Curcusone Diterpenoid Synthesis for BRAT1 Target Identification
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Solution Overview
Problem
Accessing sufficient quantities of curcusone diterpene natural products and their analogs for comprehensive biological investigation and therapeutic development is challenging due to their natural scarcity and structural complexity, and the BRCA1-associated ATM activator 1 (BRAT1) protein has been considered an 'undruggable' target without identified small-molecule inhibitors.
Innovation Solution
The development of novel curcusone diterpenoid analogs through total synthesis, including a convergent synthesis route using a cheap chiral pool molecule and innovative chemical reactions, and the design of an alkyne-tagged probe molecule for chemoproteomics studies to identify cellular targets, specifically targeting BRAT1.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If total synthesis is employed to supply key materials and analogs, then access to sufficient quantities of curcusone diterpenoids is improved, but the structural complexity and difficulty of synthesis increase
Solution Approach 1:
The synthesis pathway is divided into discrete, manageable steps (halogenation, methylation, etc.) that build the complex tricyclic carbon skeleton and cycloheptadienone core incrementally. This segmentation allows systematic construction of the complex molecule from simpler precursors, resolving the contradiction between obtaining sufficient quantities and managing structural complexity.
Solution Approach 2:
The patent establishes a preliminary synthetic methodology that can be applied to multiple curcusone diterpenoids (A-D and analogs) using a standardized sequence of reactions. This preliminary action framework enables efficient production of multiple compounds without requiring entirely new synthesis routes for each, thereby increasing quantity availability while managing complexity through methodological reuse.
2Loss of information
If natural products are used as probe molecules for elucidation of biological pathways, then identification of novel disease targets is improved, but natural scarcity and structural complexity hamper comprehensive biological evaluations
Solution Approach 1:
The patent creates synthetic copies of curcusone diterpenoids that replicate the biological activity and target interaction profiles of the natural products. These synthetic analogs can be produced in sufficient quantities for comprehensive biological evaluations, chemoproteomics profiling, and target validation, thereby overcoming the natural scarcity issue while preserving the ability to elucidate biological pathways and identify disease targets.
3Loss of information
If collaborative efforts in total synthesis and chemoproteomics profiling are undertaken, then identification of BRAT1 as a target is improved, but the time and resource requirements increase
Solution Approach 1:
The synthetic methodology developed is universally applicable to multiple curcusone diterpenoids (A-D) and their analogs, allowing a single research team to systematically explore the biological activities of an entire series of compounds. This multi-functionality approach enables comprehensive chemoproteomics profiling and target identification across multiple compounds simultaneously, reducing the time and resources required compared to studying each natural product separately.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The synthesis provides curcusones A-D and dimericursone A efficiently, revealing BRAT1 as a key cellular target, and the alkyne probe 37 retains anticancer properties, enabling the first small-molecule inhibitor of BRAT1, potentially enhancing cancer treatment strategies.
Implementation Method 1
treating the compound of Formula A under a halogenation condition to provide a compound of Formula B; wherein X is Cl, Br, or I
Implementation Method 2
treating the compound of Formula B under a first methylation condition to provide a compound of Formula C; and treating the compound of Formula C under a second methylation condition to provide a compound of Formula D
Data Source
AI summary
The present disclosure provides the first asymmetric total synthesis and target identification of the curcusone natural products. The novel convergent synthesis is built upon a cheap and abundant chiral pool molecule (8) and features a thermal [3,3]-sigmatropic rearrangement and an FeCl3-promoted global hydrolysis/adol condensation cascade to rapidly construct the critical cycloheptadienone core. By performing chemoproteomics with the alkyne probe 37, we identified the previously “undruggable” oncogenic protein BRAT1 as a key cellular target of 1d. Furthermore, 1d inhibits BRAT1 in cancer cells, thereby reducing cancer cell migration, increasing susceptibility to DNA damage, and inducing chemosensitization to the approved drug etoposide. Compound 1d is the first known small-molecule inhibitor for BRAT1, a master regulator of the DDR and DNA repair. Composition matters and methods of uses are within the scope of this disclosure.