Collective syntheses of picrotoxanes and structural analogues via oxidative cascade cyclization

Project: Research project

Project Details

Description

Natural product-based drug discovery has been a very promising strategy in drug development. In the past 30 years, about 34% of new medicines approved by US Food and Drug Administration (FDA) were based on natural products or their derivatives (Harvey AL, et al., Nature Rev., 2015, 14, 111). Picrotoxinin is a well-known plant toxin isolated from the dried fruit of Menispermun cocculus (a liana growing in South Asia and India) and is one of the most studied picrotoxane sesquiterpenes due to its high abundance and potent non-competitive antagonistic activities against γ-aminobutyric acid (GABA, a major inhibitory neurotransmitter in the central nervous system). Although picrotoxinin has been developed into a be a useful tool for neurobiological studies, its applications as therapeutics are highly restricted due to its strong neurotoxicity and limited structure-activity relationship (SAR) studies. Thus, developing a practical synthetic route to the picrotoxanes and their structural analogues will enable a systematic SAR study that could provide valuable information for rational design of picrotoxinin analogues with a better safety profile and picrotoxinin-based molecular probes for studying its mode of biological actions.

One of the long-standing interests in our group is to develop efficient synthesis of bioactive natural products via cascade cyclization strategies for biological studies. Inspired by our strategy for biomimetic synthesis of yezo’otogirin C, we have recently developed an oxidative free-radical cascade cyclization for establishing 2-oxatricyclo[5.3.1.04,11]undecane, which can be readily transformed to the tricyclic core of picrotoxane sesquiterpenes. In this proposal, we have decided to utilize this oxidative cascade cyclization reaction for total synthesis of picrotoxane sesquiterpenes and their structural analogues for a systematic SAR study. The target picrotoxanes include dendrowillins A/B, flakinin A and picrodendrin Q, which contain different substitution patterns of the γ-lactone moieties around the cis-hydrindane core. After establishing an efficient and versatile synthetic route to the picrotoxane sesquiterpenes, we will prepare a library of picrotoxinin analogues for a systematic SAR study. The results of the SAR could enable rational design of the second generation picrotoxane analogues that can be used for neurotoxicity and mechanistic studies

StatusFinished
Effective start/end date1/01/2131/12/23

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