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US-12617745-B2 - Curcusone diterpenoids and uses thereof

US12617745B2US 12617745 B2US12617745 B2US 12617745B2US-12617745-B2

Abstract

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.

Inventors

  • Mingji Dai
  • Chengsen Cui
  • Zhongjian Cai
  • Alexander Adibekian
  • Brendan Dwyer

Assignees

  • PURDUE RESEARCH FOUNDATION
  • UNIVERSITY OF FLORIDA RESEARCH FOUNDATION, INCORPORATED

Dates

Publication Date
20260505
Application Date
20210927

Claims (17)

  1. 1 . A compound of Formula I: or any stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 1 is H, F, Cl, Br, I, CO 2 R 4 , CONR 5 R 6 , an optionally substituted C 1 -C 6 straight or branched alkyl group, or an optionally substituted C 3 -C 6 carbon ring, wherein 1 or 2 carbon of the C 3 -C 6 carbon ring can be replaced by N, O, or a combination thereof, wherein R 4 , R 5 , and R 6 are each independently H, or an optionally substituted C 1 -C 6 straight or branched alkyl group, or an optionally substituted C 3 -C 6 carbon ring, wherein 1 or 2 carbon of the C 3 -C 6 carbon ring can be replaced by N, O, or a combination thereof.
  2. 2 . The compound of claim 1 , wherein the compound has a Formula II:
  3. 3 . The compound of claim 1 , wherein R 1 is H, I or methyl.
  4. 4 . A method of using a compound of Formula III as a BRCA1-associated ATM activator 1 (BRAT1) inhibitor to treat cancer in a subject, the method comprising administering a compound of Formula III to the subject, wherein the compound of Formula III is: or any stereoisomer, any pharmaceutically acceptable salt thereof, wherein R 1 and R 3 are each independently CN, CO 2 R 4 , CONR 5 R 6 , an optionally substituted C 1 -C 6 straight or branched alkyl group, or an optionally substituted C 3 -C 6 carbon ring, wherein 1 or 2 carbon of the C 3 -C 6 carbon ring can be replaced by N, O, or a combination thereof, R 2 is H, —(SO 2 )—R 7 , or —(C═O)—R 7 , wherein R 4 , R 5 , and R 6 are each independently H, or an optionally substituted C 1 -C 6 straight or branched alkyl group, or an optionally substituted C 3 -C 6 carbon ring, wherein 1 or 2 carbon of the C 3 -C 6 carbon ring can be replaced by N, O, or a combination thereof, wherein R 7 is an optionally substituted C 1 -C 6 straight or branched alkyl group, or an optionally substituted C 3 -C 6 carbon ring, wherein 1 or 2 carbon of the C 3 -C 6 carbon ring can be replaced by N, O, or a combination thereof, or R 7 is NR 8 R 9 , wherein R 8 and R 9 are each independently H, an optionally substituted C 1 -C 6 straight or branched alkyl group, or an optionally substituted C 3 -C 6 carbon ring, wherein 1 or 2 carbon of the C 3 -C 6 carbon ring can be replaced by N, O, or a combination thereof, or R 8 and R 9 can jointly form an nitrogen-containing 3-8 membered ring, wherein the ring can have 1-3 hetero atom selected from the group consisting of O, N, and S.
  5. 5 . The method of claim 4 , wherein the compound has a Formula IV: or any pharmaceutical acceptable salt thereof.
  6. 6 . The method of claim 4 , wherein R 2 is —(C═O)—CH 2 —NR 8 R 9 , wherein R 8 and R 9 are each independently H, an optionally substituted C 1 -C 6 straight or branched alkyl group, or an optionally substituted C 3 -C 6 carbon ring, wherein 1 or 2 carbon of the C 3 -C 6 carbon ring can be replaced by N, O, or a combination thereof, or R 8 and R 9 can jointly form an nitrogen-containing 3-8 membered ring, wherein the ring can have 1-3 hetero atom selected from the group consisting of O, N, and S.
  7. 7 . The method of claim 4 , wherein the compound is selected from the group consisting of:
  8. 8 . A compound of Formula III: or a pharmaceutically acceptable salt thereof, wherein R 1 and R 3 are each independently CN, CO 2 R 4 , CONR 5 R 6 , an optionally substituted C 1 -C 6 straight or branched alkyl group, or an optionally substituted C 3 -C 6 carbon ring, wherein 1 or 2 carbon of the C 3 -C 6 carbon ring can be replaced by N, O, or a combination thereof, R 2 is H, —(SO 2 )—R 7 , or —(C═O)—R 7 , wherein R 4 , R 5 , and R 6 are each independently H, or an optionally substituted C 1 -C 6 straight or branched alkyl group, or an optionally substituted C 3 -C 6 carbon ring, wherein 1 or 2 carbon of the C 3 -C 6 carbon ring can be replaced by N, O, or a combination thereof, wherein R 7 is an optionally substituted C 1 -C 6 straight or branched alkyl group, or an optionally substituted C 3 -C 6 carbon ring, wherein 1 or 2 carbon of the C 3 -C 6 carbon ring can be replaced by N, O, or a combination thereof, or R 7 is NR 8 R 9 , wherein R 8 and R 9 are each independently H, an optionally substituted C 1 -C 6 straight or branched alkyl group, or an optionally substituted C 3 -C 6 carbon ring, wherein 1 or 2 carbon of the C 3 -C 6 carbon ring can be replaced by N, O, or a combination thereof, or R 8 and R 9 can jointly form an nitrogen-containing 3-8 membered ring, wherein the ring can have 1-3 hetero atom selected from the group consisting of O, N, and S, provided that the compound is not: or any stereoisomer thereof.
  9. 9 . The compound of claim 8 , wherein R 2 is —(C═O)—CH 2 —NR 8 R 9 , wherein R 8 and R 9 are each independently H, an optionally substituted C 1 -C 6 straight or branched alkyl group, or an optionally substituted C 3 -C 6 carbon ring wherein 1 or 2 carbon of the C 3 -C 6 carbon ring can be replaced by N, O, or a combination thereof, or RR and R 9 can jointly form an nitrogen-containing 3-8 membered ring, wherein the ring can have 1-3 hetero atom selected from the group consisting of O, N, and S.
  10. 10 . The compound of claim 8 , wherein the compound is a compound of Formula IV: or any pharmaceutically acceptable salt thereof.
  11. 11 . The compound of claim 8 , wherein the compound is selected from the group consisting of: and any pharmaceutically acceptable salt thereof.
  12. 12 . A synthetic method to prepare a curcusone compound D or an isomer thereof, comprising: providing a compound of Formula A and treating the compound of Formula A under a halogenation condition to provide a compound of Formula B; treating the compound of Formula B under a first methylation condition to provide a compound of Formula C, or any isomer thereof; and treating the compound of Formula C under a second methylation condition to provide a compound of Formula D or an isomer thereof, wherein X is Cl, Br, or I.
  13. 13 . The method of claim 12 , wherein X is I.
  14. 14 . A method of inducing cytotoxicity in cancer cells, the method comprising treating cancer cells with a compound of Formula III, wherein the compound of Formula III is: or any stereoisomer, any pharmaceutically acceptable salt thereof, wherein R 1 and R 3 are each independently CN, CO 2 R 4 , CONR 5 R 6 , an optionally substituted C 1 -C 6 straight or branched alkyl group, or an optionally substituted C 3 -C 6 carbon ring, wherein 1 or 2 carbon of the C 3 -C 6 carbon ring can be replaced by N, O, or a combination thereof, R 2 is H, —(SO 2 )—R 7 , or —(C═O)—R 7 , wherein R 4 , R 5 , and R 6 are each independently H, or an optionally substituted C 1 -C 6 straight or branched alkyl group, or an optionally substituted C 3 -C 6 carbon ring, wherein 1 or 2 carbon of the C 3 -C 6 carbon ring can be replaced by N, O, or a combination thereof, wherein R 7 is an optionally substituted C 1 -C 6 straight or branched alkyl group, or an optionally substituted C 3 -C 6 carbon ring, wherein 1 or 2 carbon of the C 3 -C 6 carbon ring can be replaced by N, O, or a combination thereof, or R 7 is NR 8 R 9 , wherein R 8 and R 9 are each independently H, an optionally substituted C 1 -C 6 straight or branched alkyl group, or an optionally substituted C 3 -C 6 carbon ring, wherein 1 or 2 carbon of the C 3 -C 6 carbon ring can be replaced by N, O, or a combination thereof, or R 8 and R 9 can jointly form an nitrogen-containing 3-8 membered ring, wherein the ring can have 1-3 hetero atom selected from the group consisting of O, N, and S.
  15. 15 . The method of claim 14 , wherein the compound has a Formula IV: or any pharmaceutical acceptable salt thereof.
  16. 16 . The method of claim 14 , wherein R 2 is —(C═O)—CH 2 —NR 8 R 9 , wherein R 8 and R 9 are each independently H, an optionally substituted C 1 -C 6 straight or branched alkyl group, or an optionally substituted C 3 -C 6 carbon ring, wherein 1 or 2 carbon of the C 3 -C 6 carbon ring can be replaced by N, O, or a combination thereof, or R 8 and R 9 can jointly form an nitrogen-containing 3-8 membered ring, wherein the ring can have 1-3 hetero atom selected from the group consisting of O, N, and S.
  17. 17 . The method of claim 14 , wherein the compound is selected from the group consisting of:

Description

CROSS-REFERENCE TO RELATED APPLICATION This application is a U.S. national stage filing under 35 U.S.C. 371 from International Application No. PCT/US2021/052148, filed on 27 Sep. 2021, and published as WO 2022/072266 A1 on 7 Apr. 2022, which claims priority to U.S. Provisional Application No. 63/084,594 filed on 29 Sep. 2020, the entirety of which are incorporated herein by reference. GOVERNMENT RIGHTS This invention was made with government support under CA023168 and GM128570 awarded by the National Institutes of Health (NIH). The government has certain rights in the invention. TECHNICAL FIELD The present disclosure relates to novel curcusone diterpenoid analogs, to novel synthesis of curcusone diterpenoids and analogs, and to methods of using the curcusone diterpenoids and analogs. BACKGROUND This section introduces aspects that may help facilitate a better understanding of the disclosure. Accordingly, these statements are to be read in this light and are not to be understood as admissions about what is or is not prior art. Natural products have been valuable sources and inspirations of lifesaving drug molecules. Their accumulated evolutionary wisdom together with their structural complexity, novelty, and diversity makes them unparalleled for novel therapeutic development. Additionally, natural products can serve as important probe molecules for the elucidation of fundamental biological pathways and identification of novel disease targets. However, their natural scarcity and structural complexity often hamper comprehensive biological evaluations and the elucidation of their mechanisms of action. The latter is also considered as a major bottleneck for natural product-based drug discovery. To overcome these obstacles, total synthesis can be employed to supply key materials and analogs. Meanwhile, many attractive and biologically validated disease targets, especially in cancer, are considered as “undruggable” from a chemical standpoint due to the lack of enzymatic activity and/or small molecule binding sites. The BRCA1-associated ATM activator 1 (BRAT1) protein has been validated as an oncogenic protein but belongs to the “undruggable” category and no small-molecule inhibitor has been identified to target BRAT1. Therefore, collaborative efforts in the total synthesis and chemoproteomics profiling of curcusone natural products are still needed. SUMMARY The present disclosure relates to novel curcusone diterpenoid analogs, to novel synthesis of curcusone diterpenoids and analogs, and to methods of using the curcusone diterpenoids and analogs. In one embodiment, the present disclosure provides a compound of formula I: or any stereoisomer, wherein R1 is H, F, Cl, Br, I, CO2R4, CONR5R6, an optionally substituted C1-C6 straight or branched alkyl group, or an optionally substituted C3-C6 carbon ring, wherein 1 or 2 carbon of the C3-C6 carbon ring can be replaced by N, O, or a combination thereof, wherein R4, R5, and R6 are each independently H, or an optionally substituted C1-C6 straight or branched alkyl group, or an optionally substituted C3-C6 carbon ring, wherein 1 or 2 carbon of the C3-C6 carbon ring can be replaced by N, O, or a combination thereof. In another embodiment, the present disclosure provides a synthetic method to prepare a curcusone compounds A, B, C, and D or an isomer thereof, wherein the method comprises: providing a compound of Formula A and treating the compound of Formula A under a halogenation condition to provide a compound of Formula B;treating the compound of Formula B under a first methylation condition to provide a compound of Formula C, or any isomer thereof; andtreating the compound of Formula C under a second methylation condition to provide a compound of Formula D or an isomer thereof, wherein X is Cl, Br, or I. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 illustrates curcusone diterpenes and their synthesis. FIG. 2 illustrates total syntheses of curcusones A-D, dimericursone A, and their analogs. FIG. 3 illustrates identification of BRAT1 as a cellular target of 1d. (A) Viability of MCF-7 cells following 24 h compound treatment with EC50 values in brackets (n=3). (B) Scatter plot of proteins competed by 1d from probe 37 (10 μM) enrichment in MCF-7 cells with BRAT1 highlighted (n=3). (C) Western blot (top) and quantification (bottom) of thermal shift assay of overexpressed FLAG-BRAT1 lysate treated with 1d. (D) Western blots of BRAT1 following treatment of live cells with 1d and enrichment by probe 37 in competitive pulldown assays. (E) Western blot (top) and quantification (bottom) of pulldown of BRAT1 with probe 37 in HeLa cells and dose-dependent competition with 1d. All error bars are S.D. FIG. 4 illustrates syntheses of additional curcusones analogs 41-43. DETAILED DESCRIPTION For the purposes of promoting an understanding of the principles of the present disclosure, reference will now be made to the embodiments illustrated in the drawings, and specific language will be used to de