Doctoral thesis

Total synthesis of furanoheliangolides, hunting druggability of the nuclear transport protein importin-5

ContributorsPatouret, Rémi
Imprimatur date2021-11-09
Defense date2021-11-05

This thesis is composed of two parts: the first is about goyazensolide and second part about Withaferin A. The first part started with the total synthesis of the sesquiterpene lactone goyazensolide via the first example of a Barbier allylation / lactonization merging an α-methylene-γ-butyrolactone with the closure of a 10-membered germacrene in one step. An analog, 5-epi-isogoyazensolide, was also synthesized to validate the strategy. Synthesis of a goyazensolide probe with an alkyne tag allowed the identification of importin-5 (IPO5) as a covalent target of goyazensolide. As this protein has interesting anti-cancer activities, we have demonstrated that goyazensolide inhibits in cellulo the translocation of RASAL2, a negative regulator of RasGAP, causing a drastic decrease in the level of p-AKT, a marker of cell proliferation. Moreover, incubation of goyazensolide with a cell lysate indicated a perturbation in the pull-down of IPO5 with two nuclear localization sequence (NLS) of viral proteins belong to influenza and HIV. A structure activity relationship study of related furanoheliangolides demonstrated that only goyazensolide and atripliciolide were able to bind IPO5. The second part was focused on the study of the anti-influenza A activity by withaferin A. Surprisingly, withaferin A also binds IPO5 while its structure is significantly different to goyazensolide. A drastic reduction in the rate of influenza replication was observed when cells were treated with withaferin A and the probes WAPs, while a moderate effect was observed in the presence of goyazensolide. Literature reported that withaferin A targets several proteins related to influenza A. This compound can be also called “multi-target compound”. Keap1 is one of the targets of withaferin A and its inhibition induced heme oxygenase 1 (HO-1) expression, promoting the interferon-stimulated genes (ISGs) induction which inhibits the influenza A replication. While the prediction of the anti-IAV activity from the Keap1 inhibitor bardoxolone methyl was successful, the myriad of biological pathways during the influenza A life cycle combined to the use of non-selective compounds drastically increase the difficulty to determine the whole mode of action. Natural products as goyazensolide and withaferin A are typically multi-target compounds and, despite their tremendous therapeutic potential, their rational development still represent a formidable challenge.

  • Furanoheliangolides
  • Goyazensolide
  • Importin-5
  • IPO5
  • RASAL2
  • Influenza
  • Withaferin
Research group
Citation (ISO format)
PATOURET, Rémi. Total synthesis of furanoheliangolides, hunting druggability of the nuclear transport protein importin-5. 2021. doi: 10.13097/archive-ouverte/unige:156506
Main files (1)
accessLevelPrivateaccessLevelPublic 11/06/2023

Technical informations

Creation11/09/2021 4:06:00 PM
First validation11/09/2021 4:06:00 PM
Update time03/16/2023 1:51:09 AM
Status update03/16/2023 1:51:08 AM
Last indexation09/18/2023 9:33:44 PM
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