of the co-crystal structure of hENT1 in complex with two known inhibitors, dilazep and NBMPR, to rationally design novel inhibitors with improved potency, selectivity, and pharmacological properties. Herein, the generation of a small library of hENT1 inhibitors with promising analgesic activity in a streptozotocin (STZ) induced diabetic neuropathic pain model will be reviewed. Additionally, the design and synthetic progress towards a macrocyclic inhibitor and hENT3 selective compounds will be discussed.