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). ent-Kaurane diterpenoids represent a large family of natural products (more than 1300 members have been isolated) bearing a tetracyclic core with highly varied oxygenation and bond-cleavage patterns with skeletal rearrangements. Many family members have exhibited a variety of important biological activities such as antibacterial, anticancer, anti-inflammatory, and immunosuppressive activities. Although ent-kaurane diterpenoids have been popular targets for synthetic and medicinal chemists, there are only three C13-hydroxy-ent-kaurane diterpenoids, including gibberellic acid, steviol and 13-methoxy-15- oxozopatlin have been synthesized, and the biological activities of the synthetic compounds have not been studied. Thus, developing a practical synthetic route to the 13-hydroxy-ent- kaurane diterpenoids and their structural analogues will enable systematic SAR and comparison studies that could provide valuable information for rational design of second generation ent- kaurane analogues with better safety profiles and efficacy.
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. In our previous study, we have developed a scalable and versatile synthesis to the 7,20-epoxy-ent-kaurane diterpenoids and successfully identified neolaxiflorin L as a potent lead compound for further development. In this proposal, we have decided to develop a synthetic route for the synthesis of the C13-hydroxy-ent-kaurane diterpenoids based on our recently developed Lewis acid- induced cascade cyclization, which could established the C,D ring systems with the C13- hydroxy in a single operation. The target natural products include enanderianin L and laxiflorin M were selected due to their same tetracyclic core structures with different position of the oxygen-bridge. After establishing an efficient and versatile synthetic route, we will prepare a focus library of C13-hydroxy-ent-kaurane derivatives based on the single-variable principle for studying the importance of a particular functional group. These studies could lead to a great extension of the scope of the structure-activity relationship study and the development of ent- kaurane-based molecular probes for studying the mode of actions that associate with their anti- cancer activities.
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. In our previous study, we have developed a scalable and versatile synthesis to the 7,20-epoxy-ent-kaurane diterpenoids and successfully identified neolaxiflorin L as a potent lead compound for further development. In this proposal, we have decided to develop a synthetic route for the synthesis of the C13-hydroxy-ent-kaurane diterpenoids based on our recently developed Lewis acid- induced cascade cyclization, which could established the C,D ring systems with the C13- hydroxy in a single operation. The target natural products include enanderianin L and laxiflorin M were selected due to their same tetracyclic core structures with different position of the oxygen-bridge. After establishing an efficient and versatile synthetic route, we will prepare a focus library of C13-hydroxy-ent-kaurane derivatives based on the single-variable principle for studying the importance of a particular functional group. These studies could lead to a great extension of the scope of the structure-activity relationship study and the development of ent- kaurane-based molecular probes for studying the mode of actions that associate with their anti- cancer activities.
Status | Finished |
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Effective start/end date | 1/01/22 → 31/12/24 |
UN Sustainable Development Goals
In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):
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