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Accessible Synthesis of the Tricyclic Core of Forskolin as an Adenylyl Cyclase Activator against Cellular Senescence

CSEF · 2023 Chemistry Third Award

Chatwin Alexandra, Su Sarah · 12

Overview

Cellular senescence is the singular most significant risk factor in disease pathogenesis, particularly for chronic diseases including cancer, diabetes, disease, stroke, and dementia. Senescent cells naturally accumulate as time passes as aged cells permanently withdraw from the cell cycle, resulting in restricted stem cell function, increased base-level inflammation, and compromised tissue repair and regeneration. As such, here we present the synthesis of accessible small molecule nuclear reprogramming factors in an effort to combat cellular senescence, mitigating its widespread effects. While historically, most of medicinal chemistry efforts have focused on the development of inhibitors, the therapeutic value of small molecule based pathway activators is underrepresented. One such molecule derived from nature is forskolin, a labdane diterpenoid derived from the plant Coleus barbatus. Forskolin has been identified as a small molecule adenylyl cyclase activator, triggering transcription cascades through increasing levels of intracellular cAMP, which has implications in regenerative therapeutics. Currently, this compound is difficult to source from nature and is costly to isolate. Its total synthesis is complicated by its heavily oxygenated and polyfunctionalized carbocyclic core. To date, the shortest total synthesis of forskolin proceeds through 24 steps. Moreover, the exact contribution of the many oxidation functionalities of this compound, including the C1 hydroxyl and C9 hydroxyl groups, has not been fully established. Thus here, we present an accessible synthetic route to the tricyclic core of the forskolin scaffold, enabled through a complexity building diels-alder reaction, as well as in silico studies toward deconvoluting the SAR of the forskolin scaffold.

Source coverage

This record comes from a published award list, not a complete project archive. Its abstract comes from CSEF's public project showcase as archived by the Internet Archive before judging (https://web.archive.org/web/20230401224130/https://ca-csef.zfairs.com/showcase/ShowcaseInfo?f=838e60b7-ea75-46e8-865c-fde4864244b3); the version presented may differ.

Awards (1)

Competition history

  • CSEF 2023 Chemistry · Entry S0607

Resources

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